DRUG DISPOSITION
Clin. Pharmacokinet. 26 (I): 16-43, 1994 0312-5963/94/0001-0017/$14.0010 © Adis International Limited. All rights reserved.
Clinical Pharmacokinetics of Tenoxicam Odd G. Nilsen Department of Pharmacology and Toxicology, Faculty of Medicine, University of Trondheim, Trondheim, Norway
Contents 16 17 J8
J8 18 18 19 19
22 22 24 27 29 34 34 36 37 37 38 39
Summary
Summary 1. Methods of Analysis 2. Structure, Physicochemical Properties, and Metabolites 2.1 Structure 2.2 Physicochemical Properties 2.3 Metabolites 3. Pharmacokinetics 3.1 Excretion and Metabolism 3.2 Linearity in Single Dose Plasma Pharmacokinetics 3.3 Absorption 3.4 Plasma Pharmacokinetics in Healthy Volunteers and Patients with Rheumatic Diseases 3.5 Distribution and Pharmacokinetics in Other Fluids and Tissues in Patients with Rheumatic Diseases 3.6 Plasma Pharmacokinetics in Illness and Old Age 4. Protein Binding 4.1 . Binding in Plasma and Synovial Fluid 4.2. Binding to Other Sites 5. Pharmacokinetic Drug Interactions 5.1. Effect of Other Drugs on Tenoxicam Pharmacokinetics 5.2. Effects of Tenoxicam on the Pharmacokinetics of Other Drugs 6. Clinical Considerations and Conclusions
Tenoxicam is a nonsteroidal anti-inflammatory drug (NSAID) in the oxicam group. It is completely absorbed by the oral route and is about 99% protein bound in human plasma. Intake of food delays absorption without affecting bioavailability. There is no evidence for enterohepatic recycling of the drug in humans. Peak plasma concentrations of 2.7 mg/L (range 2.3 to 3.0 mg/L) have been reported in different groups of fasted healthy volunteers 1.9 hours (1.0 to 5.0 hours) after a single oral dose of 20mg. A mean elimination half-life of 67 hours (49 to 81 hours) has been estimated. Tenoxicam demonstrates linear single-dose pharmacokinetics over doses of 10 to 100mg. Because of its low Iipophilicity and high degree of ionisation in blood (",99%), the drug is poorly distributed to body tissues and is slowly taken up by hepatic cells. A small apparent volume of distribution of9 .6L (7.5 to 11.5L), and low total plasma clearance of 0.106 LIh (0.079 to 0.142 LIh), have been reported in different groups of healthy volunteers after oral and intravenous administration. Peak concentrations of tenoxicam in synovial fluid are less than one-third of those in plasma
Tenoxicam Pharmacokinetics
17
and they appear later, 20 hours (10 to 34 hours) after an oral dose. A parallel decrease in synovial fluid and plasma concentrations with time for both total and unbound tenoxicam has been reported. In vivo pH differences between synovial fluid and plasma in patients with rheumatoid arthritis may indicate significantly lower concentrations of unbound ionised tenoxicam in synovial fluid than in plasma. Data on relative binding capacities for tenoxicam in plasma and synovial fluid, and between different groups of individuals, are not conclusive. The protein binding of tenoxicam is pH dependent. The drug is almost entirely eliminated by liver metabolism. The 2 main metabolites, the inactive 5'-hydroxy and 6-0-glucuronidated forms, are excreted in urine and bile, respectively. The existence of additional metabolites in human bile has been suggested. Urinary excretion of the 5'hydroxy metabolite decreases with reduced renal function. The 5'-hydroxy metabolite is detected in plasma in concentrations 1 to 5% of the parent compound and its decline parallels that of the parent compound (formation-rate limitation). Urinary and faecal excretion of unchanged tenoxicam is less than 1% of the administered dose. No significant amounts of unchanged tenoxicam are excreted in bile. Tenoxicam shows nearly linear pharmacokinetics during multiple-dose administration. The 6 to 18% underestimation of accumulation when predicted from single-dose pharmacokinetic data is thought to be of minor clinical significance. An equal degree of underestimation is found for all categories of individuals investigated, so tenoxicam steady-state concentrations are easily predicted. The long elimination half-life of the drug produces small and similar fluctuations in steady-state concentrations both in plasma and synovial fluid, which should justify single daily doses. Apart from a protein-binding displacement interaction with aspirin (acetylsalicylic acid), tenoxicam demonstrates a low interaction profile with most other drugs. However, high plasma bilirubin concentrations (>100 to 200 f.LIDollL) may predispose patients to displacement of tenoxicam from plasma albumin binding sites. No significant differences have been demonstrated in either single- or multiple-dose pharmacokinetics of tenoxicam in healthy volunteers, patients with rheumatic or inflammatory diseases, renal failure, liver cirrhosis (single-dose studies only) or in the elderly. Thus, no dosage adjustments seem justified for these patients on the basis of pharmacokinetics. However, some attention should be paid to long term treatment of patients with liver disease, especially those patients with elevated plasma bilirubin.
Tenoxicam is a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs are heterogeneous in structure and pharmacokinetics, although sharing the common feature of inhibiting prostaglandin biosynthesis. Tenoxicam belongs to the oxicam group of the NSAIDs, with a structure closely related to piroxicam and isoxicam (fig. 1). Oxicam drugs are generally characterised by long elimination half-lives (VIz). The pharmacokinetics of tenoxicam were previously reviewed in part by others (Bird 1987; Crevoisier & Heizmann 1986; Gonzales & Todd 1987; Guentert et al. 1987; Todd & Clissold 1991; Woolf & Radulovic 1989). This article reviews the overall pharmacokinetics of tenoxicam and from
this basis makes recommendations for its clinical use.
1. Methods of Analysis Tenoxicam is sensitive to light, and degrades in a linear fashion in plasma with time (15 to 20% per hour) [Heizmann et al. 1986]. The drug was unstable in aqueous solutions, but was highly stable in darkened rooms at room temperature «20 hours) and in the dark at -18°C (>3 months). Due to the low pKa values of tenoxicam and its 5'-hydroxy metabolite, extraction from body fluids or tissues into an organic phase must be performed at a low pH. For extraction from plasma, a pH of 3 or 4, depending on concentration, seems to be fa-
Clin. Pharmacokinet. 26 (1) 1994
18
al. 1986). Heizmann et al. (1986) were able to codetermine tenoxicam and its 5' -hydroxy metabolite in plasma, and Dell et al. (1984) estimated tenoxic am glucuronides in urine. Methods are also available for detection of the drug in synovial fluid (Bird et al. 1985a; Corvetta et al. 1991; Bannwarth et al. 1991) and joint cartilage (Bannwarth et al. 1991). Tenoxicam
2. Structure, Physicochemical Properties and Metabolites 2.1 Structure
Plroxlcam
Tenoxicam is a thienothiazine oxic am NSAID (fig. 1). Structures of oxicam drugs, such as piroxicam and isoxicam, are unlike those of other NSAIDs, because oxicams are neither carboxylic acids nor phenylbutazone analogues. The substitution of the benzothiazine ring by a thienothiazine ring gives tenoxicam a more hydrophilic character than other oxicams. 2.2 Physicochemical Properties
Isoxlcam
Fig. 1. Structure of oxicam denvatIves.
vourable (Heizmann et al. 1986), and for urine a pH of 4 is used (Dell et al. 1984). Solid phase extraction of tenoxicam has recently been suggested as a time-saving alternative to the traditional liquid -liquid extraction (Corvetta et al. 1991). High performance reversed phase liquid chromatography is most commonly used for tenoxicam separation. Ultraviolet detection of the drug has been performed in the range from 360 to 371nm. Concentrations of 0.02 to 0.1 mg/L of the parent drug have been detected in plasma volumes of 0.5 to Iml in several studies (Corvetta et al. 1991; Dixon et al. 1984; Pickup et al. 1981; Heizmann et
Tenoxicam is a weak acid with a molecular weight of 337.4D and pKa values of 5.34 and 1.07 (Bernhard & Zimmermann 1984). At physiological pH the drug is predominately ionised (99.1 % at pH 7.4), which limits its ability to distribute into tissues. In comparison, the pKa values of piroxicam are estimated at 5.46 and 1.86, and that for isoxicam is 3.93 (Bernhard & Zimmermann 1984). The solubility of the monosodium salt of tenoxicam in water (pH 8) is about 1%. The lipophilicity of tenoxicam is relatively low with an octanol to pH 7.4 buffer partition coefficient of 0.3 (piroxicam, indomethacin and diclofenac have partition coefficients of 1.9, 9.1 and 15.6, respectively) [Fenner 1987]. These characteristics further decrease the relative ability oftenoxicam to distribute to or penetrate tissues which are rich in lipids. 2.3 Metabolites Two main metabolites of tenoxicam have been identified in humans (fig. 2). The 5' -hydroxy metabolite is excreted mainly in the urine, while the
Tenoxicam Pharmacokinetics
glucuronidated 6-0-metabolite is mainly excreted in bile. Neither of these 2 main metabolites are reponed to possess pharmacological activity. These metabolites of tenoxicam in humans have also been identified in rats (lchihara et al. 1984), animals in which as many as 6 different metabolites of tenoxicam have been identified. It has been suggested that at least some part of the anti-inflammatory activity of tenoxicam is linked to its metabolism, by tenoxicam acting as a scavenger of active oxygen or hypochlorite ions, or both. By a further exploring of the oxidation of tenoxicam by leucocyte peroxidases and hydrogen peroxide (H202), 4 additional metabolites of tenoxicam have been identified (Ichihara et al. 1989). The pattern of the oxidative metabolism of tenoxicam by leucocyte peroxidases is illustrated in figure 3.
3. Pharmacokinetics The pharmacokinetics of oxicams are different from those of other NSAIDs because of their low lipophilicity, small volumes of distribution (V d), low hepatic extraction ratios, slow metabolism and hence prolonged tY2 values.
19
has a long ty2, with a mean value of about 67 hours in healthy volunteers (see table I). The 16-day urinary excretion of the 5'-hydroxy metabolite was 36% of a 40mg dose in a healthy male volunteer (Dell et al.1984). A further 2% excretion could be attributed to a glucuronide of the 5'-hydroxy metabolite. Similar results were observed in 5 healthy volunteers after single oral lOmg doses (Kobayashi et al. 1984.) In a third study (data on file, F. Hoffmann-La Roche Ltd), _urinary excretion of the 5'-hydroxy metabolite in 5 healthy volunteers was to 29.7% of a 20mg single oral dose when urine was collected for 7 days. Thus, in healthy volunteers, the total urinary excretion of the 5'-hydroxy metabolite seems to be independent of the dose, and is about 40% of the administered dose. Little quantitative information is available about the glucuronidated 6-0-metabolite in humans apart from a study in 4 cholecystectomised patients with T-tubes inserted in the common bile duct through which bile was collected over 3 days
~~/CH3
~ '/
3.1 Excretion and Metabolism Less than 0.5% of a single oral dose of tenoxicam 40mg was excreted unchanged in the urine of a healthy volunteer (Dell et al. 1984). However, 0.7% was recovered unchanged over a 24-hour period at steady-state after administration of tenoxicam 20mg daily for 13 days (data on file, F. Hoffmann-La Roche Ltd.). When creatinine clearance (CLCR) was reduced to less than 40 mlIminl1.73m2 (2.4 L1hI1.73m2) in patients with renal failure, no unchanged tenoxicam was detected in urine after single or multiple 20mg doses (data on file, F. Hoffmann-La Roche Ltd.). No unchanged tenoxicam has been detected in bile (T. Guentert, personal communication). Tenoxicam is eliminated in humans mainly via oxidative pathways in the liver to 2 main metabolites (see section 2.3). The ability of the liver to extract tenoxicam from blood is low, so the drug
S
N
1
h
HO HNlOl 1
5'
h
OH
5'·Hydroxy·tenoxlcam (unne)
~~
GIUC~/CH3 " N o' / /6 1 h
0
HO HN'O I"" ../.:
Glucuronated 6-oxy-tenoxlcam (bile)
Fig. 2. Structure of the 2 main tenoxicam metabolites in humans.
20
Clin. Pharmacokinet. 26 (1) 1994
(Tamimura et al. 1984). After a single oral dose of tenoxicam 20mg, mean bile recovery of the 6-0metabolite was 18.8% of the dose. If biliary excretion of the 6-0-metabolite follows the same excretion profile as the urinary excretion of the 5'-hydroxy metabolite (Dell et al. 1984), the total bile excretion would be about 30% of the dose. However, wide interindividual variation in 3-day excretion was reported (5.5 to 47.4% of the dose). The possibility of 2 additional minor metabolites of ten oxic am in human bile has been suggested (Tamimura et al. 1984). In patients with liver cirrhosis, urinary excretion of the 5'-hydroxy metabolite was 21.6% of a
20mg single dose when urine was collected for 4 days (Crevoisier et al. 1989b). This is nearly identical to that reported for healthy volunteers (Kobayashi et al. 1984; data on file, F. HoffmannLa Roche Ltd). Urinary excretion of the 5'-hydroxy metabolite has been reported to decrease with reductions in renal function. Less than 5% of a 20mg dose was excreted in urine as the 5' -hydroxy metabolite when CLcR was less than 20 ml/min/1.73m2 (1.2 L1hI1.73m2) [Horber et al. 1986]. Then, not surprisingly, a reduced rate of cumulative urinary excretion of the 5'-hydroxy metabolite (15 to 25% depending on age compared with young healthy
+
HOOC
I( N"-r:~
oV
Tenoxicam
O~
S
-:?o
ff'{-""H \S~COOH
Fig. 3. Metabolic pathways of tenoxlcam ill solubihsed peroxidases from rat leucocyte extracts when hydrogen peroxide IS added.
Tenoxicam Pharmacokinetics
21
Table I. Pharmacokinetics of tenoxlcam after administration of single oral doses to fasted healthy volunteers and patients with rheumatic diseases No. of study participants
Dose (mg)
!1,'2« (h)
tm8x (h)
Cmax (mg/l)
F
(%)
tl,. (h)
VdlF (l)
CUF (Uh)
References
Healthy volunteers 12
10
26
1.5
72
8.2
0097
FrancIs et al (1987)
6
20
1.3
26
74
11.38
0.106
Benveniste et al. (1990)
8
20
5.0
28
66
7.8
0.082
Crevolsler et al. (1989a)
12
20
1.8
3,0
79
7.58
0.0798
Day et al (1987)
12
20
2.3
3.0
81
9.7
0092
FrancIs etal. (1987)
01338
Heintz et al. (1984)
6
20
10
2.3
60
1158
6
20
1,1
2.6
66
10.0
0.110
Heintz et al (1988)
8
20
1,1
27
49
103
0142
Data on file, F. Hoffmannla Roche Ltd
018
107
12
40
25
53
75
98
0098
FrancIs et al (1987)
6
40
0.42
1.3
5,2
67
10.3
0.120
FrancIs et ai, (1985)
6
40
0.18
2.3
5,1
68
9.2
0.100
FrancIs et al. (1985)
6
40
17
55
65
96
0.104
Heintz et al (1988)
6
70
1.4
97
63
9.7
0109
Heintz et al. (1988)
6
100
12
135
66
101
0110
Heintz et al (1988)
Patients with rheumatic diseases 6
40
1,6
5,9
42
958
01588
Bird et al. (1985a)
5
40
4.6
45
52
8.98
01198
Crevolsler et al (1984)
4
40
6.0
4.3
40
8.68
01498
Hlnderllng et al (1988)
a
0.32
Calculated from the presented data by the equations CUF = Dose/AUC and VdlF = (CUF x t1,.)/ln2. The values given are the mean
Abbreviations: AUC = area under the concentration-time curve from zero to infinity; CUF = oral total body clearance of drug from plasma; Cm8x = maximum drug concentration, F = fraction of the administered dose systemically available; t1,.« = absorption half-hfe; t1,. = ehmlnatlon half-hfe associated With the terminal slope of a semllogarithmlc concentration-time curve; tmax= time to Cm"" VdlF oral apparent volume of distribution
=
volunteers) was reported in elderly patients after a single oral dose of lOmg (Kobayashi et al. 1984). After administration of a single oral dose of tenoxicam 20mg to patients with rheumatic diseases or healthy volunteers (Heizmann et al. 1986) the 5'-hydroxy metabolite was not detected in plasma. However, after multiple 20mg daily doses it was identified in small concentrations in plasma from patients with rheumatic diseases (Heizmann et al. 1986), healthy volunteers and patients with impaired renal function (data on file, F. Hoffmann-La Roche Ltd). Concentrations of the 5'-hydroxy metabolite were 1 to 2 % of the corresponding plasma ten oxic am concentrations, but relatively higher plasma metabolite concentrations (about 5%) were
observed when CLcR was reduced to 20 to 40 mlIminll.73m2 (1.2 to 2.4 Llhll. 73m2). In a patient with a CLcR of 20 ml/minl1.73m2 receiving a sin-
gle tenoxicam 20mg dose the peak: plasma concentration of the metabolite was 0.04 mg/L, or about 2% that of the parent compound (Horber et al. 1986). The decline of plasma 5'-hydroxy metabolite concentrations was similar to that of the parent compound, obviously not reflecting the intrinsic t~ of the metabolite (Horber et al. 1986; data on file, F. Hoffmann-La Roche Ltd). Debrisoquine or mephenytoin phenotypes do not influence the formation of the 5'-hydroxy metabolite (Guentert et al. 1987; Zhao et al. 1992).
22
Clin. Pharmacokinet. 26 (1) 1994
From available literature, it is difficult to conclude with certainty the relative extents to which tenoxicam metabolites are excreted in urine and bile of humans. Mean biliary excretion of the glucuronidated 6-0-metabolite and still unidentified metabolites can in theory account for about 30% or more of the administered dose. Renal excretion of the 5'-hydroxy metabolite (making up nearly 40% of an administered dose) seems, however, to be well documented. 3.2 Linearity in Single-Dose Plasma Pharmacokinetics Pharmacokinetics after single oral doses of tenoxicam have been investigated over doses from 20 to 100mg in 6 healthy males (Heintz et al. 1988) and from 10 to 40mg in 12 healthy males (Francis et al. 1987). Figure 4 shows linear pharmacokinetics over this dose range in relation to both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax). Heintz et al. (1988) found the coefficient of variation in AUC and Cmax was less than 26 and 14%, respec-
tively, at each dose. Francis et al. (1987) found Cmax values varied approximately 2-fold at each dose, while the 24-hour AUC and AUC extrapolated to infinity showed 2- and 5-fold variations, respectively, at each dose. No statistically significant differences were observed in total plasma clearance (CL), Vd, t\l2 or time to reach Cmax (tmax ) for the different doses (Francis et al. 1987; Heintz et al. 1988). Linearity in single-dose tenoxicam pharmacokinetics was also shown over doses from 20 to 40mg in a Japanese study (Sugawara et al. 1984). 3.3 Absorption 3.3.1 Oral Bioavailability and Absorption
The complete bioavailability of oral tenoxicam 20mg (107%, range 97 to 121%) administered to healthy volunteers (Heintz et al. 1984) and the linear pharmacokinetics demonstrated in figure 4 (Francis et al. 1987; Heintz et al. 1988), indicate that oral doses from 10 to 100mg reach the systemic circulation in an unchanged form without first-pass gastrointestinal or hepatic metabolism.
1500
15
1000
:2
o•
AUG} G Heintz et al (1988) max
o•
AUG} FranCIS at al (1987) G max
r2=0940 10
...J
:J"
.s J
.s
0,
0,
~
E
Q
Q
~
«
500
5
100
o
20
40
60
80
100
Single dose of tenoxlcam (mg)
Fig. 4. Correlation between the size of the administered single oral dose of tenoXlcam to young healthy volunteers and the corresponding area under the plasma concentration-time curve (AUC) or maximum plasma concentration (Cmax).
23
Tenoxicam Pharmacokinetics
Table II. Influence of food on the single dose absorption of tenoxlcam In healthy volunteers (HV); values given are mean ± SO No.
Dose
Fasted
ofHV
(mg)
6
40
Non-fasted
ka
Gmax
(h-1)
(mg/L)
tmax (h)
AUG (mg/L· h)
ka (h-1)
2.1 ± 1.1
5.2± 1.0
1.3±0.7
370 ± 180
1.3±0.5
Reference Gmax (mg/L)
tmax (h)
AUG
4.6±06
4.1 ± 2.2a
380 ± 220
(mg/L· h) FrancIs et al (1985)
12
20
3.0±39
1.8± 10
2.4 ± 0.6a
253±110
58±46a
224±65
Day et al. (1987)
a
Significantly different from the fasted state
Abbreviations: AUG = Area under the concentration-time curve from zero to infinity; Gmax = maximum drug concentration after single dose administration;
ka = absorption rate constant (first-order); tmax= time to Gmax.
Table I shows single oral dose absorption characteristics of tenoxicam in healthy volunteers and patients with rheumatic diseases. Slightly lower mean Cmax values (4.5 and 4.3 mg/L) are indicated in 2 clinical studies (Crevoisier et al. 1984; Hinderling et al. 1988) than are seen in healthy volunteers (range 5.1 to 5.5 mg/L). This could be due to the longer time needed to attain Cmax in the 2 patient groups than in healthy volunteers. This is in accordance with the third clinical study presented in table I (Bird et al. 1985a). It appears, however, that the variation in tenoxicam absorption between different groups of patients with rheumatic diseases is higher than between different groups of healthy volunteers. 3.3.2 Influence of Food
Intake of food increases the mean tmax after a single oral tenoxicam dose by more than 200% and decreases the Cmax by more than 10% (table II). Francis et aL (1985) administered food 2 hours after the dose and Day et aL (1987) gave food 4 hours postdose. Neither the t'/z or the AUC of tenoxicam was influenced by food in these 2 studies. Thus, tenoxicam total bioavailability was not significantly influenced by food. It is therefore unlikely that the effects of food will be of clinical significance during long term administration of tenoxicam, although food was not administered concurrently with drug in either study. 3.3.3 Enterohepatic Recycling
The extent to which tenoxicam can access the intestinal lumen in humans was evaluated indi-
rectly in studies using cholestyrarnine as an intestinal binder of intestinally available drug. A single tenoxicam 20mg intravenous injection to 8 healthy young men (Guentert et al. 1988) or single oral 20mg dose to 6 healthy young men (Benveniste et al. 1990), with or without cholestyrarnine, produced the parameters shown in table III. Enhanced tenoxicam elimination occurred in the presence of cholestyrarnine. Care should, however, be taken in interpreting the data because biliary excretion is not the only pathway for systemically circulating drugs to enter the intestinal lumen. The presence of an adsorbent in the intestinal lumen may also enhance nonbiliary intestinal drug excretion Table III. Mean (± SO) pharmacokinetlc parameters of tenoXlcam 20mg (D administered in single Intravenous or oral doses to young healthy volunteers With and Without oral coadministration of cholestyramine (G) Drug
t1/:!
GUF
GL
(h)
(Uh)
(Uh)
Reference
Intravenous administration T
T+G
67±20
32±9
0.129
Guentert et al.
±0.052
(1988)
0264
Guentert et al.
±0053
(1988)
Oral administration T
T+G
74 ± 21
36±16
0.106
Benveniste et al.
±0.032
(1990)
0.225
Benveniste et al
±0072
(1990)
Abbreviations: GL = total body clearance of tenoxicam from plasma; GUF = oral total body clearance oftenoxlcam from plasma, t'!:! = terminal elimination half-life.
24
Clin. Pharmacokinet. 26 (1) 1994
(Guentert et al. 1988). Cholestyramine did not affect the Cmax of tenoxicam, indicating that the ion exchange resin does not influence the absorption of the drug. 3.3.4 Special Formulations Pharmacokinetics of parenteral tenoxicam, a lyophilisate with 20mg to be diluted in 2ml of water, were investigated in patients with rheumatic diseases and acute severe pain (Jeunet et al. 1989). Administration of intravenous, intramuscular and oral doses revealed no differences in the AUC or t'l2 of tenoxicam. A 20mg milk formulation (volume not given) of tenoxicam had a bioavailability of 94% relative to oral tablets in patients with rheumatic diseases (Enz & Jeunet 1989).
3.4 Plasma Pharmacokinetics in Healthy Volunteers and Patients with Rheumatic Diseases Changes in the plasma drug concentration with time are assumed to represent changes in drug concentrations at the receptor site. This assumes that some covariance exists between drug concentrations in plasma and at the site of action, which need not be a I-to-l relationship. Thus, knowing the plasma pharmacokinetic parameters of a drug, suitable dosage regimens for optimal efficacy can be constructed, accounting for any accumulation that may occur after repeated doses. Since most initial pharmacokinetic trials are performed in healthy volunteers and much valuable information is usu-
ally collected for this group, it is important to link these data with data from patients who will actually receive the drug. 3.4.1 Total Plasma Concentrations
Single Dose Single dose intravenous studies of tenoxicam have been performed in healthy volunteers, with the main pharmacokinetic parameters presented in table IV (Crevoisier & Heizmann 1986; Guentert etal. 1988; Heintz et al. 1984). The study by Heintz et al. (1984) also includes oral administration, data presented in table I, allowing a calculation of bioavailability and comparison between intravenous and oral plasma profiles with time. From these investigations, some pharmacokinetic characteristics of tenoxicam can be summarised as follows: 1. The plasma concentration of unchanged tenoxicam follows the characteristics of a 2-compartment model after oral administration. However, the AUC during the distribution phase adds only about 3% to the total AUC and therefore contributes little to the overall decline of tenoxicam in plasma. 2. The intravenous and oral plasma concentration-time profiles of unchanged tenoxicam overlap when plasma-tissue equilibrium is achieved. 3. Tenoxicam has a small Vd and a low CL which is reflected in a long t'l2' 4. The low CL has led to the classification of tenoxicam as a low extraction ratio drug. 5. The relative magnitude of the disposition rate constants from the central to peripheral (k12) and peripheral to central (k21) compartments indicates
Table IV. Mean (± SO) basIc pharmacoklnetlc parameters after a single Intravenous tenoXlcam 20mg injection to healthy volunteers (HV) No of HV
k12 (h-1)
k21 (h-1)
t1;, (h)
Vc (l)
Vd (l)
Vss (l)
Cl (Uh)
Reference
12
0.781 ± 0.932
0.885 ± 0.917
67 ± 18
67 ± 1.7
12.3 ± 3.2
12.1 ± 3 2
0.132 ± 0 060
Heintz et al. (1984)
12.Sa
11.3 ± 2.0
0129±00S2
Guentert et al. (1988)
11 Oa
100±18
0.114 ± 0.036
Crevoisier &
8
67±20
12
67±27
42±07
Helzmann (1986) a
Calculated from the presented data by the equatIOn Vd = {Cl x t1/2)/ln2.
Abbreviations: Cl = total body clearance from plasma; k12 = first-order transfer rate constant from the central to a penpheral compartment; k21 =iirst-ordertransfer rate constant from a peripheral to a central compartment, t1/2 =terminal elimination half-life; Vc =volume of distribution of the central compartment; Vss = apparent volume of distribution at steady-slate; Vd = apparent volume of distribution.
Tenoxicam Phannacokinetics
25
Table V. Mean (± SO) pharmacokinetics of tenoxlcam and 5'-hydroxy-tenoxlcam after single and repeated oral doses of tenoxlcam 20mg in healthy volunteers (HV) No. (age) Single dose ofHV Cmax tmax (mg/L) (h)
Repeated dose 11,1, (h)
AUC CUF (mg/L 0 h) (Uh)
66 ±15
242±74
142 ± 16
8 (24 ± 1)a
27
50
±0.5
±30
8 (30 ± 6)a
27
1.1
49
±0.6
±05
±6
8b
SO
SO
SO
a
0090 ±0.029 0142 ±0015
SO
tmax (h)
t'l2 (h)
AUC (mg/Lo h)
5.0 ±30
74 ±13
262±67
±3.3 5.3 ±07
1.9 ±13
54
163±39
±9
C~ax (mg/L)
C~m
13.6
9.7
±33 7.4 ±01
(mg/L)
0.11
0.09
15
±005
±0.04
±20
53 ±27
R
Reference
CrevOisier et al. (1989a)
CUF (Uh) 0076
58
±0.021
±0.6
0128
39
±0.026 ± 1.2 2.0±0.7
Data on file, F HoffmannLa Roche Ltd Data on file, F. HoffmannLa Roche Ltd
Single-dose or dally repeated doses for 2 weeks.
b Co-determination of the 5'-hydroxy metabolite of tenoxlcam.
Abbreviation: AUC = steady-state area under the concentration-time curve over the first 24 hours postdose, SO = below quantification limit (0.05 mg/L), C ~ax = maximum concentration at steady-state, C ~'" = minimum concentration at steady-state; R = accumulation factor (ratio of 24-hour AUC values after multiple and single doses); for other abbreViations see tables I and II.
that the reflux from the periphery is not rate limiting for the elimination of tenoxicam. Of interest is the observation that V d is not much larger than volume of distribution of the central compartment (Vc), further indicating a small tissue distribution of tenoxicam. This observation is also in line with the low lipophilicity of tenoxic am (see section 2.2). The overall pharmacokinetic data from intravenous tenoxicam in table IV compare well with the oral data presented in table I, further underlining the complete oral bioavailability of the drug. However, table I indicates a slightly higher CL and shorter tl;2 in patients with rheumatic diseases than in healthy volunteers. Taking the interindividual variation of tenoxicam pharmacokinetics into consideration' these deviations will not be statistically significant and will probably be of minor clinical significance in the extrapolation of tenoxicam single-dose data from healthy volunteers to patients with rheumatic diseases. Uncertainties in extrapolation will, however, always exist when making comparisons between historical groups and controls. Repeated Administration After multiple doses of 20mg daily to healthy volunteers, the steady-state tenoxicam concentra-
tion is reached after about 10 to 14 days (Crevoisier et al. 1989a; data on file, F. Hoffmann-La Roche Ltd). Table V demonstrates a slight increase in the tl;2 and AUC for tenoxicam after repeated administration as a consequence of a 10 to 15% decrease in CL at steady-state. The differences between single- and multiple-dose parameters were not statistically significant. The approximate 10 to 15% underestimation of tenoxicam accumulation in healthy volunteers, calculated from single-dose data, may be due to the slight decrease in CL after multiple doses (Crevoisier et al. 1989a). This could also occur because accumulation is difficult to calculate for drugs given at intervals which are short relative to their tl;z values, such as tenoxicam (Colburn 1983). For piroxicam, an increase in the tl;z was also reported after multiple doses, with trough steady-state concentrations 32% greater than those predicted from single-dose data (Richardson et al. 1987). Thus, although steady-state accumulation of tenoxicam is slightly underestimated when calculated from the single-dose data, steady-state plasma concentrations of the drug are predictable from singledose pharmacokinetic parameters, demonstrating nearly linear pharmacokinetics during repeat administration in healthy volunteers. While satisfac-
26
CUn. Pharmacokinet. 26 (1) 1994
tory predictability of accumulation exists for groups of patients, the predictability for individual healthy volunteers is relatively poor (Crevoisier et al. 1989a). This has also been reported for elderly (Bird et al. 1985b). In line with the long t\l2' small fluctuations are found in the plasma concentration of tenoxicam over a dosage interval at steady-state (table V), with a Cmax-to-minimum ratio of about 1.4. Average steady-state plasma concentrations (C i~) in 2 groups of 8 healthy volunteers were calculated as 10.9 mg/L (range 7.7 to 13.9 mg/L) and 6.8 mg/L (range 4.9 to 10.4 mg/L), respectively (Crevoisier et al. 1989a; data on file, F. Hoffmann-La Roche Ltd) after tenoxicam 20mg daily for 2 weeks. The lower steady-state mean concentrations in the unpublished study (data on file, F. Hoffmann-La Roche Ltd) are due to relatively faster elimination of tenoxicam in these healthy volunteers, also producing a lower accumulation ratio than that reported by Crevoisier et al. (1989a). The terminal decline of the 5'-hydroxy metabolite concentrations in healthy volunteers at steadystate has been calculated as equal to that of tenoxicam (see table V). This indicates that the metabolite has formation-rate limited pharmacokinetics. Steady-state plasma concentrations of the 5'-hydroxy metabolite contribute little (1 to 2%) to the combined plasma concentrations in healthy volunteers (table V). 13 patients with classical rheumatoid arthritis had mean steady-state plasma tenoxicam concentrations of 11.1 mg/L(range 7.6 to 13.9 mg/L) after receiving 20mg daily for 6 weeks (Corvetta el al. 1991). Administration of tenoxicam 20mg daily for
more than 2 weeks in 10 patients produced mean steady-state plasma concentrations of 9.2 mg/L (range 3.5 to 15.0 mg/L) [Day et al. 1991]. The range of steady-state tenoxicam concentrations in healthy volunteers (Crevoisier et al. 1989a; data on file, F. Hoffman La Roche Ltd) are, thus, smaller than those reported for patients with rheumatic diseases, indicating higher interindividual variation in the steady-state pharmacokinetics in these patients. However, interindividual variation in mean steady-state concentrations within each of the 2 groups is greater than the differences between mean values for the 2 groups. Thus, no statistically significant difference is likely to exist between steady-state plasma concentrations in healthy volunteers and patients with rheumatic diseases, although available data are scarce. No data are available on the pharmacokinetics of the 5'-hydroxy metabolite in patients with rheumatic diseases, except for failure to detect the metabolite in plasma from patients who had received a 20mg single oral dose (Heizmann et al. 1986). 3.4.2 Unbound Plasma Concentrations
Plasma pharmacokinetics of unbound tenoxicam have been investigated in 2 trials in patients with rheumatoid arthritis and chronic knee effusions (Crevoisier et al. 1984; Day et al. 1991; table VI). An equal ratio between the total and unbound plasma tenoxicam concentration is seen after single and multiple doses. A constant degree of plasma protein binding during the entire postdose period is indicated by equal total to unbound ratios of plasma concentrations and AUC values. Furthermore, the tmax and t\l2 were identical for unbound and total fractions of tenoxicam (Crevoisier
Table VI. Comparative mean (± SO) plasma pharmacokinetics of total and unbound tenoXlcam In patients With rheumatoid arthntls Dosage
40mg single dose 4.48 ± to 5 patients 20mg daily for
AUC (mg/L • h)
Cmax(mg/L) total
0.38
unbound
ratio
0.05 ± 0.03 89 6
Reference
C ~~ (mg/L)
total
unbound
ratio
333± 155
3 72 ± 2.19
89.5
total
free
ratio Crevoisier et al (1984)
9.2±3.7
0.11 ±0.08
~2weeksto
10 patients
Abbreviations: C ~~ = mean steady-state concentration after multiple doses; for other abbreviations see table II.
83.6
Day et al. (1991)
27
Tenoxicam Pharmacokinetics
Barrier
Synovial fluid
Plasma pH = 7.4
Bound~
r Free
WI
/r~~j
If'
pH
-=~k=I=2::t:~
= 7.1·7.4
Free
/Borund
IHAI ~
• k 21
Free
. . . . .~-.
[A-)
RESPONSE
Fig. 5. Reversible processes affecting the total amount of drug on each side of a biological membrane permeable only to the unionised, unbound form. Abbreviations: see table IV.
et al. 1984). Thus, the data demonstrate parallel changes in the unbound and total plasma concentrations of tenoxicam over time. 3.5 Distribution and Pharmacokinetics in Other Fluids and Tissues in Patients with Rheumatic Diseases The principal target tissue in most rheumatic diseases is the synovium. Swelling in the joint originates both from synovial tissue hyperplasia and accumulation of synovial fluid. Synovial fluid pharmacokinetics therefore provide an insight to a more peripheral compartment than circulating plasma. Covariance between drug concentrations in plasma and synovial fluid with time is important information for a successful extrapolation from plasma concentration measurements to the time course of the drug near the presumed site of action. Compartmental models for the pharmacokinetics of NSAIDs (Graham 1988) and tenoxicam (Hinderling et al. 1988) in synovial fluid have been published, as has a review on the extravascular pharmacokinetics of antirheumatic drugs (Wallis et al. 1983).
3.5.1 Distribution to the Synovial Fluid Water and small solutes appear to move quite readily from plasma across the synovial interstitium. While proteins are transported in a one-way path from plasma to the synovial fluid , most ions and drugs are transported bidirectionally. Crossing the synovium in both directions is, for most drugs, governed by simple unrestricted diffusion. The rate of drug transit is, however, dependent upon pKa values, molecular radius and degree of protein binding (Wallis el al. 1983). For tenoxicam the plasma-synovial fluid exchange is restricted to the unbound and un-ionised drug molecule (Hinderling et al. 1988). However, within both compartments, unbound tenoxicam concentrations will consist of drug in both unionised and ionised forms , in accordance with its pKa value (fig. 5). A decrease in pH will reduce the unbound concentration of ionised tenoxicam in plasma as well as in the synovial fluid . In vivo, at distribution equilibrium, equal unbound concentrations of unionised tenoxicam are expected in plasma and synovial fluid . This would, in rheumatic patients, imply lower total (ionised plus un-ionised) concentrations of unbound tenoxicam in synovial fluid than in plasma. Assuming a pH of7.2 in the synovial fluid of rheumatic patients (Cummings & Nordby 1966), a pH of 7.4 in plasma and a pKa of 5.3 for tenoxicam, the concentration of unbound ionised tenoxicam in the synovial fluid will be about 60% of the corresponding concentration of unbound ionised tenoxicam in plasma. Bearing in mind that about 99% of tenoxicam is present in the ionised form in the pH range from 7.2 to 7.4, the in vivo plasma-synovial fluid pH differences are significant to the relative distribution of unbound drug between plasma and synovial fluid. The lower the pH in the synovial fluid, the lower the unbound concentration of total and ionised tenoxicam compared with that in plasma. Thus, under highly inflammatory conditions with a very low and variable pH in the synovial fluid, unbound tenoxicam concentrations in synovial fluid must be expected to be much lower than the
28
CUn. Pharmacokinet. 26 (1) 1994
Table VII. Comparative mean pharmacokinetics of total tenoxicam in plasma and synovial flUid after single and multiple doses to patients with rheumatoid arthntls and osteoarthritis Dosage
Cmax(mg/L)
tmax(h)
AUC (mg/L • h)
11,. (h)
plasma synovial ratioa fluid
plasma synovial ratioa fluid
plasma synovial ratloa fluid
plasma synovial ratioa fluid
Reference
Single doseD
59
18
32
16
10.1
0.16
252
134
19
42
45
0.9
Blrdetal (1985a)
Single dosec
45
1.2
3.7
4.6
344
013
333
109
30
52
52
10
Crevolsler et al (1984)
Single dosed
43
1.4
3.1
6.7
160
042
268
117
23
40
40
10
Hinderllng et al. (1988)
Repeated doses·
9.2
3.9
24'
a
Day et al. (1991)
Ratio between the concentrations of tenoxlcam In plasma and synovial fluid.
b 40mg to 6 patients c
40mg to 5 patients.
d
40mg to 4 patients
e
20 mg/day for at least 2 weeks to 10 patients. Average steady-state concentrations
Abbreviations: see table V
corresponding unbound concentrations in plasma, and to show a higher degree of interindividual variability. 3.5.2 Total Synovial Fluid Concentrations Comparative pharmacokinetic data on total tenoxicam in plasma and synovial fluid are presented in table VII. Some striking differences can easily be observed: 1. The Cmax of total tenoxicam in plasma is about 3 times higher than that in synovial fluid. This also applies approximately to mean steadystate concentrations. 2. The Cmax of tenoxicam in synovial fluid is reached 3 to 7 times later than that in plasma. 3. The AUC is 2 to 3 times higher in plasma than in synovial fluid. 4. The disappearance rate of tenoxicam from synovial fluid equals that from plasma. Since the concentration of total tenoxicam in synovial fluid increases more slowly and is lower than that in plasma, several investigators have concluded that the synovial fluid represents a peripheral pharmacokinetic compartment different from the central plasma compartment (Bird et al. 1985a; Crevoisier et al. 1984; Day et al. 1991; Hinderling et al. 1988).
Compared with other NSAIDs with short tY2 values such as ibuprofen (Day et al. 1988b) and indomethacin (Graham 1988), tenoxicam shows the highest rates of transfer in and out of the synovial space relative to the plasma elimination rate (Graham 1988). This is thought to be the main reason why the concentration of tenoxicam in synovial fluid does not exceed that in plasma at the end of a dosage interval at steady-state, as observed for other NSAIDs. Furthermore, the lower elimination rate constant of tenoxicam from plasma, compared with the diffusion rate constant of the drug from synovial fluid to plasma, makes plasma elimination the rate-limiting step for elimination, and thus the decrease in synovial fluid concentrations is always parallel to that observed in plasma. The small fluctuations observed in the plasma concentration of tenoxicam over time should then also be seen in synovial fluid. At steady-state in 10 patients with rheumatoid arthritis, peak to trough concentration ratios (± SD) for tenoxicam in plasma and synovial fluid were 1.76 ± 0.36 and 1.50 ± 0.33, respectively (Day et al. 1991). These ratios indicate small and proportional fluctuations in both fluids over a dosage interval, thus confmning the anticipated small fluctuations. However,
29
Tenoxicam Pharmacokinetics
though a significant relationship has been demonstrated in individuals between the oral dose in mglkg bodyweight and mean plasma concentrations of total tenoxicam at steady-state, no such correlation has been found between the oral dose and the individual concentration of total drug in synovial fluid (Day et al. 1991). 3.5.3 Unbound Synovial Fluid Concentrations The total and unbound concentrations of tenoxicam in synovial fluid were shown to decrease in parallel in 5 patients with rheumatoid. arthritis after a single oral dose of tenoxicam 40mg (Crevoisier et al. 1984). Cmax and AVC ratios of total to unbound drug of 75 and 78, respectively, indicate, as in plasma (see section 3.4.2), a constant degree of protein binding in the synovial fluid after administration. The synovial fluid concentrations of both albumin and total protein (about 20 and 30 giL, respectively) are lower than those in plasma (about 37 and 64 gIL, respectively) in patients with various rheumatic diseases (Crevoisier et al. 1984; Hinderling et al. 1988). Thus, the total concentration of tenoxicam in the synovial fluid would be expected to be lower than that in plasma. Furthermore, when equilibrium is achieved, equal concentrations offree, unbound (un-ionised plus ionised) tenoxicarn would be expected in both fluids, but only if pH is equal in the 2 fluids. Some apparently incompatible data on the unbound concentration of tenoxicam in plasma and synovial fluid are given in table VIII. This incompatibility probably reflects experimental problems with determination of the unbound fraction (see
section 4). Crevoisier et al. (1984) report an equal percentage binding of tenoxicam in plasma (98.9%) and synovial fluid (98.7%) resulting in a ratio of AVC values for unbound tenoxicam between plasma and synovial fluid of greater than unity (2.0 ± 1.1). The unbound tenoxicam concentrations were significantly higher in plasma than in synovial fluid, with a plasma to synovial fluid ratio of 1.9 ± 1.2. In contrast, Day et al. (1991) report a higher percentage binding of tenoxicam in plasma (98.8%) than in synovial fluid (97.7%), resulting in a ratio of C ~~ values for unbound tenoxicam between plasma and synovial fluid of nearly unity (1.2 ± 0.4). In both studies a substantial variation (> 2-fold) was reported in individual plasma to synovial fluid ratios for both total and unbound drug. 3.5.4 Distribution to Other Fluids and Tissues Little information is available on the distribution of tenoxicam to other fluids and tissues. Table IX indicates, however, a higher steady-state distribution of the drug to synovial tissue (Bannwarth et al. 1991) than to synovial fluid, which may have clinical significance. Tenoxicam seems to penetrate to a lesser extent into joint cartilage. The low concentration of the drug reported in synovial tissue by Corvetta et al. (1991) may result from the short dosage time, indicating that steady-state conditions had not yet been reached.
3.6 Plasma Pharmacokinetics in Illness and Old Age Despite thorough evaluation of the pharmacokinetics of tenoxicam in young healthy populations
Table VIII. Comparative mean (± SD) pharmacokinetics of unbound tenoxicam in plasma and synovial fluid after single and multiple doses to patients with rheumatoid arthritiS or osteoarthritis Dosage
AUC (mg/L • h)
plasma
synOVial flUid
ratioa
Single doseb
372±219
1.40±055
2 O± 1 1
Multiple dosese a
Reference
C ~~ (mg/L)
plasma
synovial fluid
Crevoisler et al. (1984) 110 ± 78
89±44
Calculated from indiVidual values
b
40mg to 5 patients, unbound concentrations measured by equilibrium dialYSIS
c
20 mg/day for at least 2 weeks to 10 patients, unbound concentrallOns measured by ultrafiltrallOn
AbbreVIations: see tables II and VI.
ratioa
1 2 ± 0.4
Day et al (1991)
Clin. Pharmacokinet. 26 (1) 1994
30
and in some detail in patients with rheumatic diseases, it is also important to evaluate pharmacokinetics in special target populations. 3.6.11mpaired Renal Function Prostaglandin synthetase inhibitors may affect kidney function, especially in renally diseased or elderly patients, by decreasing renal clearance or renal blood flow (Clive & Stoff 1984; Swain et al. 1975). Thus, it is important to evaluate both the effect of renal function on tenoxicam pharmacokinetics and the effect of tenoxicam on renal function.
Effect on Renal Function Studies of possible effects of tenoxicam on renal function in humans have been performed by several investigators. One double-blind, placebocontrolled study involved 16 healthy male volunteers aged 22 to 42 years. The investigators found no changes in glomerular filtration rate (GFR), CLCR, renal clearance of p-aminohippuric acid (PAH), renal blood flow, urinary electrolyte excretion or urinary excretion of N-acetyl-glucosaminidase and ~2-microglobulin. Patients received tenoxicam 40mg daily for 2 days, followed by 20mg daily for a further 8 days (McAuslane et al. 1988). These results have been confirmed in a study of 8 healthy volunteers receiving tenoxicam as described above and 8 healthy volunteers receiving placebo (Freestone et al. 1991). Ten patients aged 60.5 ± 7.0 years with chronic renal failure [CLCR 46.7 ± 11.9 mllmin/1.73m2 (2.8 ± 0.7 Llh/1.73m 2)] received tenoxicam 40mg daily for 2 days then 20mg daily for 8 days. They exhibited a temporary increase in plasma creatinine on the third and sixth days of treatment, which returned to pretreatment levels on the tenth day of
treatment. Minor but significant increases in the plasma half-lives of inulin and PAH of 11 and 9%, respectively, were observed together with a significant decrease in the urinary excretion of prostaglandin E2. However, no changes were observed either in plasma inulin levels or in CLCR (Freestone et al. 1991). The investigators concluded that tenoxicam may exert minor effects on renal function in patients with chronic renal failure and recommended, in line with other NSAIDs, that tenoxicam be used with caution in these patients (Freestone et al. 1991). Four elderly patients, 68 to 87 years of age, with osteoarthritis and mild to moderate renal impairment [CLCR >30 mllmin (1.8 Llh)] showed no changes in GFR or effective renal plasma flow after receiving tenoxicam 20mg daily for 12 weeks. Measurements were performed by single intravenous injections of [51 Cr]edetic acid (EDTA) and 25 I]iodohippurate (Ghose & Burch 1989). Amodest decrease in CLCR from 64.7 to 57.9 mllmin (3.88 to 3.47 Llh) has been reported in 58 elderly patients (mean age 69 years) who had osteoarthrosis or rheumatoid arthritis and were receiving tenoxicam 20mg daily for 12 weeks (Bird et al. 1989). 'High risk renal patients', including 10 elderly patients (mean age 77 years) with cardiovascular diseases or hepatic cirrhosis in addition to renal impairment, showed a significant (13%) decrease in GFR measured with [51 Cr]edetic acid after 5 days' treatment with tenoxicam 20mg daily (Giovannoni et al. 1990). Treatment of 56 outpatients (mean age 63 years), from a rheumatology clinic, with tenoxicam 20mg for I to 5 years did not appear to change plasma creatinine values (Giovannoni et al. 1990).
e
Table IX. Mean (± SO) or range oftenoxlcam concentrations In synovial tissue and joint cartilage after multiple doses administered to patients No. of patients
Dose
Plasma
Synovium
Cartilage
(mg)
(mg/L)
(mg/kg)
(mg/kg)
20
62±38
7.6±47
2.1 ± 1.4
20
3.5-41
0.9-1.0
a
Total arthroplasty of the hlP, daily administration for 8 to 30 days.
b
Surgical synovlectomy; dally administration for 3 days
Reference Bannwarth et al. (1991) Corvetta et al. (1991)
Tenoxicam Pharmacokinetics
In summary, tenoxicam-induced changes in renal function in different groups of patients appear to be small. No secondary changes in the pharmacokinetics of tenoxicam are thus expected.
Effect of Renal Failure Pharmacokinetics of tenoxicam in patients with impaired renal function should be evaluated on the basis of our knowledge of its excretion in humans (see section 3.1). Unchanged tenoxicam appears in urine only in insignificant amounts « 0.5% of the dose), while the 5'-hydroxy metabolite in urine accounts for about 40% of the dose. Changes in hepatic drug metabolism of some drugs have been reported in chronic renal failure (Simon et al. 1981). The use of historical controls in between group comparisons is not fully accepted and studies that use these controls must be seen as supplements to studies in which adequate controls were used. Results of 2 single-dose studies with tenoxicam 20mg (Horber et al. 1986; data on file, F. Hoffmann-La Roche Ltd; table X) reveal similar pharmacokinetics of tenoxicam in patients with renal impairment, patients with rheumatic diseases and healthy volunteers (see table I). The unpublished data in tables V and X are from the same study (data on file, F. Hoffmann-La Roche Ltd), in which healthy volunteers were tested in parallel with patients with renal failure. This study found no statistically significant differences between the 2 groups with respect to single-dose pharmacokinetics. In the study of Horber et al. (1986), no significant differences were found between pharmacokinetic parameters of tenoxicam after single doses in patients with renal impairment and healthy volunteers (historical controls). Therefore, this study conf"mns the fmdings of other investigators that renal failure does not influence tenoxicam pharmacokinetics. No correlation was found between any calculated single-dose pharmacokinetic parameters for tenoxicam and the degree of renal function in either of the 2 studies (Horber et al. 1986; data on file, F. Hoffmann-La Roche Ltd). The steady-state concentration of tenoxicam after multiple 20mg daily doses to patients with renal
31
failure has, as in healthy volunteers, been reported to be reached after about 10 days (data on file, F. Hoffmann-La Roche Ltd). In table X, as in the parallel group of healthy volunteers (table V), a slight increase is seen in 11/2 and AUC values for tenoxicam after multiple doses, resulting from a nonsignificant 6% decrease in CL at steady-state. From these data it appears that multiple-dose pharmacokinetics and accumulation of tenoxicam do not differ between patients with renal failure and healthy volunteers. No correlation was found between any calculated steady-state pharmacokinetic parameters for tenoxicam and the degree of renal function. Changes in steady-state pharmacokinetics of the 5'-hydroxy metabolite have been reported with decreasing renal function (data on file, F. Hoffmann-La Roche Ltd). A reduction in CLcR to 20 to 40 mlIminl1.73/m2 (1.2 to 2.4 LIhI1.73m2) resulted in a more than 300% increase in AUC and 80% decrease in renal clearance compared with those in healthy volunteers. An interesting observation was the 5-fold longer time needed for the 5'-hydroxy metabolite to reach Cmax at steady-state compared with the parent compound itself. Similar results were also demonstrated in the parallel group of healthy volunteers (data on file, F. Hoffmann-La Roche Ltd). For further data on the excretion of the 5'-hydroxy metabolite, see section 3.1. From a pharmacokinetic point of view, no dosage adjustment should be required for tenoxicam in patients with renal failure (Horber et al. 1986; data on file, F. Hoffmann-La Roche Ltd). This is in line with recommendations made for piroxicam and isoxicam, but not for such NSAIDs as diflunisal, ketoprofen or indoprofen (Horber et al. 1986). It has recently been reported that tenoxicam is not dialysable and that no dosage adjustment seems to be necessary for tenoxicam in patients with end-stage renal failure undergoing haemodialysis (AI-Ghamdi et al. 1992).
32
Clin. CZin. Pharmacokinet. 26 (1) 1994
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3.6.2 Liver Cirrhosis The liver is the main organ of elimination for tenoxicam. Here, metabolic conversion of ten5' -hydroxy tenoxic am to its 2 main metabolites, oxicam metabolites,S' oxicam oxic am and the glucuronidated 6-0-tenoxicam, takes place. Thus, any damage of the liver could in theory influence the pharmacokinetics of tenoxicam, logically by decreasing its CL. No difference was seen in a number of pharmapharm acokinetic parameters in patients with liver disease and healthy volunteers after a single 20mg oral dose of tenoxicam was administered to 6 patients with liver cirrhosis, ranging in age from 41 to 60 j..lmol/L years, with plasma bilirubin from 12 to 30 I-lmollL (Crevoisier et al. 1989b). Mean (± SD) parameter values were as follows: C Cmax max 2.6 ± 0.9 mg/L, ttmax max 2.5 ± 0.8 hours and t\l2 53 ± 19 hours in the patients compared with C Cmax max 3.2 ± 1.6 max 2.7 ± 0.7 mg/L, tmax hours and t\l2 tIh 69 ± 19 hours in 14 healthy historical controls (Crevoisier et al. 1989b; data on file, F. Hoffmann-La Roche Ltd). Urinary excretion of the 5'-hydroxy metabolite of tenoxicam also did not differ between the patients with liver cirrhosis and the healthy historical control volunteers, being 21.6 ± 3.8 and 22.1 ± 3.1% of the dose, respectively, when urine was collected for 4 days postA UC for tenoxicam was observed, dedose. A low AUC creasing to a statistically significant extent from 254 ± 92 mg/L • h in healthy volunteer historical controls to 159 ± 65 mg/L. h in the cirrhotic patients. There was an increase in oral plasma clear± 0.051 Lih ance (CLlF) (CLIP) in cirrhotic patients (0.142 (0.142± Llh vs 0.088 ± 0.033 Llh in the healthy historical controls ). trols). However, the CLIF CLIP and t\l2 of tenoxicam in the cirrhotic patients were judged to fall within the relatively broad range observed in healthy volunteers (Crevoisier et al. 1989b). Thus, the suggestion by Crevoisier et al. (1989b) that no dosage adjustment is required in patients with the investigated degree of hepatic impairment seems justified (see section 4.1 for the influence of bilirubin on the unbound plasma concentration of tenoxicam), although some reservations must be expressed as a result of the limited amount of data, and the use of historical
Tenoxicam Pharmacokinetics
controls. Furthermore, multiple-dose studies, with adequate controls, have not been performed in cirrhotic patients and are needed for a final confrrmation. Similar to tenoxicam, the pharmacokinetics of ibuprofen, another NSAID that is mainly eliminated by metabolism, are reported to be uninfluenced by liver pathology (Juhl et al. 1983). 3.6.3 Old Age
Age-related decreases in renal and hepatic clearance functions, plasma albumin, fat and total body water, all may lead to changes in the pharmacokinetics of a drug. Also, anti-inflammatory agents are commonly prescribed in the elderly patients. Single-dose pharmacokinetics of tenoxicam in elderly patients with osteoarthrosis or rheumatoid arthritis (Bird et al. 1985b), moderate pain and stiffness in joints and skeletal system (Nilsen et al. 1988) and rheumatoid arthritis (Schmitt et al. 1988) are shown in table XI. Diagnosis was not available from the study by Kobayashi et al. (1984). The single dose parameters given for tenoxicam in the elderly do not differ significantly between the 4 studies. The higherCmax (3.6 and 3.7 mg/L, respectively) in studies by Nilsen et al. (1988) and Schmitt et al. (1988) compared with the Cmax (2.6 mg/L) in the study by Bird et al. (1985b), may be partly due to the slower absorption of tenoxicam in patients in the latter study. The single-dose pharmacokinetics of tenoxicam in elderly are reported to fall within the range earlier observed for healthy volunteers (Bird et al. 1985b; Nilsen et al. 1988; Schmitt et al. 1988). The single-dose study of Kobayashi et al. (1984), with a control group of 5 healthy young volunteers, also reported no significant differences between healthy volunteers and elderly patients, with the exception of an increase in the oral apparent Vd in elderly patients (0.23 ± 0.06 L/kg vs 0.15 ± 0.02 L/kg in the volunteers). This increase was thought to be caused by decreased plasma albumin in the elderly patients (Kobayashi et al. 1984). The steady-state concentration of tenoxicam after 20mg daily doses to elderly patients is, as in healthy volunteers and patients with renal impair-
33
ment, reported to be reached after 10 to 14 days (Bird et al. 1985b; Horber et al. 1986; data on file, F. Hoffmann-La Roche Ltd). Table XI demonstrates, as in young healthy volunteers and in renal impairment (tables V and X), a statistically nonsignificant 17 to 18% decrease in CL at steadystate, resulting in a slight increase in the V/2 and AUC after repeated administration. Four elderly patients with osteoarthritis, aged 75 ± 8 years, receiving tenoxicam 20mg daily for 12 weeks, showed steady-state minimum concentrations of 8.8 ± 1.8 mg/L (Ghose & Burch 1989), while 26 elderly patients (age 69 ± 9 years) with osteoarthrosis or rheumatoid arthritis showed steadystate minimum concentrations of 10.9 ± 3.9 mg/L (Bird et al. 1989). The multiple-dose pharmacokinetics and accumulation of tenoxicam are, thus, not apparently different in elderly patients and young healthy volunteers. Altogether, the presented data indicate no need for tenoxicam dosage adjustments in elderly patients. The cumulative urinary excretion rate of the 5'hydroxy metabolite was about 18% lower in elderly patients than in young healthy volunteers (Kobayashi et al. 1984). This can be explained by differences in renal function, since CLcR values of 55 ± 28 mllmin (3.30 ± 1.68 LIh) and 103 ± 14 mllmin (6.18 ± 0.84 LIh), respectively, were measured (see section 3.6.1). In general, oxicam NSAIDs seem to be less affected by age than propionic acid derivatives when pharmacokinetics of tenoxicam, piroxicam, isoxicam, ketoprofen, naproxen and ibuprofen are compared. Apart from the CL of piroxicam being reduced by 40%, and the Viz being increased by 24% in elderly women (Richardson et al. 1985) compared with healthy adult volunteers, no effects of age are found for the other oxicams. For the propionic acid derivatives, a general feature in the elderly is a reduction in CL from 14 to 60% and a prolonged Viz from 26 to 72%, when compared with healthy adult volunteers. Some differences have been reported between the sexes (Schmitt & Guentert 1989).
34 34
Clin. CUn. Pharmacokinet. 26 26 (1) (1) 1994 1994
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Drug protein binding is usually measured in vitro by equilibrium dialysis or ultrafiltration. In both methodologies it is vital to establish an equilibrium between unbound and bound drug in the medium, and to maintain an adequate pH (i.e. physiological, such as 7.4 for plasma) during dialysis or filtration. In synovial fluid pH ranges from 7.32 to 7.64 (mean 7.43) in healthy volunteers and from 7.09 to 7.41 (mean 7.21) in patients with rheumatoid arthritis (Cummings & Nordby 1966). Interestingly, 1 patient with osteoarthritis and no inflammatory characteristics in the joint fluid showed a normal pH of 7.47 in the synovial fluid (Cummings & Nordby 1966). Protein binding of tenoxicam is strongly affected by pH, as illustrated in figure 6. This makes strict pH control during all in vitro measurements essential. The human plasma protein binding of tenoxic am has been reported to be constant over a total oxicam concentration range from 0.1 to 40 mg/L (data on file, F. Hoffmann-La Roche Ltd), or 1 to 150 Ilmol/L (Bree et al. 1989), covering therapeutic concentration ranges. Albumin is the only protein binding tenoxicam to a significant extent (Bree et al. 1989; data on file, F. Hoffmann-La Roche Ltd). Two binding sites are identified for tenoxicam: site I (the warfarin site) and site II (the diazepam site). Interestingly, the 2 binding sites are not independent, as the binding capacity of site I for tenoxicam is enhanced by diazepam, probably by an allosteric effect (Bree et al. 1989).
ctl
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Table XII illustrates the binding of tenoxicam
e C-labelled) in different categories of patients. 44
The following characteristics are demonstrated:
35
Tenoxicam Pharmacokinetics
1. Tenoxicam is highly bound in plasma from different categories of patients and in synovial fluid from patients with rheumatic disease. 2. The plasma protein binding of tenoxicam is apparently overlapping for different patient categories. This is, however, mainly due to interlaboratory differences. 3. The plasma protein binding of tenoxicam is apparently not related to the plasma concentration of albumin. 4. At equal pH, conflicting results are presented on the relative degree of tenoxicam binding in plasma and synovial fluid. 5. If tenoxicam binding experiments in synovial fluid are performed at a pH of 7,4 instead of the physiological pH of about 7.2, an overestimation of the binding will occur. In only one study (data on file, F. Hoffmann-La Roche Ltd) was a control group of healthy volunteers used. This in some cases is due to the specific nature of the study, in other cases historical controls were used. This makes direct comparison of the presented results somewhat difficult. Some comments can, however, be made. The plasma protein binding of tenoxicam in healthy volunteers (Day et al. 1988a) was performed by ultrafiltration without referring to the actual pH at which filtration was performed. With no pH control, plasma pH will rapidly rise towards 8.0 or more. This will, in accordance with figure 6, decrease the unbound fraction of tenoxicam in plasma. An overestimation of binding in the study of Day et al. (1988b) is therefore possible. No explanation apart from unknown differences in methodology can be given for the lower binding in other studies (Bree et al. 1989; data on file, F. HoffmannLa Roche Ltd). Endogenous compounds such as free fatty acids are thought to interfere with the binding of tenoxicam (Bree et al. 1989; data on file, F. HoffmannLa Roche Ltd). Since an influence of fatty acids on the protein binding of other NSAIDs has also been suggested (Wanwimolruk et al. 1983), high interindividual variability in the protein binding of tenoxicam can be expected in patients with renal dis-
18
~
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72 74 pH buffer Side
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78
Fig. 6. Effect of pH on the plasma protem bmding of tenoXlcam in humans. Measurements performed by equilibrium dialysis at 37°C against a 0.133 mollL Sorensens phosphate buffer and a total concentration of tenoXlcam of 4.4 mglL (data on file, F. Hoffmann-La Roche Ltd).
ease. No correlation existed between plasma albumin concentrations or CLcR [7 to 53 ml/minJ1.73m2 (0,42 to 3.18 LIhI1.73m2)] and the plasma protein binding of tenoxicam (Horber et al. 1986). The patients with liver cirrhosis in the study of Crevoisier et al. (1989b) had normal plasma levels of bilirubin (22.9 ± 6.2 IlmollL, normal range 3 to 26IlmollL). The population investigated in the unpublished study (data on file, F. Hoffmann-La Roche Ltd) had plasma bilirubin levels 154 ± 210 IlmollL. Thus, the lower plasma protein binding observed in this study (data on file, F. HoffmannLa Roche Ltd) is most likely due to binding interferences between tenoxicam and bilirubin, with bilirubin displacing the drug from plasma albumin binding sites. In cirrhotic patients a significant positive correlation has been demonstrated between the concentration of unbound tenoxicam in serum and serum bilirubin concentrations (Crevoisier et al. 1989b).
36
Clin. Pharmacokinet. 26 (1) 1994
Table XII. Mean (± SO) in vitro protein binding of tenoXlcam In plasma and synovial fluid at therapeutic concentrations Study participants
Age
Concentration of albumin (giL)
Unbound (%)
(no.)
(y)
plasma
plasma
Healthy volunteers (12)
43± 10
39.8±2.4
synovial fluid
pH
Reference
7.4
data on file, F. Hoffmann-
synovial flUid
0.85 ± 0.15
La Roche Ltd Healthy volunteers (8)
22± 1
NR
056 ± 0.05
NR
Day et al. (1988a)
Healthy volunteers (10)
NR
NR
1.5b
7.4
data on file, F. Hoffmann-
Healthy volunteers (NR)
NR
46.8
1.6b
7.4
Bree et al. (1989)
Renal failure (8)
46± 11
392±27
1.81 ± 0 48
7.4
data on file, F. Hoffmann-
Renal failure (12)
55± 14
38.0±58
1.3 ± 0.5
7.4
Harber et al (1986)
Hepatic disease (9)
66±21
327±118
1.58 ± 0.79
7.4
data on file, F. Hoffmann-
Hepatic disease (6)
50±7
39.9
0.78 ± 0 34
7.4
Crevoisier et al. (1989b)
Elderly (15)
81 ±7
42.0±3.9
1.69 ± 0.37
7.4
data on file, F. Hoffmann-
Rheumatic disease (10)
57± 10
36.5±2.3
23.5 ± 6.1
1.23 ± 0.70
2.47± 1.23
NR
Dayet al. (1991)
Rheumatic disease (5)
NR
370±2.5
19.6±4.8
111±054
1.29±0.42
7.4
data on file, F. Hoffmann-
1.69
728
data on file, F. Hoffmann-
La Roche Ltd
La Roche Ltd
La Roche Ltd
La Roche Ltd
La Roche Ltd La Roche Ltd a
Concentration in synovial fluid when calculated back to a pH of 7.22 by using the data presented in fig. 6.
b
Pooled plasma
Abbreviation: NR
=not reported.
The evaluation of binding of a drug which is as highly as 99% bound to plasma proteins with the use of 14C-Iabelled tenoxicam means that radioactive impurities of only 1% could in theory explain all differences observed between the different investigated groups of patients, thus making essential the use of adequate control groups. With the exception of decreased plasma protein binding in patients with extremely high concentrations of plasma bilirubin, no safe conclusions can be made from existing literature on the relative degree of plasma protein binding of tenoxicam in different categories of patients. However, a high degree of interindividual variation has been observed, which could be of significance for the observed interindividual variation in pharmacokinetics of the drug. 4.2 Binding to Other Sites In blood, 94.5% of a dose of tenoxicam was reported to distribute to albumin, 3.3% to erythro-
cytes, 0.8% to aI-acid glycoprotein and negligible amounts of the drug were found in lipoproteins, lymphocytes and neutrophils (Bree et al. 1989). Binding of the drug is relatively limited to erythrocytes, with an erythrocyte to plasma concentration ratio of between 0.24 to 0.30 when tenoxicam concentrations ranged from 0.5 to 50 mgIL (Heintz et al. 1984). A total concentration of tenoxicam 0.04 mgIL was reported in human breastmilk when the drug was found in plasma at therapeutic concentrations, with an unbound fraction in skimmed milk of 0.88% at pH 6.42 (Stebler & Guentert 1990). The casein fraction was shown to be the major binding component in milk. As casein concentrations in milk drop during the first few days postpartum from 25 to 5 gIL, a higher milk to plasma ratio can be expected in the first few days postpartum compared with that expected later during lactation. However, the clinical significance of this is minor,
Tenoxicam Pharmacokinetics
due to the low total concentration of tenoxicam in human breastmilk.
5. Pharmacokinetic Drug Interactions Tenoxicam drug interactions can be divided into 2 major categories: effects of other drugs on tenoxicam and effects of tenoxicam on other drugs. Changes in pharmacokinetic parameters for a drug will alter the C ~~ in accordance with the following equation: C ~~ =(F x D)/(CL x 't) This equation demonstrates that changes in the extent of absorption (F) of an oral dose (D) will produce proportional changes in the C ~~. Similarly, changes in CL or dosage frequency ('t) will produce inversely proportional changes in the C ~~. In the following sections, no interactions of a pharmacodynamic nature are mentioned. A comprehensive review of pharmacokinetic drug interaction profile of several NSAIDs has recently been published (Verbeeck 1990). 5.1 Effect of Other Drugs on Tenoxicam Pharmacokinetics 5.1.1 Absorption Effects of antacids on the single dose absorption of tenoxicam are summarised in table XIII. Despite the observation of a significant decrease in absorption half-life and increase in tmax of tenoxicam in the presence of ambutonium bromide, the extent of tenoxicam absorption, remained essentially unchanged (Francis et al. 1985). The absorption of tenoxicam is not influenced by aluminium or magnesium hydroxides (Day et al. 1987). This implies that these antacids will not significantly change the steady-state concentration or efficacy of tenoxicam during multiple-dose administration, although extrapolation to the effects of long term antacid therapy on long term tenoxicam treatment should be made with care. Ingestion of food with aluminium hydroxide appeared to protect against possible aluminium-induced reductions in tenoxicam bioavailability, and a combination of magnesium and aluminium hydroxides was thought to
37
be preferred to aluminium hydroxide alone when antacid and tenoxicam are taken concomitantly (Day et al. 1987). In the latter case, however, clinical benefits may be marginal. Concomitant administration of cimetidine does not appear to influence the rate or extent of tenoxicam absorption (Heintz & Guentert 1987). The risk of a clinically significant interaction of antacids with NSAID absorption is believed to be small, but cannot be totally excluded (Gugler & Allgayer 1990). This also seems to apply for tenoxicam. 5.1.2 Protein Binding Steady-state concentrations of aspirin (acetylsalicylic acid) were reported to significantly change pharmacokinetics of tenoxicam after single and multiple doses in healthy volunteers (Day et al. 1988a; table XIII). The dose of aspirin was reduced for some study participants to 3.25 or 2.6 g/day. Single doses of tenoxicam were administered before and along with aspirin at steady-state. Repeated doses of tenoxicam were given with aspirin at steady-state and after discontinuation of aspirin. Aspirin (150 mg/L) was shown to compete with tenoxicam (1 to 20 mg/L) for plasma albumin binding sites, creating a significant increase in the unbound concentration of tenoxicam in plasma (0.56 to 1.24%) [Day et al. 1988a]. This displacement is thought to be the main reason for the significant increase in tenoxicam elimination when the drug is given with aspirin. The same interaction has been reported between aspirin and other NSAIDs (Day et al. 1984). 5.1.31ntestinal Binding Oral cholestyramine appears to approximately double the CL of a single oral or intravenous dose of tenoxicam (Benveniste et al. 1990; Guentert et al. 1988; table XIII). Since the distribution of tenoxicam was not affected by cholestyrarnine, a decrease in the Viz of the drug was found (Guentert et al. 1988). Cholestyrarnine is not absorbed after oral administration, so the mechanism behind this interaction is thought to be binding of intestinally available tenoxicam.
Clin. Pharmacokinet. 26 (1) 1994
38
Table XIII. Pharmacoklneltc Interactions between tenoXlcam and other drugs after oral administration to healthy volunteers No. of
Drug
Dose
volunteers 6
Ambutomum bromide
SD 15ml
AI(OH)2, Mg(OH)2
SD 15ml
Dose of
Site of
Pharmacoklnetic
tenoXlcam (mg)
interaction
consequences for tenoXlcam (%)
SD40
Absorption
t'/,!a.J..161
Reference
FrancIs et al. (1985)
C max .J..18 t max 1104
12
Aspirin 13ga (acetylsalicylic aCid)
8
SD20
Absorption
No slgmflcant effects
Day et al. (1987)
SD20
Protein binding
C max .J..23
Day et al. (1988a)
11/,!.J..24 Vss 149 Cll98 FI121
AspIrin
5
1.3gb
20c
Protein binding
C.J..44
Day et al. (1988a)
Cll81 Cholestyramine
6
8gd
SD20
Intestinal binding
t'f.!.J..51
Benvemste et al
Cl i 112
(1990)
AUC.J..57 8
Cholestyramlne
4g8
SD20lV
Intestinal binding
t,/,!.J..53 Cl i 105
a
Three times dally for 22 days.
b
Three times dally for 34 days
c
Once daily for 34 days.
d
Three times dally for 4 days
e
Three times dally for 10 days
Abbreviations and symbols: IV = Intravenous, SD = Single dose, .J.. = decreased,
i
Guentert et al. (1988)
= Increased, for other abbreviations, see tables
I, IV and VII
5.2 Effects of Tenoxicam on the Pharmacokinetics of Other Drugs NSAIDs are among the most widely used drugs and are often administered over a long period. An important clinical question is the possibility of drug-drug interactions in patients on maintenance therapy with tenoxicam who are receiving concurrent treatment with drugs with a more narrow therapeutic index than seen in NSAIDs. 5.2.1 Unspecified Sites No significant changes from normal were observed in the urinary excretion of furosemide (frusemide) or in the steady-state trough plasma concentrations of tenoxicam during repeated coadministration of tenoxicam 20mg daily and furosemide 40mg daily for 7 days to 12 patients. The mean age was 59 ± 10 years and all had mild heart
insufficiency and needed anti-inflammatory treatment (Hartman et al. 1987). In a single-blind, placebo-controlled study, 16 healthy volunteers received glibenclamide (glyburide) 2.5mg once daily for 12 days, the last 7 days in combination with a daily oral dose of tenoxicam 20mg or placebo (Hartmann et al. 1990). During coadministration, tenoxicam did not affect the AUC of glibenclamide. Other pharmacokinetic parameters for glibenclamide were difficult to calculate because of several double peaks in the plasma profile of this drug. The CLIP of tenoxicam (0.150 ± 0.090 L/h) was in the upper range compared with that reported previously for healthy volunteers, and the trough steady-state concentration (5.7 ± 2.5 mg/L) was in the lower range. It was concluded that tenoxicam did not affect the pharmacokinetics of glibenclamide or overall glycoregulation in healthy volunteers at steady-state, but
Tenoxicam Pharmacokinetics
that glibenclamide could influence tenoxicam pharmacokinetics, although without affecting tenoxicam efficacy (Hartmann et al. 1990). In another interaction study, 8 healthy volunteers received a single intravenous dose of glibornuride 25mg on the flrst study day. After a 7-day washout period, tenoxicam 20 mg/day was administered for 14 days. On the last day of tenoxicam administration, another 25mg intravenous dose of glibornuride was coadministered (Stoeckel et al. 1985). The C i~ of 8.6 ± 3.9 mg/L did not affect the CL, Vd, volume of distribution at steadystate (Vss) or tY2 of glibornuride. The C ~~ of tenoxicam and the AUC (over 0 to 24 hours) at steadystate in presence of glibornuride were similar to literature data on tenoxicam alone. It was concluded that tenoxicam did not interfere with the single-dose pharmacokinetics of glibornuride nor did a single dose of glibornuride affect the steady pharmacokinetics of tenoxicam. Tenoxicam also did not affect the response of plasma insulin or blood glucose to glibornuride (Stoeckel et al. 1985). Tenoxicam has also been reported not to show clinically significant interactions with hydrochlorothiazide, phenprocoumon or warfarin (Eichler et al. 1992; Guentert et al. 1987; Heintz & Guentert 1987).
6. Clinical Considerations and Conclusions With exception of aspirin, most NSAIDs are well absorbed from the gastrointestinal tract. NSAIDs are in general highly bound to plasma albumin, metabolised by liver microsomal enzymes and conjugated with glucuronic acid. Their rates of metabolism and conjugation are the rate-limiting steps for elimination and excretion. The renal excretion of unchanged drug is low, usually less than 5 % of the dose. The high binding of NSAIDs to plasma albumin, high degree of ionisation and low lipophilicity limit signiflcantly their tissue distribution. Thus, their Vd values are low (usually < 20L) and CL is usually < 12 Lih. However, great differences exist between the different classes of NSAIDs with respect to tY2 values, synovial fluid
39
to plasma concentration ratios over time, the influence of sex, age and illness, and drug-drug interaction proflles. For reviews, see Rainsford (1988); Schmitt & Guentert (1989); Verbeeck (1990); Verbeeck et al. (1983); Wallis & Simkin 1983). Tenoxicam has lower lipophilicity (octanol to water partition coefficient 0.3,) higher plasma protein binding ("" 99%), higher binding constant in human serum (2.7 x 105 Limo!), and lower pKa values (pKa 5.34 and 1.07) than most other NSAIDs, including most oxicams (Bernhard & Zimmermann 1984; Fenner 1987). These factors extensively restrict the tissue distribution of tenoxicam and its capacity for diffusion into hepatic cells. They also contribute to a low Vd of about 7 to 12L, a low hepatic extraction ratio, and CL of about 0.080 to 0.150 Lih. Since tenoxicam is eliminated almost completely by metabolism, less than 0.5% of an oral dose is excreted unchanged in urine. With its slow metabolism, the drug is also eliminated slowly. This is illustrated by a long ty2, ranging between different groups of patients from about 42 to 81 hours. This degree of variation is similar to that observed for other NSAIDs. Tenoxicam exhibits linear single dose pharmacokinetics in healthy volunteers over doses from 10 to 100mg, demonstrating no saturation of elimination pathways (metabolism) in the expected clinical range of plasma concentrations. Thus, from single-dose studies, the drug seems to possess pharmacokinetic properties which make a controlled and reliable dosage of the drug feasible. This seems valid also for patients with rheumatic diseases, impaired renal function, liver cirrhosis and for the elderly. The long tY2 of tenoxicam means that it takes 10 to 15 days to reach steady-state. Plasma concentrations at steady-state after multiple doses should be 5 to 6 times higher than those observed after single doses, when based on single-dose pharmacokinetic parameters and linear pharmacokinetics. The 6 to 18% greater accumulation of tenoxicam than that predicted from single-dose data is thought to be of minor clinical significance in a multiple-dose regimen and can be ignored when considering the in-
40
terindividual variation in plasma steady-state concentrations. The small discrepancy from linearity was similar in healthy volunteers, patients with rheumatic diseases or renal impairment, and in the elderly, demonstrating a high degree of homogeneity between different categories of patients. No statistically significant differences have been reported between healthy volunteers, patients with rheumatic diseases, renal or liver impairment, and the elderly in either single- or multiple-dose pharmacokinetics oftenoxicam (patients with liver impairment were included in single-dose studies only). Thus, no dosage adjustments seem to be required for any of these groups. However, in patients with liver cirrhosis and plasma bilirubin levels above 100 to 200 IlmollL, a significant increase in the unbound plasma tenoxicam concentration may occur. Care should, therefore, be taken in multiple-dose administration of tenoxicam to these patients, since the possible consequences of this increase in unbound plasma concentration at steady-state are unknown in this patient group. The Cmax of both total and unbound tenoxicam was reached much later in synovial fluid than in plasma, indicating slow distribution of tenoxicam. If the presence of tenoxicam in the synovial fluid is the most clinical relevant parameter for efficacy, the rate-limiting factor for initial efficacy would be its distribution rate to the synovial fluid, thus making the absorption rate of tenoxicam a poor indicator for the onset of an effect. The diffusion rate for a molecule from plasma into the synovial fluid is diffusion-limited, more inhibited for hydrophillic molecules than for fatsoluble ones, and partly also depends on the degree of plasma and synovial fluid protein binding (Wallis & Simkin 1983). Diffusion of protein-bound ibuprofen has also been reported in some patients (Graham 1988). After considering pH variability in the synovial fluid of patients with rheumatic diseases and its consequences for synovial concentration of unbound ionised tenoxicam, the reported high interindividual variation in synovial fluid to plasma concentration ratio of both total and un-
Clin. Pharmacokinet. 26 (1) 1994
bound tenoxicam (Day et al. 1991) is not surprising. For NSAIDs with a short tY2, such as ibuprofen (Day et al. 1988b) the decline in synovial fluid concentration is slower than that in plasma, resulting in smaller fluctuations in the synovial fluid concentration over a dosage interval at steady-state than are seen in plasma. This is explained by slower diffusion of ibuprofen from the synovial fluid into plasma than the elimination rate of ibuprofen from plasma. For tenoxicam, the diffusion rate from the synovial fluid into plasma (t~ ",,1.4 to 10.5 hours) [Bird et al. 1985a], is much faster than elimination of tenoxicam from plasma. This brings forward a parallel decline of tenoxicam in the synovial fluid and serum. Thus, at steadystate there are small and similar fluctuations of tenoxicam concentrations over a dosage interval in both the synovial fluid and plasma. This makes plasma concentrations of tenoxicam a more reliable measure of changes in synovial fluid concentrations than it is for NSAIDs with short tY2 values. NSAIDs are among the most frequently prescribed drugs worldwide. Of NSAID-tenoxicam interactions, only that with high doses of aspirin may be clinically significant, increasing tenoxicam elimination significantly. To avoid an increased risk of adverse effects, this combination should be avoided (Guentert et al. 1987). In general, there is also thought to be little rationale for combination of NSAIDs with oral aspirin in the treatment of rheumatic diseases (D' Arcy 1989). None of the reported interactions between tenoxicam and antacids are considered to be of clinical significance. The most relevant interactions clinically are, however, those between NSAIDs and oral anticoagulants or oral hypoglycaemic agents. Several clinically significant interactions between NSAIDs and drugs with narrow therapeutic indexes have been reported, and recommended actions have been published (Verbeeck 1990), among these the use of alternative NSAIDs. Tenoxicam has a low potential to interact with other drugs, such as commonly used diuretics, hypoglycaemic drugs, anticoagulants or H2-antagonists (Heintz &
Tenoxicam Pharmacokinetics
Guentert 1987), and can be considered as an alternative to other NSAIDs in combined therapy. However, careful monitoring is recommended for patients receiving tenoxicam with either anticoagulants or oral antidiabetic agents (Todd & Clissold 1991). The efficacy and tolerability of tenoxicam have been investigated during different dosage regimens (Vischer 1987). A daily dose of 20mg was optimal, while 10mg was suboptimal and doses greater than 20mg did not significantly increase efficacy. With observations for up to 1 year in 4415 treated patients, the number of reported adverse effects increased from 13.3 to 18.4% when the daily dosage was increased from 20 to 40mg. In conclusion, tenoxicam shows nearly linear pharmacokinetics, with predictable steady-state concentrations after multiple doses. No significant differences are observed in the pharmacokinetics of tenoxicam in healthy volunteers, patients with rheumatic or inflammatory diseases, renal failure, liver cirrhosis or in elderly. Thus, no dosage adjustments seem to be required for these categories of patients. Multiple-dose pharmacokinetics of tenoxicam in patients with liver cirrhosis and high levels of bilirubin should be further evaluated, as should protein binding in plasma and synovial fluid and possible binding differences between different categories of patients. The long Viz and small fluctuations in tenoxicam concentrations in both plasma and synovial fluid justify single daily doses. In evaluations of efficacy, the low pH in the synovial fluid should be considered, as this produces a lower unbound concentration of the drug in synovial fluid than in plasma. The pharmacokinetic properties of tenoxicam and its low interaction profile towards other drugs make tenoxicam a useful supplement to existing NSAlDs.
References AI-Ghamdi MS, AI-Mohanna FA, AI-Mustafa ZH, AI-Saed IS. The effect of haemodialysiS on the phannacokinetics of tenoXlcam m patients with end-stage renal disease. European Journal of Clinical Phannacology 43: 197-199, 1992 Bannwarth B, Netter P, Lapicque F, Mamard D, Fener P, et aI. Tenoxicam concentrations in synovium and joint cartilage m humans Agents and Actions 32: 295-298, 1991
41
Benveniste C, Striberni R, Dayer P. IndIrect assessment of the enterohepatic recirculation of plfOxicam and tenoxicam. European Journal of Clinical Phannacology 38: 547-549, 1990 Bernhard E, ZImmermann F. Contribution to the understanding of OXlcam lOmzatIon constants. Drug Research 34: 647-648, 1984 Bird HA. Clinical experience with tenoXIcam: a review. Scandmavian Journal of Rheumatology (Suppl. 65): 102-106, 1987 BIrd HA, Allen JG, Dixon JS, Wright V. A phannacokinetic comparison of tenoxicam in plasma and synOVIal flUId. Bntish Journal of Rhemnatology 24: 351-356, 1985a Bird HA, Clarke AK, Fowler PD, Little S, Podgorski MR, et al. An assessment of tenoxicam, a nonsteroidal antiinflanunatory drug of long half-life, m patIents WIth Impaired renal function suffenng from osteoarthritis or rheumatoid arthntis. Clmical Rheumatology 8: 453-460, 1989 Bird HA, Francis RJ, Le Gallez P, HIll J, Dixon JS, et al. Single and multiple oral dose phannacokmetics of tenoxicam in the elderly. European Journal of Rheumatology and Inflanunation 8: 60-69, 1985b Bree F, Nguyen P, Urien S, Riant P, Albengres E, et al. Blood drstribution of tenoxicam in humans: a particular HSA drug mteraction. Fundamentals in Clinical Phannacology 3: 267-279, 1989 Clive DM, Stoff JS. Renal syndromes associated with non-steroidal antI-mflanunatory drugs. New England Journal of Medrcme 310: 563-572, 1984 Colburn WA. EstImatIng the accumulation of drugs. Journal ofPharmaceutical SCIences 72: 833-834, 1983 Corvetta A, Della Bitta R, Luchetti MM, Pompomo G, CiuffolettI V. TenOXIcam and ketoprofen level momtoring WIth high performance liqUId chromatography in patients affected by rheumatOId arthritis. Chmcal and ExperinIentai Rheumatology 9: 143-148, 1991 Crevoisier C, Gerber N, Ott H, Meyer J, Heizmann P. Simultaneous phannacokinetics of tenoXIcam m plasma and synovial fluid. Abstract P369. 1st World Conference on Inflammation Antirhemnatics, Analgesics and Immunomodulators, Venice, April 16-18, 1984, Congressbook II, 1984 Crevoisier C, HelZmann C. Phannacokinetics of tenoXlcam LItera Rheumatoiogia 5: 7-14, 1986 CrevOIsier C, Heizmann P, Forgo I, Dubach UC. Plasma tenoXlcam concentratIons after single and multIple oral doses. European Journal of Drug Metabolism and PhannacokInetIcs 14 (1): 23-27, 1989a Crevoisier CH, Zaugg PY, Heizmann P, Meyer J. Influence of liver cirrhosis upon the phannacokInetics of tenoXlcam. InternatIonal Journal of CIIDlcai Pharmacology Research 5: 327-334, 1989b Cummings NA, Nordby GL. Measurement of SynOVIal flUId pH m normal and arthntIc knees. ArthntIs and Rheumatism 9: 47-55, 1966 D' Arcy PF. Drug reactIons and mteractIons: aspirin-tenoxicam interaction. International Phannacy Journal 2: 44-46, 1989 Day RO, Gralram GG, ChampIon GD, Lee E AntI-rheumatIc drug mteractIons. Clinics m Rheumatic DIseases 10 (2): 251-275, 1984 Day RO, Lam P, Paull P, Wade D. Effect of food and various antaCIds on the absorptIon of tenoXlcam. Bntish Journal of ClInical Pharmacology 24: 323-328, 1987 Day RO, Paull PD, Lam S, Swanson BR, Williams KM, et aI. The effect of concurrent aspirin upon plasma concentrations of tenoxicam. British Journal of Clinical Phannacology 26: 455-462, 1988a Day RO, Williams KM, Gralram S, Handel M. The phannacokinetIcs of total and unbound concentratIons of tenoXlcam m synovial fluid and plasma. Arthntis and RheumatIsm 34: 751-760,1991 Day RO, Williams KM, Gralram GG, Knihimcki RD, Lee EJ, et aI. Stereoselective drspOSItIon of ibuprofen enantiomers m SynOVIal flnid. ClinicalPhannacology and Therapeutics 43: 480-487, 1988b Dell D, Joly R, MeIster W, Arnold W, Partos C, et al. Deternrination of tenoxicam, and the IsolatIon, identification and deternrination
42
of RO 17-6661, its major metabolIte, m human unne. Journal of Chromatography 317: 483-492,1984 DIXon JS, Lowe JR, Galloway DB. Rapid method for the determmatIon of eIther prrOlGCam or tenoxicam in plasma usmg high-performance liqwd chromatography. Journal of Chromatography 310: 455-459, 1984 Eichler HG, Jung M, Kyrle PA, Rotter M, Korn A. Absence of interactIon between tenoxlcam and warfann. European Journal of ClInical Pharmacology 42 (2): 227-229, 1992 Enz W, Jeunet F. TenOXlcam mIlk formulatIon m the treatment of rheumatic conditions. Scandinavian Journal of Rheumatology (Suppl. 80): 54-58, 1989 Fenner H. ComparatIve bIOchemIcal pharmacology of the OXlcams. Scandmavlan Journal of Rheumatology (Suppl. 65): 97-101, 1987 Francis RJ, Allen JG, Lom D, DIxon JS, BIrd HA, et al. PharmacokmetIcs of tenoXlcam after oral adminIstration m healthy human subjects of vanous smgle doses European Journal of Drug MetabolIsm and Pharmacokinetics 12 (1): 59-63, 1987 FranCIS RJ, DIxon JS, Lowe JR, Hams PA. The effect of food and of antaCId on the single oral dose pharmacokinetIcs of tenoXlcam. European Journal of Drug Metabolism and Pharmacokinetics 10 (4): 309-314, 1985 Freestone S, McAuslane JAN, Prescott LF. Effect of tenoxlcam on renal functIon and the dIspOSItIon of mulm and p-aminohIppurate in healthy volunteers and patIents WIth chronic renal failure. BritIsh Journal of ClInical Pharmacology 32: 495-500, 1991 Ghose K, Burch A Measurement of renal functIons by double ISOtope techmques m elderly patIents durmg tenoXlcam therapy. ArchIves of Gerontology and Genatry 9: 115-122,1989 Giovannom J-L, Ott H, Torrente de A. Le tenoXlcam et la fonction renale: etude prospectIve a court et long termes. Schweltzerische Medtzimsche WochenschrIft 120. 793-797,1990 Gonzales JP, Todd PA TenoXlcam: a prelimInary revIew of ItS pharmacodynamIC and pharmacokinetic properhes, and therapeutIc efficacy. Drugs 34: 289-310, 1987 Graham GG. KmetIcs of non-steroidal anti-mflammatory drugs m synovial fluid. Agents and ActIons 24: 66-75, 1988 Guentert TW, Defom R, Mosberg H. The mfluence of cholestyramine on the elimination of tenoxicam and piroxicam. European J ournal of Climcal Pharmacology 34' 283-289, 1988 Guentert TW, Hemtz RC, Joly R. OvervIew on the pharmacokinetIcs of tenoXlcam. European Journal of Rheumatology and JnflanrrnatIon 9: 15-25, 1987 Gugler R, Allgayer H. Effects of antacIds on the climcal pharmacokinetics of drugs: an update. Clinical PharmacokmetIcs 18: 210219, 1990 Hartmann D, Klembloesem CH, Lucker PW, Vetter G. Study on the pOSSIble mteraction between tenoxlcam and furosemIde. Drug Research 37: 1072-1076, 1987 Hartmann D, Korn A, Komjati M, Heinz G, Haefelfinger P, et al. Lack of effect of tenoXlcam on dynamic responses to concurrent oral doses of glucose and glIbenciamIde. BntIsh Journal of Pharmacology 30: 245-252,1990 Hemtz RC, Ducarre IM, Bloum RA, Guenzl A. Influence of oral dose escalatIon on the pharmacokmetIcs of tenoXlcam m healthy male subjects. Litera Rheumatologia 10. 9-15, 1988 Hemtz R, Guentert TW. PharmacokmetIc profile of tenoxicam. In Fenner (Ed.) Tenoxicam, a new nonsterOIdal antI-mfIanrrnatory drug, pp. 23-34, Eular, Basel, 1987 Hemtz RC, Guentert TW, Enrico JF, Dubach DC, Brandt R, et al. PharmacokmetIcs of tenoXlcam m healthy human volunteers. European Journal of Rheumatology and InflanrrnatIon 7' 33-44, 1984 Helzmann P, Komer J, Zmapold K. DetefIDlfiatIon of tenoXlcam m human plasma by hIgh-performance IIqwd chromatography. Journal of Chromatography 374: 95-102, 1986 Hmderling PH, Hartmann D, CrevOlsier C, Moser D, Heizmann P. Integrated plasma and synoVIal flwd pharmacokmetics of tenOXlcam in patients with rheumatoid arthritis and osteoarthntIs: fac-
CUn. Pharmacokinet. 26 (1) 1994
tors detenmnmg the synovial fluid/plasma dIstrIbutIon ratio. Therapeutic Drug Momtormg 10: 250-260, 1988 Horber FF, Guentert TW, Weldekanrrn E, Helzmann P, Descoeudres C, et al. PharmacokmetIcs of tenoXlcam m patIents WIth rrnparred renal functIon European Journal of Climcal Pharmacology 29: 697-701,1986 IchIhara S, Tomlsawa H, Fukazawa H, Tatelshl M, Joly R, et al. OXldatIon of tenoxlcam by leukocyte peroxldases and H202 produces novel products. Drug MetabolIsm and DIspOSItion 17: 463468, 1989 IchIhara S, TsuynkI Y, Tomlsawa H, Fukazawa H, Nakayama N, et al. Metabolism of tenoXlcam in rats. XenobiotIca 14: 727-739, 1984 Jeunet F, Enz W, Guentert T. Tenoxlcam used as a parenteral formulatIon for acute pain in rheumatIc condItions. ScandInavian Journal of Rheumatology (Suppl. 80): 59-61, 1989 Juhl RP, Van Thiel DM, Dlttert LW, Albert KS, Smith RB.lbuprofen and sulindac kmetIcs in alcoholic lIver dIsease ClImcal Pharmacology and Therapeutics 34: 104-105, 1983 Kobayashi S, Oba T, OguchI K, Sakamoto K, Yasuhara H, et al. Pharmacokmetics of tenoXlcam m healthy volunteers and elderly patIents. Japanese Journal of Clinical Pharmacology 15: 399-405, 1984 McAuslane JAN, Freestone S, Cowie J, Prescott LF. TenOXlcam: effect on renal function in normal man. BntIsh Journal of Chmcal Pharmacology 25 (1). 93-94, 1988 NIlsen OG, Walstad RA, Eckert M, Heizmann P, Buckert A, et al. Single and multiple dose pharmacokmetIcs of tenoxicam in the elderly. European Journal of ClImcal Pharmacology 35: 563-566, 1988 PICkup ME, Lowe JR, Galloway DB. DetenninatIon ofRo 12-0068, a new antI-mflanrrnatory and analgesIc compound, m plasma by means of high performance IIqwd chromatography. Journal of Chromatography 225: 493-497,1981 Ramsford KD. Novel non-sterOIdal antI-mflanrrnatory drugs. Brulliere's Clinical Rheumatology 2: 485-511, 1988 RIchardson CJ, B10cka KLN, Ross SG, Verbeeck RK. Effects of age and sex on prroxlcam dIspositIon. Climcal Pharmacology and Therapeutics 37: 13-18, 1985 RIchardson CJ, Blocka KLN, Ross SG, Verbeeck RK. Prroxicam and 5'-hydroxyplroxlcam kmetIcs followmg multiple dose ruhninistratIon of plroxlcam. European Journal of ClImcal Pharmacology 32: 89-91,1987 SchmItt M, Guentert TW. Effect of age on the pharmacokmetIcs of tenoxlcam m companson to other non-steroidal antI-inflammatory drugs (NSAIDs). ScandInavian Journal of Rheumatology (Suppl. 80): 86-89, 1989 Schnlltt M, Kolle D, Stockel K, Heizmann P, Vetter A, et al. PharmacokmetIc profIle of tenoxlcam in elderly patients with rheumatoid arthritIs. LItera Rheumatologla 10: 25-31, 1988 Simon P, Meyner A, Bnssot P. Dremia and the lIver: drugs and the liver m uremIC patients. Nephron 29: 7-13, 1981 Stebler T, Guentert TW. Binding of drugs in milk' the role of casem m nulk protem bmdIng. Pharmaceutical Research 7 (6): 633-637, 1990 Stoeckel K, Trueb V, Dubach DC, Heintz RC, Ascalone Y, et al. Lack of effect of tenoxicam on glibornnride kinetIcs and response. BritIsh Journal of Chmcal Pharmacology 19: 249-254, 1985 Sugawara S, et al. TenOXlCam. Japanese Pharmacology and Therapeutics 12:4527-4539, 1984 Swam JA, Heyndnckx GR, Boettcher DH, Varner SF. ProstaglandIn control of renal crrculatIon m the unanesthetIzed dog and baboon. Amencan Journal of PhYSIOlogy 229: 826-830, 1975 Tamrrnura H, Mukruhara S, Mme Y, Yotsumoto F, Setoyama M, et al. BIlIary excretIon of tenoxicam m cholecystectomIzed patIents. NIppon Geka Hokan (ArchIv fUr Japanlsche Chrrurgie) 53: 779785, 1984
43
Tenoxicam Pharmacokinetics
Todd PA, Clissold SP. Tenoxicam: an update of its phannacology and therapeutic efficacy in rheumatic diseases. Drugs 41: 625-646, 1991 Verbeeck RK. Phannacokinetic drug interactions with nonsteroidal anti-inflammatory drugs. Clinical Pharmacokinetics 19: 44-66, 1990 Verbeeck RK, Blackburn JL, Loewen GR. Clinical pharmacokinetics of nonsteroidal anti-inflammatory drugs. Clinical Pharmacokinetics 8: 297-331,1983 Vischer TL. Efficacy and tolerability of tenoxicam: an ·overview. European Journal of Rheumatology and Inflammation 9: 51-57, 1987 Wallis WJ, Simkin PA. Antirheumatic drug concentrations in human synovial fluid and synovial tissue: observations on extravascular phannacokinetics. Clinical Phannacokinetics 8: 496-522, 1983
Wanwimolruk S, Brooks PM, Birkett DJ. Protein binding of non-steroidal antiinflammatory drugs in plasma and synovial fluid of arthritic patients. British Journal of Clinical Pharmacology 15: 91-94, 1983 WoolfTF, Radulovic LL. Oxicams: metabolic disposition in man and animals. Drug Metabolism Reviews 21 (2): 255-276, 1989 Zhao J, Leemann T, Dayer P. In vitro oxidation of oxicam NSAIDs by a human liver cyctochrome P450. Life Sciences 51 (8): 575581,1992
Correspondence and reprints: Professor Odd G. Nilsen, Department of Pharmacology and Toxicology, Medical Technical Centre, 7005 Trondheim, Norway.
Second International Symposium on
Measurement and Kinetics of In Vivo Drug Effects Date: 14-16 April 1994 For further information, please contact: Symposium Secretariat Mrs F.J. Velthorst LACDR
P.O. Box 9502 2300 RA Leiden THE NETHERLANDS Tel.: 31 71 274341 Fax: 31 71274277
