CJin. Pharmacokinet. 1997 Sep; 33 (3); 184-213 031 2-5963/97 /CXXl9-D 184/$ 15.00/0
DRUG DISPOSITION
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Clinical Pharmacokinetics of Diclofenac Therapeutic Insights and Pitfalls Neal M. Davies 1 and Keith E. Anderson2 1 Faculty of Medicine, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada 2 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Contents Summary ......... . . 1. Analytical Methods . . . . . 2. Pharmacokinetic Properties 2.1 Absorption. 2.2 Distribution. 2.3 Metabolism 2.4 Elimination . 3. Implications of Pharmacokinetic Properties for Therapeutic Use 3.1 Dose, Therapeutic Range and Concentration/Effect Relationships 3.2 Diclofenac Pharmacokinetics and Disease States . 3.3 Influence of Age on Diclofenac Pharmacokinetics . . . . . . 4. Pharmacokinetic Drug Interactions . . . . . . . . . . . . . . . . . . 4.1 Effect of Other Drugs on the Pharmacokinetics of Diclofenac 4.2 Effect of Diclofenac on the Pharmacokinetics of Other Drugs . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary
184 185 185 185 195 198 199
200 200
202 204 204 204
206 208
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class. When given orally the absorption of diclofenac is rapid and complete. Diclofenac binds extensively to plasma albumin. The area under the plasma concentration-time curve (AUC) of diclofenac is proportional to the dose for oral doses between 25 to 150mg. Substantial concentrations of drug are attained in synovial fluid, which is the proposed site of action for NSAIDs. Concentration-effect relationships have been established for total bound, unbound and synovial fluid diclofenac concentrations. Diclofenac is eliminated following biotransformation to glucoroconjugated and sulphate metabolites which are excreted in urine, very little drug is eliminated unchanged. The excretion of conjugates may be related to renal function. Conjugate accumulation occurs in end-stage renal disease; however, no accumulation is apparent upon comparison of young and elderly individuals. Dosage adjustments for the elderly, children or for patients with various disease states (such as hepatic disease or rheumatoid arthritis) may not be required.
185
Clinical Pharmacokinetics of Diclofenac
Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), lithium, digoxin, methotrexate, cyclosporin, cholestyramine and colestipol.
DicIofenac {2-[(2,6-dichlorophenyl)amino]phenylacetate} is a phenylacetic acid nonsteroidal antiinflammatory drug (NSAID) and is a potent inhibitor of prostaglandin synthesis. [1) For the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and acute gouty arthritis therapeutic doses of diclofenac have been proven to be equiefficacious when compared with other commonly used NSAIDsP,3) Diclofenac exhibits potent analgesic effects and is used clinically for the short term alleviation of post-operative pain, dysmenorrhoea and in various ocular conditionsp-4) Gastrointestinal complications are the most common adverse effect of diclofenac, however, renal dysfunction and hypersensitivity reactions can also occurp·3) General review articles are available which deal with the pharmacological properties and therapeutic indications of diclofenacp-5) however these articles do not discuss in detail the unique features ascribed to the clinical pharmacokinetics of diclofenac. This article reviews the clinical pharmacokinetics of diclofenac. 1. Analytical Methods Several analytical methods are available for quantitative analysis of diclofenac in biological specimens (table I). Earlier methods employed high performance thin-layer chromatography,[6) gas chromatography,[6.IO,1l,32,47) gas chromatography-mass spectrometry[15,20,21,23,27,36,40) and also radioisotopes)52,53) However, because of the need for greater precision and facile sample preparation, these methods have largely been replaced by the use of high performance liquid chromatography (HPLC). [7-9, 12, 14, 16, 18, 19,22,26,28,30,31 ,33-35,37,39,42-45,49,51) The analytical methods are capable of quantifying total monohydroxylated metabolites of diclofenac,[54) each metabolite separately[46) or the majority of individual metabolites)17,29,30,38,40,48,50) More recently, analysis has been accomplished us© Adis internationai Limited. All rights reserved.
ing micellar electrokinetic capillary chromatography and capillary zone electrophoresis, however, the application of this to pharmacokinetic studies remains limited)55) 2. Pharmacokinetic Properties 2.1 Absorption
Diclofenac is most often administered orally, but it has also been administered topically, intravenously, intramuscularly, intracolonically and rectally. Conventional regular release tablets and capsules, enteric-coated tablets, sustained-release preparations, suspensions, gels, suppositories, ampoules and optic drops are commercially available. The systemic absorption of dicIofenac is directly proportional to the dose within the range of 25 to 150mg)56-58) Administration of multiple doses yields absorption characteristics which are similar to those seen following single doses.[25,52,57,59-61) Absolute bioavailability of 90 ± 11.6% is reported following the oral administration of a single dose of [14C]diclofenac 50mg)52,59) There are conflicting reports which suggest that diclofenac undergoes first pass metabolism with about 60% of the drug reaching the systemic circulation as intact diclofenac)57,62) Absorption characteristics for diclofenac are not significantly different when comparing disease states or age effectsPO,63,64) However, 1 study has suggested that elderly patients with osteoarthritis have a reduced hepatic clearance, leading to an increased peak plasma drug concentration (C max ), area under the concentration-time curve (AVC) and bioavailability)65) Colonoscopy has been performed in order to examine the capacity of the colonic mucosa for absorption of diclofenac. Oral and colonic administration resulted in comparable C max and AVe. The relative bioavailability of dicIofenac from the colon ranged from 54 to 109% with a mean of78%. There Clln. Pharmacokinet. 1997 Sep; 33 (3)
Davies & Anderson
186
Table I. Chromatographic assays for diclofenac Specimen
MOC (mg/L)
Volume
Serum
0.01
1.0
Serum
0.025
0.5 0.1
Reference
Serum
0.02
Serum
0.01
1.0
Blood/serum/plasma
0.1
2.0
Plasma
1.0
0.5
6 7 8 9 10 11
Plasma
0.2
0.2
12
Plasma
0.1
1.0
Plasma
0.005
0.5
Plasma
0.002
1.0
13 14 15
Plasma
0.Q1
1.0
16
Plasma
0.0000095
0.5
17
Plasma
0.02
0.03-0.2
18
Plasma
0.01
0.5
Plasma
0.4
0.2
Plasma
0.000002
0.5
Plasma
0.000001
0.5
18 19 20 21
Plasma
0.0005
0.5
22
Plasma
0.002
0.5
23
Plasma
0.02
1.0
24
Plasma
0.Q1
1.0
25
Plasma
0.005
1.0
26
Plasma
0.002
1.0
27
Plasma
0.01
0.5
28
Plasma
0.000006
0.050
29
Plasma
0.0007
0.5
30
Plasma
0.001
0.2
Plasma
0.005
NR NR
31 32 33
Plasma
0.Q1
Plasma
0.0010
0.5
34
Plasma
0.025
0.2
35
Plasma
0.000001
36
38
Rabbit plasma
1.0
1.0 0.1
Urine
0.25
0.05
Urine
0.01
Urine
0.2
0.25
Urine
0.000001
5.0
39 40 41
Plasma/synovial fluid
0.005
0.5
42
Plasma/synovial fluid
0.001
0.5
Plasma/synovial fluid
0.Q1
0.5
43 44
10.0
37
Serum/plasma
0.05
2.0
45
Cerebrospinal fluid
0.0002
0.5
30
Plasma/urine
0.01/0.2
1.010.25
Plasma/urine
0.1
1.0
46 47 48
Plasma/urine
0.0212.5
0.1/0.1
Plasma/urine
0.211.0
0.511.0
49
Cell suspensions
0.005
1.0
50
Ocular fluids
0.003
0.1
51
Abbreviations: MOC = reported minimum quantifiable concentration ; NR not reported.
=
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was no differences in absorption after diclofenac administration to the cecum or splenic flexure. Rectal absorption may bypass the liver with a corresponding reduction in first-pass metabolism, which may explain the higher bioavailability in 1 patient after administration of diclofenac into the splenic flexure.[66] Table II shows the absorption properties of diclofenac when administered in different formulations and disease states. 2. 1. 1 Formulation-Dependent Factors Conventional Dosage Forms
Diclofenac appears to be completely absorbed when given as a suspension, capsule or tablet. The administration of a diclofenac solution shows rapid absorption with C max being attained within 10 to 40 minutes.[57,7I,82) Single doses of diclofenac in the form of enteric-coated tablets, rectal suppositories and solutions are rapidly absorbed, with C max observed between 1.5 and 2 hours post-drug administration.[6,52,56,57) In addition, compared with enteric-coated tablets, sustained release and controlled release preparations have a lower Cmax and delayed time to reach peak concentration following drug administration (tmax), with the relative bioavailability of most sustained release preparations equal to the enteric-coated preparations. [23,76,77,79,83,94,101,109,115) The comparative bioavailability of 2 commercially available enteric-coated tablet formulation s has revealed differences in absorption rates which are correlated to different in vitro dissolution rate profiles, resulting in dissimilar tmax profiles. Bioequivalence should not be assumed for all sustained release or enteric-coated preparations. A study on an experimental sustained release preparation showed differences in the extent of absorption, with the bioavailability of the sustained release formulation found to be 53% of the conventional enteric-coated products,l86) The relative bioavailability of 4 enteric-coated diclofenac products demonstrated that only 1 generic product was fully bioequivalent with the reference prodUCt.[105) In addition, multiple peak concentrations of diclofenac have been observed following the administration of sustained release products to C lin. Pharrnaco kinet. 1997 Sep : 33 (3)
187
Clinical Pharmacokinetics of Diclofenac
Table II. Absorption characteristics of diclofenac (oral dosage formulations administered in single doses in healthy adults except where indicated) n (patient type)
Agea (y) [range]
Dose (mg) [no. of days]
C max (mg/L)
AUC (mg/L· h)
t max (h)
Reference
4
NR
25mgEC
0.889
NR
1.75
6
5
[20-42]
50mg solution
NR
2.0543
NR
67
50mg + aspirin 20 mg/kg
NR
0.99815
NR
50mg + aspirin 20 mg/kg following aspirin 60 mglkg/daily for 6 days
NR
0.89769
NR
6
NR
75mg 1M
2.69
3.5
0.25
50mg Supp
0.81
NR
0.67
50mg EC
0.74
NR
1.5
50mg solution
1.12
NR
0.5
8 Young
19.4 [18-21]
50mg EC
1.5045
1.4553
1.56
8 Elderly
68.1 [62-78]
50mg EC
1.6251
1.877
2.25
18
NR
25mg
0.626
NR
2.25
50mg
1.126
NR
1.5
52
63 68
25mg tid for 10 days 9 6 4
NR NR [19-22]
Day 1
0.759
2.98
1.92
Day 10
0.537
2.28
1.83
50mg EC
NR
1.683
NR
SOmg EC and aspirin 19
NR
1.083
NR
50mg EC
NR
1.858
2.13
50mg IV
NR
2.067
0
10ND 100A
36.7 [24-36]
50mg EC
1.329
1.44
-2
73.9
50mg EC
1.414
1.47
-2
7
[20-22]
50mg EC
2.0
1.67
2.5
50mg IV
NR
3.29
NR
50mg EC with 100ml H2O
1.98
1.79
2.5
50mg EC with 600mg aspirin in 100ml H2O
1.21
1.28
3.1
6
3
22
NR
50mg IV
-9.8
3.23
0
50mg IV and 600mg aspirin in 100ml
9.7
2.18
0
50mg 2h before breakfast
NR
1.444
NR
NR
1.447
NR
NR
1.717
NR
NR
1.550
NR
NR
1.753
NR
NR
1.099
NR
100mg SR 2h before breakfast
NR
3.134
NR
100mg SR immediately after breakfast
NR
2.964
NR NR
50mg immediately after breakfast 50mg immediately after lunch 3
12
NR
[18-28]
6
100mg SR during dinner
NR
3.644
50mg EC fasting
1.325
1.304
1.8
50mg EC fed
0.782
1.038
5.4
50mg EC fasting
1.668
NR
1.8
50mg fed
0.698
NR
9.7
50mg bid for 5 days fasting
1.3n
NR
2.5
50mg bid for 5 days fed
1.367
NR
5.9
57 59 59 62 69
70
70
60
10RA
57 [46-68]
50mg EC
0.99
1.37
2.0
64
10 10
24.6 [20-34]
100mg solution
2.135
2.705
-0.67
71
0.5
6
22.5 [18-29]
50mg solution
0.772
1.266
50mg day 1
1.05
1.42
0.22
50mg day 8 and paracetamol 1000mg
1.25
1.53
0.27 Continued over page
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188
Table II. Contd n (patient type)
Agea (y) [range)
Dose (mg) [no. of days)
C max (mg/L)
AUC (mg/L· h)
t max (h)
Reference
Day 9 to 22 x 25mg daily (at 8,14 and 20 hours) and 3 x 500mg paracetamol daily (at 8, 14 and 20 hours)
10 Cirrhotic/ chronic hepatitis
NR
Day 2350mg
1.54
1.58
0.17
Day 30 50mg
1.97
1.55
0.17
100mg EC
2.2
3.2
0.5
1.25
72
10
NR
100mg EC
1.9
2.6
7 RA
4.3[2-7)
25mg EC
1.682
1.57-4.73
1.0
73
10
NR
100mg
1.35
4.302
3.7
74
100mg and 0.4g 19 weeks
1.16
4.19
4.05
8 9 10 7 8 9
NR NR NR NR [24-76) [41-87)
100mg
1.47
4.61
3.9
100mg and 600mg penicillamine 12 weeks
1.4
4.5
4.0
100mg
1.18
3.86
4.07
100mg and 250mg chloroquine 24 weeks
1.13
3.82
4.38
100mg
1.58
4.76
3.85
100mg and 150mg azathioprine 3-5 weeks
1.62
5.07
3.65
50mg
1.40
4.9
3.28
50mg and 15mg prednisolone for 10 days
1.65
5.94
3.6
100mg
1.46
3.98
3.1
100mg and 1000mg cefadroxil for 1 week
1.25
5.1
2.9
100mg
1.21
3.76
4.28
100mg and 100mg doxycycline for 1 week
1.3
4.13
3.7
75 75 75 75 75 75
10 RAand OA
26 [23-31)
1OOrng SR for 22 days
0.417
3.04
NR
76
9
28.9 [21-34)
100mg SR
0.438
2.4
5.5
77
100mgSRG
0.48
2.15
2.7
6 8
26 [20-30) NR
12 10 15 12 12
[25-35) 25 [20-38) [22-42) 32.8
50mg oral losenge
1.336
1.19
0.3
100mgEC
NR
3.76
NR
100mg suspension IC
NR
4.13
NR
A 100mg Supp
1.87
3.37
1.13
B 100mg Supp
1.24
3.021
1.2
C 100mg Supp
0.9858
3.211
2
D 100mg Supp
1.8
3.18
0.7 0.4
E 100mg Supp
1.749
2.77
100mg SR
2.44
2.366
1.25
100mg EC
0.939
2.524
2.13
75mg 1M
2.73
4.93
0.42
75mg 1M and 40mg triamcinolone diacetate
3.38
5.38
0.37
50mg EC dragees
3.37
2.28
2.4
A 50mg EC dragees B
1.908
2.48
2.0
100mg
0.461
3.414
4
100mg + sulglicotide 200mg
0490
3.658
4
66 78
79 16 80 81
3
[28-47)
100mg solution
3.5
2.35
0.33
82
18
21.8
50mg EC
4.38
6.31
2.4
83
NR
50mg ECJ
4.49
5.91
1.2
100mg EC
4.6
6.82
2
6.98
=5
4.09
NR
100mg SR 6
[25-26)
50mg I
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2.026
83 84
Clin. Pharmacokinet. 1997 Sep; 33 (3)
189
Clinical Pharmacokinetics of Diclofenac
Table II. Cantd
n (patient type)
Agea (y) [range]
Dose (mg) [no. of days]
C max (mg/L)
AUC (mglL· h)
t max (h)
Reference
11
[22-30]
100mg SR
0.654
NA
6.4
22
10
14
6 10
12AA
[20-24]
NA
21.8 [20-33] 25 [23-45]
51 .9
100mgSAIS
0.497
NA
7.4
Fasting 50mg EC
1.34
1.422
1.47
2 x 25mg EC
1.509
1.44
1.5
75mg SAA capsules
0.473
1.555
2.5
75mg SAA capsules q12h for 4 days l00mg SA tablets
0.453
1.75
2.5
l00mg SA tablets
0.408
1.788
3.0
q12h for 4 days
0.564
2.528
3.5
50mg BAS
2.398
1.357
0.25
100mg BAS
5.001
2.748
0.25
150mg BAS
7.171
4.468
0.25
100mg SAE
0.54
3.33
3.6
100mg SA
4.12
6.21
2.5
HC + 75mg BAS
1.175
1.906
0.43
HC+75mg EC
2.074
2.3629
1.83
HC + 100mg SA HC
0.694
2.1635
2.69
l00mg EC
2.1
3.81
2.5
l00mg DIEP
2.33
3.62
0.62
5 Children
5.4 [1-5]
0.5 mglkg IV 5-minute INF
5.78
NA
NR
5 Children
5.4 [6-10]
0.5 mglkg IV 15-minute INF
3.71
NA
NA
85 25
58
86 87
88 89
6
NR
100mg Supp
3.2
3.97
0.5
3
NA
50mg
0.734
1.8
1.5
27
14
[21-33]
100mg EC
2.734
5.386
2.96
91
6 10 6 10
8 24
24
[21-33] 31 39 [28-45]
[23-29] NA
NR
100mg ECJ
3.528
6.260
2.14
50mg
1.571
2.459
2.5
50mg ECJ
2.355
2.482
1.25
50mg EC 7am
2.791
3.681
1.6
50mg EC 7pm
1.886
2.807
2.3
50mg with 150ml H2O
1.8
1.9
1.9
50mg + 850mg magnesium hydroxide
1.4
1.8
1.4
l00mg EC
3.6
4.42
1.95
100mgSA
0.895
4.50
4.4
100mg SRI
0.821
4.57
4.7
50mg gelatin capsule fasting 50mg gelatin capsule fed
1.2
1.2
0.8
1.04
1.04
2.4
DicJafenac 50mg UST fasted
1.138
1.252
2.7
Diclafenac-placeba 50mg fasted
1.018
1.299
2.7 2.4
DicJafenac 50mg CSTA fasted
1.330
1.315
DicJafenac 50mg CSTB fasted
1.282
1.255
2.4
DicJafenac 50mg UST nanfasted
0.896
1.131
3.7
DicJafenac-placeba 50mg nanfasted dicJafenac
0.722
1.035
4.5
90
92 93 94
95 96
96
50mg CSTA nanfasted
0.723
0.975
4.0
24
NR
Single dose Day 1 50mg UST
1.397
1.980
3.6
Single dose 50mg UST and Misa 200~g
1.031
1.460
4.1
24 E
NA
Steady-state dose day 5 50mg UST
1.182
1.707
3.8
1.043
1.557
3.7 Continued over page
50mg UST and Misa
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200~g
96
96
Clin. Pharmacokinet. 1997 Sep; 33 (3)
Davies & Anderson
190
Table II. Contd
n (patient type)
Agea (y) [range]
Dose (mg) [no. of days]
C max (mg/L)
AUC (mg/L· h)
t max (h)
Reference
11 E
NR
Nonfasting single dose
1.088
1.803
3.5
96
Day 1 50mg EC Initial treatment 50mg EC replicate treatment
1.319
1.814
4.3 3.7
12 E
NR
Nonfasting steady-state day 5 50mg EC initial treatment
1.042
1.974
50mg EC replicate treatment
0.964
1.402
3.9
36
NR
Nonfasting 50mg EC
1.313
1.682
4.1
50mg EC + 200fl9 Miso
1.036
1.480
4.1
8 12
12
18
10 24
12 15 18 8
8
32.8 32 [19-46]
37.8 [26-52]
27.1 [21-42]
NR 27.9 [20-36]
33.58 [22-45] 27.3 [19-32] 27.5 [21-38] [20-26]
[20-26]
50mg EC + 200fl9 Miso A
1.130
1.628
3.9
100mgSR MP
0.177-0.841
0.874-2.166
0.9-3.9
100mgSRT
0.276-0.1008 0.156-3.214
0.4-5.2
300mg emulsion gel topically'
0.03936
0.32192
7.17
300mg solution gel topically
0.08133
0.49529
3.5
25mg 1M
0.89633
1.2352
0.48
150mg fed HGB
0.3116
2.2742
6.25
150mg fasted HGB
0.5023
2.5113
1.85 0.33
150mg solution
6.8389
4.1846
75mg EC
2.3
1.97
2.25
75mg and 2nd dose of 150mg ranitidine HCI tabletq12h
2.44
1.54
2.25
DHEP plaster 185.5mg bid for 7 days
0.0174
0.1193
5.4
1% Gel 50mg DHEP
0.0281
0.1047
3.1
50mg q8h for 9 days
0.772
1.162
2.03
Day 7 reference + 300mg cyclosporin on day 1.284 8 test
2.088
2.96
50mg + sucralfate 200mg
0.773
1.837
1.01
50mgEC
0.612
1.84
1.95
100mg SR
0.736
3.34
4.5
100mg SRJ
0.536
3.045
4.1
50mg EC MUF
1.159
1.57
1.4
50mg EC
1.481
1.582
1.8
50mg EC 30 minutes after placebo
1.38
2.72
1.94
50mg EC 30 minutes after 200fl9 nocloprost clathrate
1.50
1.94
1.08
50mg EC 30 minutes after repeated placebo
1.59
2.39
0.52
50mg EC 30 minutes after 200fl9 bid nocloprost clathrate for 7 days
1.50
1.69
0.435
96
96
31 32
97
98
99 33
100 101 102 103
103
98
71.4 [39-93]
52.0fl9 10
0.082
0.384
2.4
104
16
[18-30]
Fasting
1.22
1.43
NR
105
50mg EC
1.28
1.37
NR
50mg K
1.33
1.37
NR
8
16RA
60[20-70]
50mg P
1.28
1.31
NR
50mgS
1.33
1.7
NR
Fasting
1.23
1.54
NR
50mgK
1.62
1.75
NR
50mg K + 150mg ranitidine evening + 6:30am 1.56 50mgS 50mg S + 150mg ranitidine evening + 6:30am
1.68
NR
150mg resinate bid for 5 days
1.64
4.72
1.41
150mg EC dragees bid for 5 days
2.59
4.75
2.56
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106
Clin. Pharmacokinet. 1997 Sep: 33 (3)
Clinical Pharmacokinetics of Diclofenac
191
Table II. Contd n (patient type)
Agea (y) [range]
Dose (mg) [no. of days]
C max (mg/L)
AUC (mg/L· h)
t max (h)
Reference
12
27.08 [24·30]
50mg EC MUF fasting
0.695
1.359
1.2
107
50mg EC MUF fed
0.452
1.302
4.8
50mg EC fasting
1.039
1.368
2.2
50mg EC nonfasting
0.580
0.964
7.8
100mg EC
3.3553
4.1965
2.0
100mg EC and 109 colestipol
1.4175
2.8134
4.3
6
33.3 [25-42]
29.4 [21-47]
18
l00mg EC and 8g cholestyramine
0.8385
1.6052
5.7
105mg CAT suspension
0.001759
0.03494
0.5
105mg FLO suspension
0.01374
0.003388
0.5
108
34
6
NR
100mg EC
0.714
NR
3.085
9
6
23.8 [22-36]
375mg R1CR
0.259
1.411
3.3
109
375mg R3CR
0.3187
1.771
3.5
375mg R4CR
0.3022
2.1715
4.7
375mg R5CR
0.3548
2.1901
4.0
100mg EC
1.88
4.375
4.591
lOOmg D
1.607
3.924
1.614
12
25.2 [20-29]
12
30.6 [21-40]
12
[25-45]
20RA
70 18 a
52 [21-70]
23.9 [19-38]
50mg + 50mg CP Tablets
1.649
1.3
0.38
50mg + 50mg CP Supp
0.704
1.441
0.75
50mg
0.899
2.4053
1.58
50mg Supp
1.1935
2.5789
0.625
128 ± 35mg bid-tid [28d]
1.863
3.950
1.9
128 ± 35mg bid-tid + 3.0 ± 0.15 mg/kg/day cyclosporin [28]
2.692
8.122
2.3
50mg EC + 200l1g Miso 105mg PDS + SUC PT 2000mg bid [5]
1.9132
NR
2.28
1.2977
NR
2.57
1.135
2.383
1.0
0.701
1.961
1.0
35 110 111 112
113 114
Mean age; range in parentheses.
Abbreviations and symbols: A = Arthrotec® combination of misoprostol and diclofenac; AC = alcoholic cirrhosis; ALOH = aluminum hydroxide; AUC = area under the concentration-time curve; BAS = Buffered Aqueous Solution; C = children; CAT = Cataflam, Ciba-Geigy potassium salt suspension; Crnax = peak plasma drug concentration; CP = codeine phosphate; CR = controlled release; CSM = cholestyramine; CST = Canadian standard tablets; CW = Carbowax; D = dispersible; DHEP = diclofenac hydroxyethylpyrolidine; DIEP = diethylpyrrolidine; DM = diabetes mellitus; E = elderly; EC= enteric coated; ECJ = enteric coated formulation from Jordan; FLO = Flogan, Merck potassium salt suspension; HC = Heidelberg Capsule; HF = healthy fasted; HGB = hyrdrogel bead capsules; HNF = healthy non-fasted; IA = Indian Formulation; IC = intracolonic; 1M = intramuscular; INF = infusion; K = Katwijk Generic; Miso = misoprostol; MA= migraine attacks; MGOH= magnesium hydroxide; MRF= moderate renal failure; n = number of patients; ND = neurological disorders; NH = neoplastic hyoproteinemia; NR = not reported; OA = osteoarthritis; PB = probenecid; P = Pharbita Generic; PDS = potassium diclofenac suspension; PT = pre-treatment; qid = 4 times daily; q6h (q12h) = every 6 (12) hours; qd = daily; RA = rheumatoid arthritis; RI = renal insufficiency; SGT = sulglycotide; SIM = simethicone; SRA = sustained release Austria; SRE = sustained release experimental Jordan; SRF = severe renal failure; SRG = sustained release Germany; SRI = sustained release from India; SRJ = sustained release from Jordan; SRIS = sustained release from Israel; SRMP = sustained release micropellets; SRT = sustained release tablets; SUC = sucralfate; Supp = suppository; t""", = time taken to achieve Crnax; UST = US standard tablets; WS = whitesupol; • 30g of gel applied on back on 2 areas of 400cm 2 for 8h and covered with airtight dressing.
fasting individuals. This behaviour has been attributed to changes in the release pattern of this dosage form with changes in the pH of the gastrointestinal tract during its transit.[87,1OI,116] Sustained release products have variable absorption lag times corresponding to their gastric residence time. DicIo© Adis Inlernoftonal Umiled. All rights reserved.
fenac is rapidly and well absorbed by the intestinal tract from suppositories)2s,46,56,57,78,9o,1 10, III,117-119J Immediate Release Formulations
Diclofenac is a weak acid (pKa = 4.00) and attempts have been made to enhance the rate of absorpClin. Pharmac okinel.
1997 Sep: 33 (3)
192
tion from different diclofenac formulations and, thereby, provide an earlier onset of effect. Faster absorption rates may have therapeutic implications for acute conditions where the rapid onset of the pharmacological effects may be desirable such as with pyrexia, dental pain and dysmenorrhoea)83,91] The potassium salt suspensions have been shown to be absorbed at higher rates with corresponding higher plasma concentrations, and may provide an earlier onset of effect when required for analgesia)34] Diclofenac hydroxyethylpyrolidine (DHEP) soluble salt packed in sachets are bioequivalent when compared with diclofenac sodium administered as enteric-coated tablets. The DHEP salt, however, shows a much quicker absorption rate with the appearance of diclofenac in plasma 15 minutes after oral administration)88] Also, a new dispersible formulation of diclofenac has a significantly shorter tmax when compared with enteric-coated formulations)35] Multiple peak phenomena for the dispersible formulations of diclofenac are observed. This behaviour may be attributed to pH-dependent release profiles of this dosage form within the gastrointestinal tract. The secondary peaks appeared 2 hours after breakfast and it was suggested that patient positioning (i.e. the supine position) could effect gastric emptying and that food intake also modifies gastric emptying. Hepatic blood flow changes, which affects drugs that are metabolised by the liver, may also be accountable for the multiple peaking phenomena. Buccal delivery has potential advantages for diclofenac as this route of delivery minimises first-pass liver and gastrointestinal metabolism. A prototype hydrogel device loaded with diclofenac sodium demonstrated measurable plasma concentrations of diclofenac after buccal administration with a lag time of 0.5 hours, a steady-state flux of 2.1 ± 0.6 mg/cm 2• h and an absolute bioavailability of 0.68)120] Topical Delivery
NSAIDs account for a high percentage of reported serious adverse drug reactions, with the incidence in the elderly 2-fold higher than in the © Adis International Limited. All rights reserved.
Davies & Anderson
younger population)2,3,121,122] There has been considerable interest in the development of topical NSAIDs in recent years. When applied topically, these drugs are formulated to penetrate the skin barrier in sufficient amounts to reach the joints and muscles and exert therapeutic activity. Some investigators suggest that locally enhanced topical delivery (LETD) will allow the clinician to deliver drug to the site of action while minimising systemic toxicity)123] This was confirmed by higher tissue to plasma ratios, as well as 2 tissue concentration peaks corresponding to an initial local delivery and a latent peak corresponding to the drug plasma profile)124] Another group showed that, after cutaneous application of diclofenac gel to 1 knee in patients with bilateral knee joint effusions, there were significant (about 85% of the peak concentration) in the contralateral knee compared with the topicallytreated knee)125] LETD for topical NSAIDs does occur in humans in the skin, subcutaneous fatty tissue and muscle, but evidence is inconclusive whether LETD occurs in deeper tissues such as the synovial joint)126] LETD also has a large dependence on the nature of the drug and vehicle, as well as the state of skin integrity and hydration. The first reports of diclofenac sodium cream absorption (1 %) to the back of a healthy volunteers (2.5g per 250 to 200cm2 times daily) showed that diclofenac was detectable in plasma (1.3 ~g/L) 2 hours after the initial application and that plasma concentrations remained steady between 6 to 10 ~g/L, decreasing to 0.4 ~g/L 98 hours after the last application)15] After the cutaneous application of diclofenac emulsion cream and gel formulations, the drug is absorbed slowly with 6 to 7% systemic bioavailability, [119.l27] as well, synovial fluid and tissue diclofenac concentrations were as high as 20 times the plasma concentrations in the joints of the fingers and wrist.[l27] After repeated topical applications of 2 different diclofenac gel formulations (DHEP 1.32% and diclofenac diethylammonium 1.16%), good percutaneous absorption was achieved, ranging between 6 and 7% of the administered dose)128] The Clin. Pharmacokinet. 1997 Sep; 33 (3)
193
Clinical Pharmacokinetics of Diclofenac
percutaneous absorption of 1.16% diclofenac diethy1ammonium applied on either side of the spine demonstrated measurable concentrations attained after 1 to 2 hours, with absorption continuing over 24 hours and high interindividual variations in plasma and urine concentrations, which were attributed to differences in permeability and hydration of the skin) 129 l DHEP plasters have been developed and permit, through an occlusive bandage, a slow release of the drug which allows the maintaining of a consistent diclofenac concentration in the plasma and inflamed area) 130l Pharmacokinetics at steady state reveal a sustained release profile with less drug released from the plaster when compared with a 1% gel, and an AVC 10 to 20 times lower than those achieved after oral administration)99l An emulsion gel and a solution gel of diclofenac were both absorbed systemically. The C max was 10% of that reached after a similar dose administered intramuscularly. The C max of the solution gel was almost twice that of the emulsion gel and was reached in a shorter time. [32l A submicron emulsion vehicle (SME) was described and demonstrated a 40% increase in activity over a currently marketed diclofenac product, which is attributable to the vehicle having smaller particle sizes and the ability of phospholipid systems to act as penetration enhancers)13ll Phospholipid systems for topical diclofenac delivery are gaining acceptance as they are well-tolerated, able to enhance the penetration of the drug through the stratum corneum and to incorporate hydrophilic, hydrophobic and amphoteric drugs. [131, 132l These investigators indicate that microemulsions with small particle sizes are optimal vehicles for diclofenac delivery. Lecithin organogels, which are phospholipid micro-emulsion systems, are widely used for topical diclofenac delivery, although evidence of percutaneous absorption is limited to in vitro testing)133,134 l Diclofenac is absorbed optically and penetrates into the ocular fluids. After a single topical dose of diclofenac 0.1 %, aqueous humor concentrations of 22 j..Lg/L at 50 minutes and 52.6 j..Lg/L at 125 minutes was observed.rs ll A further study with 98 patients © Adis International Limited< All rights reserved<
undergoing cataract surgery demonstrated mean concentrations of 82 j..Lg/L at 2.5 hours after instillation, with concentrations remaining above 20 j..Lg/L for over 4 hours) 104 l Previous studies have found a somewhat higher C max of 130 j..Lg/L with an average tmax of 1 hours.[4,135, 136l Combinotion Formulations
The pharmacokinetics of a resin-bound diclofenac formulation (diclofenac 75mg and cholestyramine 75mg) was compared with enteric-coated tablets in patients with rheumatoid arthritis. Diclofenac is absorbed significantly faster from the resinate when compared with the enteric-coated formulation with a corresponding lower C max , yet no differences in the AVCs were apparent) 106l The formulation of sucralfate with diclofenac does not reduce C max , increase tmax or decrease bioavailability)IOOl In contrast, a recent report has suggested that short term pre-treatment of healthy male volunteers with twice daily sucralfate 2000mg significantly decreased potassium diclofenac AVC and C max with no change in tmax )114 l A combination tablet containing diclofenac in an inner core and misoprostol in an outer mantle (Arthrotec®; Searle) has been developed and is absorbed to the same extent as diclofenac administered alone; however, C max is reduced when administered with food) 96 l Finally, oral and rectal application of a diclofenac-codeine phosphate combination demonstrated similar AVC values but the rate of drug input was lower for suppositories)llOl 2. 1.2 Gastrointestinal Transit and Food Effects
In single dose studies the bioavailability, as estimated from AVC, was not significantly affected by food intake after a single dose of an entericcoated diclofenac sodium 25mg tablet. A greater fluctuation or delay in absorption and tmax was shown when diclofenac was taken with food compared with when taken on an empty stomach. In a multiple dose study, absorption was almost identical regardless of whether the drug was taken before or after food and was comparable to fasting conditionsPOl Clin< Pharmacokinet 1997 Sep: 33 (3)
194
Several studies indicate that the intake of food delays the absorption of enteric-coated diclofenac tablets due to an increasing of the gastric emptying time (GET) and small intestinal transit time (SITT). A single enteric-coated diclofenac dose taken fasting or after a standard meal showed considerable delay in the onset of absorption under non-fasting conditions, with C max attained 2.5 to 12 hours after ingestion compared with 1.5 to 2.75 hours in the fasted state.!60] Although peak plasma concentrations were reduced with food intake the AUCs were comparable. After single and repeated doses under fasting and non-fasting conditions, prolonged and variable delays were observed with enteric-coated tablets taken with food)6I] A long term administration study of twice daily enteric-coated diclofenac to ambulant patients for 17 days may more closely resemble the clinical situation. There was large intra- and interindividual variability; however, no difference in the overall handling of diclofenac, whether administered under fasting or non-fasting conditions, was evident. In this study the effects of food appeared less marked when compared with the previous study. This is possibly due to the fact that the individuals in the previous study remained supine for the first 8 hours, which may have contributed to the delay in the onset of absorption.[6I] Variability in tmax exists for enteric-coated tablets administered without food)SO) When administered with food, this variability is further increased with a delay in tmax , however, no change in C max is apparent; this phenomenon is attributed to a delay in GET)I37] The interaction of diclofenac as a pure substance with and without food demonstrated that food significantly delays tmax and diminishes Cmax , however, there are no changes in AUe. It has been suggested that diclofenac may adsorb to food which, in tum, may delay gastric emptying)95) A bioavailability study following single and multiple dose administration of a multiple-unit formulation and a conventional formulation of diclofenac has been reported for fasted and non-fasted conditions. The results parallel those of Willis et al.,[60) however, the rate and extent of absorption for the mul© Adis International Urnited. All rights reseNed.
Davies & Anderson
tiple unit formulation was less influenced by food when compared with the conventional entericcoated formulation'! I02, 107) Food effects on hydrogel bead capsules (HGB) showed minimum effects on bioavailability, however, there was a 38% decrease in C max and a 3-fold increase in tmax .[97] A radiotelemetric technique using the Heidelberg capsule was employed to detect GET and the onset of drug absorption as buffered aqueous solutions or sustained release products in a fasting or fed state. Secondary peaks, shoulders and inflections were observed in 1 patient on a sustained release preparation and extensively observed in patients administered diclofenac in buffered aqueous solutions (BAS»)87) As reported by other investigators,[S5,I 3S] variable GET of precipitated diclofenac may have produced these multiple peaks in the oral concentration versus time profiles. Under fasted conditions, the rate and extent of absorption of a HGB capsule was substantially reduced to 59% relative to diclofenac sodium in BAS. In addition, there was a 92% decrease in C max and an 8-fold increase in t max following HGB capsule administration) 971 The evaluation of the gastric absorption and emptying of diclofenac under various pH conditions using a simple intubation method has been reported. The administered of diclofenac sodium dissolved in water (pH = 5.8), with a phosphate buffer (pH = 7.6) or with a homogenised meal (pH = 5.6) revealed that minimal gastric absorption occurs with a meal, but that plasma drug concentration profiles mainly reflect the process of gastric emptying)85,I38) 2.1.3 Chronopharmacokinetics
The influence of chronobiology has demonstrated a decreased Cmax and AUe for evening doses, however, absorption rate and half-life were not significantly different. A slight delay in peak concentrations with a corresponding lower absorption rate constant after dose administration at 5pm when compared with 7am administration may be attributed to retarded intestinal motility and lower blood flow at night.[92 1 Clin. Phormac okinet. 1997 Sep; 33 (3)
195
Clinical Pharmacokinetics of Diclofenac
2. 1.4 Drug Effects on Absorption
Antacids containing magnesium hydroxide appear to accelerate the absorption of diclofenac, but because of a large variability this effect did not reach statistical significance.l93 ] Ranitidine treatment, and the subsequent increase in gastric pH, causes diclofenac to be well absorbed and demonstrated that enteric-coated products with small lag times disintegrate within the non-acid stomach, whereas products with a long lag time pass the non-acid stomach intact.l IOS ] When concomitantly administered with the anion-exchange resins cholestyramine or colestipol, diclofenac bioavailability is reduced due to complex adsorption.l 108] A potential pharmacokinetic interaction of nocloprost clathrate (another prostaglandin E analogue) and enteric-coated diclofenac exists. The single premedication of nocloprost clathrate significantly increased the rate of absorption of diclofenac and total body clearance, while lowering the AVe. After repeated premedication, no significant differences in pharmacokinetic parameters existed.l 103 ] A combination of diclofenac and codeine phosphate did not affect the relative bioavailability, although peak concentrations were lower and absorption was delayedJlI7]
2.2 Distribution The apparent volume of distribution (V d/F), determined after oral administration, is between 5 and lOL in humans (0.1 to 0.2 Llkg) which suggests tissue binding is appreciably less than plasma protein binding. Table III details the pharmacokinetic parameters associated with different formulations. 2.2.1 Protein Binding
Diclofenac is extensively (>99.7%) bound in plasma and serum and in solutions of human serum albumin with a high affinity and large capacity at therapeutic concentrationsJS,S2,139-141] Binding to human serum albumin is characterised by 2 classes of binding sites with 1 site each (Kl = 5 X lOs Llmol and K2 = 0.6 X lOs Llmol). The high affinity site is likely to be shared by benzodiazepines and the low affinity site is the warfarin site.l 140] The binding to © Adis International Limited. All rights reserved.
lipoproteins was shown to be saturable with low association constants; high density lipoproteins 1.1 %, low density lipoproteins 0.3% and very low density lipoproteins 0.15%. Diclofenac is not significantly bound to
It has been shown that diclofenac does not modify other strongly protein bound drugs such as salicylic acid, tolbutamide, prednisolone, acenocoumarol or warfarin; however, diclofenac is displaced by salicylic acid in vitroJS,139] Other investigators also confirm a lack of warfarin, acenocoumarol or salicylic acid binding modifications by diclofenac in vitro.l 140 ] 2.2.2 Distribution into Synovial Fluid
Synovial membrane is the proposed primary site of action for NSAIDs in rheumatoid arthritis. Substantial concentrations of diclofenac have been detected in synovial fluid and tissues in patients with rheumatoid arthritis and osteoarthritisJS,1l8,12S,142-149] The synovial fluid studies indicate that after oral, rectal or intramuscular dose administration diclofenac synovial fluid peak concentrations were achieved 2 to 4 hours after plasma C max • Lower C max values are attained in synovial fluid when compared with plasma, elimination half-lives (tY2~) are 3 times longer in synovial fluid than in plasma, and at 12 to 24 hours after administration synovial fluid concentrations were higher than in plasmap,n,118,142,14S,146] The levels of metabolites were not reported in the synovial fluid samples. After repeated oral doses of diclofenac, the steady-state C max of diclofenac was reached 3 hours post-dose and fell by 90% within 2 hours. Synovial fluid concentrations, on the other hand, were less variable and at 4 hours post-dose were higher than those reported in plasma. Relative accumulation in synovial fluid occurs with ratios of synovial fluid to plasma of 3 : 1 being achieved. Hydroxylated metabolites (free and conjugated) were formed Clin. Pharmacokinet. 1997 Sep; 33 (3)
196
Davies & Anderson
Table III. Pharmacokinetic properties of diclofenac in healthy volunteers (oral immediate release dosage forms administered in single doses, except where indicated)
n 7 6
9
15 18
Age" (y) [rangeJ [20-22J 22
28.9 [21-34J
25 [20-38J 21.8
Dose (mg) [no. of daysJ
t1;2~
(h)
Vd/F (Ukg)
CUF (Uh/kg)
Reference 62
50mg EC
1.8
NR
NR
50mg IV
1.1
0.172
0.25
50mg EC with 1OOmL H2O
2.1
NR
NR
50mg EC with 600mg acetylsalicylic acid in 100ml H2O
1.6
NR
NR
50mg IV
1.1
0.1234
NR
50mg IV and 600mg acetyl salicylic acid in 100ml
0.9
0.183
NR
100mg SR
NR
NR
0.57
100mgSRG
NR
NR
0.60
50mg oral lozenge
1.8
NR
0.59
75mglM
3.5
0.47
0.21
75mg 1M and 40mg triamcinolone diacetate
3.72
0.364
0.20
50mg EC
1.22
NR
NR
50mg ECJ
1.26
NR
NR
69
77
16 83
6
[25-26J
50mg I
1.6
0.49
0.2082
84
11
[22-30J
100mg SR
2.8
NR
NR
22
100mg SRIS
3.7
NR
NR
Fasting 50mg EC
1.47
NR
NR
2 x 25mg EC
1.5
NR
NR
24 14
10
NR NR
25 [23-45J
50mg BAS
1.6
NR
NR
100mg
1.7
NR
NR
BAS 150mg
1.5
NR
NR
HC+75mg BAS
1.52
NR
NR
HC + 75mg EC
1.56
NR
NR
85 58
87
HC+ 100mg SR
2.53
NR
NR
6
NR
100mg Supp
1.3
NR
NR
3
NR
50mg
0.88
NR
NR
27
14
[21-33J
100mg EC
2.09
NR
NR
91
6 18
12 24
27.1 [21-42J
33.58 [22-45J 27.9 [20-36J
100mg ECJ
2.07
NR
NR
50mg
1.68
NR
NR
50mg ECJ
1.71
NR
NR
75mg EC
1.57
NR
NR
75mg and 2nd dose of 150mg ranitidine HCI tablet q12h
1.54
NR
NR
50mg + sucralfate 200mg
1.2
0.69
0.45
50mg EC
1.15
0.5
0.46
1.95
NR
0.76
50mg q8h for 9 days day 7 reference
8
8
18
[20-26J
[20-26J
29.4 [21-47J
98
100 33
+ 300mg cyclosporin on day 8 test
1.95
NR
0.34
50mg EC 30 min after placebo
0.42
0.16
0.27
50mg EC 30 min after 200l1g nocloprost clathrate
0.39
0.195
0.36
50mg EC 30 minutes after repeated placebo
0.52
0.22
0.32
50mg EC 30 minutes after 200l1g bid nocloprost clathrate for 7 days
0.42
0.248
0.44
105mg CAT suspension
1.56
NR
NR
105mg FLO suspension
1.85
NR
NR
© Adis International Limited. All rights reserved.
90
103
103
34
Clin. Pharmacokinet. 1997 Sep; 33 (3)
197
Clinical Pharmacokinetics of Diclofenac
Table III. Contd
Age" (y) [range]
n
Vd/F (Ukg)
CUF (Uh/kg)
Reference
(h)
t1;2~
Dose (mg) [no. of days]
6
NR
100mg EC
2.152
NR
NR
9
12
25.2 [20-29]
100mg EC
2.754
NR
NR
35
100mg D
3.652
NR
NR
50mg + 50mg CP tablets
0.99
NR
NR
50mg + 50mg CP Supp
1.64
NR
NR
2.4
NR
NR
2.4
NR
NR
12
30.6 [21-40]
20RA
52 [21-70]
128 ± 35mg bid-tid [28d] 128 ± 35mg bid-tid + 3.0 cyclosporin [28]
12 18 a
[25-45] [19-38]
± 0.15 mg/kg/day
50mg
1.55
NR
NR
50mg Supp
1.52
NR
NR
105mg PDS
1.7
NR
NR
+ SUC PT 2000mg bid [5]
1.8
110 112
111 114
Mean age; range in parentheses.
Abbreviations and symbols: ALOH = aluminum hydroxide; BAS = buffered aqueous solution; C = children; CUf = plasma clearance of drug after oral administration; CR = controlled release; CSM = cholestyramine; CST = Canadian standard tablets; CW = Carbowax; EC = enteric coated; HC = .Heidelberg Capsule; I = Indian Formulation; mgOH = magnesium hydroxide; MUF = multiple unit formulation; n = number of study participants; NR = not reported; PB = probenecid; PDS = potassium diclofenac solution; PT = pre-treatment; q6h (q12h) = every 6 (12) hours; qd = daily; qid = 4 times daily; RA = rheumatoid arthritis; SGT = sulglycotide; SIM = simethicone; SUC = sucralfate; Supp = suppository; t1f.<~ = elimination half-life; UST = United States standard tablets; Vd/F = apparent volume of distribution after oral administration; WS = whitesupoi.
rapidly with initial plasma concentrations higher than in synovial fluid, but after 4 hours synovial fluid concentrations were equal to or slightly elevated when compared with plasma)143] After long term administration of a sustained release formulation, peak concentrations were reduced in both the plasma and synovial fluid. The concentrations of diclofenac and the hydroxylated metabolites in synovial fluid were maintained for up to 25 hours. No correlation between drug concentration and prostaglandin EI and F2ex concentrations was evident. These samples were not taken in individual patients but pooled from different patients at intervals) 147] The metabolites of diclofenac were not confined to the synovial fluid because of the differences in their physicochemical properties, which can affect protein binding and partitioning. However, the number of samples used in these studies is limited for ethical reason. One study measured serial diclofenac concentrations in the synovial fluid of patients with osteoarthritis or rheumatoid arthritis to evaluate the kinetics of diclofenac penetration. Diclofenac was shown to penetrate rapidly into the synovial fluid, peak at © Adis International Limited. All rights reserved.
3 to 4 hours after a single dose, and to be present at higher concentrations in synovial fluid than in plasma at 4 hours post-dose and beyond. In addition, it appears that synovial diclofenac concentrations are increased and sustained for periods up to 12 hours following multiple dose administration, with a ratio of synovial fluid to plasma concentration of approximately 5)145] Lower albumin concentrations present in the synovial fluid may translate to a higher free fractions of diclofenac. The extent of binding in synovial fluid samples was consistently lower when compared with plasma samples (99.5 ± 0.2% vs 99.7 ± 0.1 %, respectively). Although the difference in extent of binding between plasma and synovial fluid was small, it was consistent and reached statistical significance. On 2 occasions where the synovial concentrations were <25 giL, the extents of binding were 99.2 and 99.0%.[141] In order to assess drug efflux from the joint after intra-articular injection an aqueous solution containing diclofenac was injected into a joint. The clearance of diclofenac was 0.0096 Llh. Diffusion of unbound diclofenac through the synovium acClin. Pharmacokinet. 1997 Sep; 33 (3)
198
counted for 0.S2 ± 0.080/0 of the total diclofenac clearance from the joint space. The main diclofenac clearance is accounted for by the efflux of solute bound to albumin. The terminal half-life of diclofenac based on synovial fluid concentrations was S.2 ± 1.1 hours.f ISO ] The topical application of diclofenac in an emulsion cream and gel produced 20 times the concentrations in both the synovial fluid and tissue of the finger and wrist joints when compared with the plasma.f I27] A subsequent study in patients with bilateral inflammatory and degenerative joint disease found total and unbound concentrations of diclofenac in synovial fluid slightly, but significantly, higher when compared with the contralateral placebotreated knee joint, however, in contrast to other studies, the synovial fluid concentrations were lower than the total plasma concentrations. The percentage of total diclofenac concentration that is unbound was significantly higher in synovial fluid than plasma. The direct transport from cutaneous application into the knee joint appears to be minimal and distribution via the systemic circulation appears to predominate.f I2S ] DHEP plasters, after repeated epicutaneous administration in patients with monolateral knee joint effusion, demonstrate low, but consistent, plasma concentrations of diclofenac as well as detectable synovial fluid concentrations, indicating a diffusion of diclofenac into the synovial fluid . The synovial fluid concentrations were on average 3S.90/0 of the plasma concentrations) I30] 2.2.3 Dlstrlbuffon Into Other Tissues
There is little data regarding the distribution of diclofenac into other tissues and fluids. The relatively low volume of distribution (V d) of diclofenac indicates that the intact drug distribution . beyond the peripheral circulation or central compartment is very small. Diclofenac does not easily cross the blood-brain barrier. The concentrations of diclofenac in cerebrospinal fluid are 8.220/0 of those in plasma. The more polar metabolites are present in cerebrospinal fluid, but to a lesser extent (4.780/0) for 4'-hydroxy and 0.40/0 for 3'-hydroxy4'-methoxy diclofenac.[30] © Adis International Urnited. All rights reseN ed.
Davies & Anderson
2.3 Metabolism 2.3.1 Phase I Metabolism
Although some reports suggest an oral bioavailability approaching 900/0)52,S9] other reports indicate that diclofenac undergoes first pass metabolism with about 600/0 of the drug reaching the systemic circulation as intact diclofenac.[S7.62] Diclofenac is metabolised by cytochrome P4S0 (CYP) phase I hydroxylation and by phase II conjugation with glucuronic acid and the amino acid taurine. The pattern of diclofenac metabolites in human urine are the same after topical and oral administration) 127, 129] Assay of diclofenac and its metabolites in plasma has not afforded sufficient accuracy at concentrations below 10 !lg/L, however, more recent advances have demonstrated the ability to detect diclofenac and the 3'-hydroxy, 4'-hydroxy, 3'-hydroxy-4'-methoxy and 4',S-dihydroxy metabolites in plasma after a single 7Smg intramuscular dose,l30] A single 100mg oral dose, in patients with healthy livers, demonstrates metabolite levels of 11 % for 4'-hydroxy, S.60/0 for S'-hydroxy, 20/0 for 3'-hydroxy, 11 % for 4' ,S'-dihydroxy and 60/0 for the unchanged diclofenac being excreted in urine, with no apparent changes in patients with hepatic diseases .f73] The principal metabolite in humans is the 4'-hydroxy derivative of diclofenac)S,ISI] Diclofenac 4'hydroxylation is most likely catalysed by CYP2C9. Inhibition of diclofenac 4'-hydroxylation occurs with tolbutamide, sulfaphenazole, phenytoin and warfarin in human liver microsomes)IS2] The amount of 4'hydroxyl metabolite excreted in urine accounts for 300/0 of the dose and 10 to 200/0 of the dose in bile.[S2.ISI ] Three other metabolites account for 10 to 200/0 of the dose excreted in urine and a small amount of the dose excreted in bile. These metabolites have been identified as the 3'-hydroxy, S'hydroxy and the 4',S'-dihydroxy metabolite.fS,ISI] The 3'-hydroxy-4'-methoxy diclofenac metabolite has been identified in plasma reaching peak concentrations at'12 hours after the oral administration of a single dose. The apparent t!,-W is 80 hours but the metabolite is only excreted in trace amounts in urine. After a 6- to 1O-month treatment C lin. Pharmacokinet. 1997 Sep; 33 (3)
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with a sustained release formulation, substantial accumulation of metabolite occurred, reaching concentrations 6-fold greater than the corresponding parent drug concentrations. This metabolite is virtually inactive in animal models of inflammation and pain, and it has been suggested that it is unlikely to contribute to the therapeutic activity of the drug)82,I53] The amounts of diclofenac, 3'hydroxy, 4'-hydroxy, 5'-hydroxy and 3'-hydroxy4' -methoxy in urine from individuals with normal renal function are 6.2, 6.1, 16,2.0 and 0.009% of an oral dose)40] The 4'-hydroxy metabolite has 30% of the anti-inflammatory and antipyretic activity of diclofenac in animal models)5,I54] All metabolites tested produce moderate analgesic effects at very high doses in pre-clinical animal tests)5,I54] More recently, using capillary gas chromatography negative impact chemical ionisation mass spectrometry (GC-NICI-MS), a new main diclofenac metabolite in human urine, [2-[(2,6-dichloro-4hydroxy-3-methoxyphenyl) amino]phenyl]acetic acid, was characterised. The metabolite is formed by catechol-O-methyltransferase after initial oxidative attack by the CYP2C isoenzyme ofCyp.[4I]
being the main metabolite (13.4%), and 3'-hydroxy4'methoxy diclofenac being a minor metabolite (1.4%). The sum of all compounds in urine amounted to 36% of the dose)82] Another study indicates that 4' -hydroxy diclofenac is the main metabolite (38.6%), while diclofenac is excreted unchanged in a considerably higher amount ( 17.8 %). The total percentage of the dose excreted in urine varied from 58.2 to 82.8%.3'-hydroxy, 4' -hydroxy, 5'-hydroxy and 4',5-dihydroxy and diclofenac were excreted as 1.7,27.2, 7.7 and 6.7 and 13.6% of the dose)90] The conflicting information within the literature in diclofenac metabolic data may be due to the instability and spontaneous hydrolysis of glucuroconjugated metabolites, which can re-form the parent drug or isomerize to form a glucuronide resistant isoglucuronide in alkaline media. Diclofenac conjugates can hydrolyse to the parent compound depending on the duration of frozen sample storage, freezing and thawing of samples, the analytical procedures used and urinary retention in the bladder. 2.4 Elimination
2.3.2 Phase II Metabolism
It has been reported that diclofenac and its phase II conjugates excreted in urine are -12.6% of dose and -22% of the phase I metabolites. [1 55] In addition, in adult volunteers the renal excretion of unchanged diclofenac was 0.2 to 0.77% of the dose and 5 to 9.4% of diclofenac was excreted as conjugates in urine)6] Another study in old and young volunteers suggest that the total percentage of phase II metabolites excreted in urine is only 4.5% and that -0.5 to 0.7% is free diclofenac)63] Total 24-hour urinary outputs of total (free and conjugated) diclofenac demonstrated between 5 to 9% of the dose being excreted in urine.[57,76]It has been reported that -2% of the dose is excreted unchanged in urine)84] In children with juvenile rheumatoid arthritis 5.4 to lO.2% of an oral dose was excreted in urine over 12 hoursP4] Another study demonstrated that 6% of the dose was excreted in urine as free or conjugated diclofenac, with 4' -hydroxy diclofenac © Adis International Limited. All rights reserved.
Diclofenac is eliminated principally by metabolism with 60 to 70% of the dose excreted in urine)53,I5I] Elimination is rapid with 90% of the drug clearance taking between 3 to 4 hours. [57] The tY,fl of diclofenac is 1.2, 1.15 and 1.6 hours following oral, intravenous and rectal administration, respectively)59,90] However, another recent report suggests a terminal tl/2fl of 3.5 hours)I6] This discrepancy may be because of the increased sensitivity of the assay procedure and more accurate estimations of the terminal elimination phase of diclofenac in the latter study. The excretion of drug and metabolites occurs in urine, bile and faeces. In humans, renal excretion is predominant and greater than 60% of each daily dose is excreted as conjugates in urine.[I5I] After oral or intravenous administration of I4C-Iabelled diclofenac, approximately 61 % of the injected dose was excreted in urine and 30% in faeces)57] It has been reported that the mono- and di-hydroxy metabolites have a Clin. Pharmacokinet. 1997 Sep; 33 (3)
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terminal tY,[3 similar to diclofenac, approximately 1 to 4 hours)82) More recent studies suggest that the 4'-hydroxy metabolite has an apparent half-life of 4.3 hours in plasma. The 4'-hydroxy, 5'-hydroxy, 3'-hydroxy and 4',5'-dihydroxy metabolites have urinary tY,f3 of 3.6,2.5,2.3, and 3.1 hours, respectively)90) It is possible that diclofenac and the metabolites undergo biliary excretion, however, few studies to date have examined the biliary elimination pathway and the degree to which diclofenac and its metabolites are enterohepatically recycled. One report of 2 patients with extrahepatic cholestasis with a percutaneous transhepatic cholangiodrainage placed in the bile duct system found 4.62% of diclofenac sodium 50mg excreted in bile. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites ranged between 1.0 to 9%)155) The theoretical possibility of diclofenac excretion into breast milk and its uptake by the infant exists. Six lactating women each received an intramuscular injection of diclofenac sodium 50mg and demonstrated normal pharmacokinetic patterns, however, no drug was detected in their breast milk. The lack of appreciable drug in breast milk may be attributable to the high degree of plasma protein binding and the lower pH of breast milk as compared with plasma. Based on extrapolation of this study to nursing mothers, infant exposure to diclofenac via breast milk appears to be minimaU5) In addition, a later study showed no detection of diclofenac in the milk from lactating mothers following single doses of 50mg or 100mg daily over the course of 1 week)156) However, the metabolites of diclofenac all possess some pharmacological properties and their presence or absence in milk has not been established.
3. Implications of Pharmacokinetic Properties for Therapeutic Use 3.1 Dose, Therapeutic Range and Concentration/Effect Relationships
The usual recommended initial dosage for diclofenac is 75 to l50mg daily or 25 to 50mg 3 times © Adis International Limited. All rights reserved.
Davies & Anderson
a day. Linear pharmacokinetics are observed within the dosage range of 25 to l50mg daily. A sustained release diclofenac 75mg preparation has recently been developed which may improve patient compliance by reducing the dosage intervals to twice daily. The efficacy of sustained release preparations have been found to be as effective as standard enteric-coated formulations in controlling arthropathies)65,157,158) The ability of sustained release preparations to maintain effective therapeutic concentrations in plasma has been demonstrated by several investigators)25,94) These preparations, however, should not be assumed to be without adverse effects to the gastrointestinal tract. There have been several emerging case reports that suggest an association between lower gastrointestinal toxicity and the ingestion of sustained release diclofenac preparations (table IV).[l22.160-172) These case reports (see table V) are consistent with a recent study which demonstrates increased intestinal permeability with a sustained release formulation of diclofenac, but which does not occur with conventional release formulation of diclofenac)173) The intestinal permeability caused by sustained release products appears to be more variable than conventional release products, which could be caused by the longer residency within the intestinal tract, which may, in turn, induce more local distal intestinal damage in addition to a systemic intestinal adverse effect. A novel approach to solving the problem of gastrointestinal toxicity induced by diclofenac and other NSAIDs has been accomplished by linking a nitric oxide releasing moiety to the carboxylic acid functionality of the parent NSAID. These compounds, which are currently undergoing clinical trials, are pharmacodynamically equivalent to diclofenac but with reduced gastrointestinal toxicity)174-177) While a relationship between C max , AUC and the analgesic activity of diclofenac has not been demonstrated, it can be assumed that detectable drug concentrations may influence the onset of pharmacological action. Diclofenac demonstrates a relatively fast elimination from plasma, however, it Clin. Pharmacokinel. 1997 Sep: 33 (3)
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Clinical Pharmacokinetics of Diclofenac
Table IV. Pharmacokinetic properties of diclofenac in patients (diclofenac was administered as an immediate release dosage formulation in single doses except where indicated) Patient group (dosage form)
n
Agea (y) [range)
t1,,~
Dose (mg)
(h)
Vd/F (Ukg)
CUF (Uh/kg)
Reference
RA(EC)
10
57[46-68)
50mg EC
1.2
NR
NR
64
Children
5
5.4 [1-5)
0.5 mglkg IV 5 min INF
1.28
0.045
0.468
89
Children
5
5.4 [6-10)
0.5 mglkg IV 15 min INF
1.32
0.046
0.462
RA
12
51.9
100mg EC
0.91
NR
NR
100mg DIEP
0.84
NR
NR
88
5 PN
NR
NR
100mg
NR
0.2
0.11
159
RA(EC)
20
52 [21-70)
128 ± 35mg bid-tid for 28d
2.4
NR
NR
112
128 ± 35mg bid-tid + 3.0 ± 0.15 mglkglday cyclosporin for 28d
2.4
NR
NR
a
Mean age; range in parentheses.
Abbreviations and symbols: AC =alcoholic cirrhosis; ALOH =aluminum hydroxide; AUC =area under the concentration-time curve; CUF = plasma clearance of drug after oral administration; C max =peak plasma drug concentration; CR =controlled release; DIEP =diethylpyrrolidine; DM =diabetes mellitus; E =elderly; EC =enteric-coated; INF =infusion; 10 =intraocular; JRA =juvenile rheumatoid arthritis; MA =migraine attacks; MGOH =magnesium hydroxide; MRF =moderate renal failure; NH =neoplastic hyoproteinemia; n =number of subjects or patients in study; NR =not reported; PB =probenecid; PN = polyarterritis nodosa; q6h (q12h) =every 6 (12) hours; q6h (q12h) =every 6 (12) hours; qd =daily; qd· =daily; qid =4 times daily; qid =4 times daily; RA = rheumatoid arthritis; RI = renal insufficiency; SRF =severe renal failure; Supp =suppository; Imax =time taken to achieve C max; t1,,~ =elimination half-life; VdlF =apparent volume of distribution after oral administration.
has a long half-life at the site of inflammation, which may explain the duration of its therapeutic effect. The effects of once daily diclofenac treatment on synovial fluid prostanoid concentrations showed a reduction in prostaglandin (PGE2) and thromboxane (TXB 2) levels.I 1561 Long term administration of diclofenac also significantly reduced synovial fluid interleukin-6 and substance P in comparison with placebo, but did not affect interleukin-l ~
concentrations.l l 781 Minimal effective concentrations of diclofenac in synovial fluid was estimated to be 100 to 500 /J-g/L,[ I791however, a 20 to 60% suppression of plasma and synovial fluid PGE 2 and TXB2 levels occurred at plasma levels of 20 to 30 /J-g/L. Furthermore, inhibition of PGE 2, leukotriene B4 (LTB 4) and 5-hydroxyeicosatetranoic acid (5-HETE) persists for over 8 to 12 hours in rheumatoid patients treated with diclofenac.[l 461
Table V. Case reports of sustained release (SR) nonsteroidal anti-inflammatories (NSAID)-induced toxicity n (gender)
Mean age (range) [sd)
Duration of use (range)
Histopathological clinical findings
Reference
56 (60% F)
53.8 [17.6)
Variable
Gastrointestinal, skin and appendages, CNS, other
122
Small intestine 5 (4M/1 F) 62.2 (38-85)
10 days-5 years
Right-sided lower abdominal pain, diarrhoea, dyspepsia, ileal and cecal ulcers, thickened wall and irregular wall surface of the jejunum, submucosal fibrosis, stercoral ulcers in ascending colon
160,168, 169, 171
Large intestine 16 (11 F/5M) 66.07 (49-85)
10 days-6 years
Cecal and colonic ulceration, anaemia stricturing scars, colitis, strictures, iron deficiency, submucosal fibros is, bloody mucous, diarrhoea, weight loss, constipation, semilunar colonic ulcers and 'diaphragm-like' stenosis, colicky abdominal pain, 'diaphragm-like' stenosis, peritonitis, perforation of mid-ileum, stercoral ulcers in ascending colon, colonic diaphragms, multiple thin circumferential mucosal membranes and cecal diaphragm
161 -167, 170, 172
Abbreviations: CNS =central nervous system ; F =female; M
© Adis Intematio nal Limited. All rights reserved.
=male; sd =standard deviation. C lin. Pharrnacokinet. 1997 Sep; 33 (3)
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It is postulated that inhibition of leukotriene production is partially mediated through modulation of arachidonic acid utilisation by leucocytes. [146] A dose-response relationship for patients with arthritis has not been elucidated. The clinical response of patients with dental pain, administered diclofenac 50 or 100mg, and its relationship to plasma concentrations showed that efficacy as measured by a visual analogue score was related to higher concentrations of diclofenac. The faster onset of analgesia correlated with increased plasma trough concentrations and the trough concentrations increased proportionately with dose.[7I] Osteoarthritis patients treated with diclofenac for 91 days demonstrated a linear correlation between plasma concentration and analgesic effects, as well as other therapeutic end-points. [180] A study in patients with rheumatoid arthritis has suggested that the onset and duration of analgesia, assessed by visual analogue scales, did not correlate with plasma concentrations.[l20] Few studies have attempted to correlate clinical, pharmacokinetic and pharmacological data. One such study has attempted to correlate diclofenac concentrations, clinical efficacy and the effect of diclofenac mediators on inflammation. Interestingly, the clinical efficacy, as shown by decreases in morning stiffness and the Lee Index (a functional index of rheumatoid arthritis), correlated with the free concentration of diclofenac in synovial fluid, which is a proposed site of action for diclofenac in rheumatoid arthritis. However, there was no significant correlation between concentration and analgesic activity demonstrated. These findings may genuinely reflect a lack of correlation, but also suggest the lack of sensitivity of the measured end-points, the subjective nature of clinical data relative to the evaluation of inflammation and pain, and the need for more sensitive quantitative surrogate markers of efficacy and toxicity. Moreover, so far no published studies have related diclofenac concentrations to adverse effects. One proposed mechanism of action for diclofenac is the competitive displacement of existing endogenous substances from binding sites on plasma proteins, and that non-protein bound forms © Adis International Limited. All rights reserved.
of these substances may protect tissue such as joints from chronic inflammatory processes. The influence of diclofenac sodium on free, protein-bound, and total plasma L-tryptophan in healthy adults after single and multiple doses demonstrated increases in free plasma tryptophan and decreases in both protein bound and total plasma tryptophan, which were correlated with plasma concentrations of diclofenac.l 68 ] Unfortunately, no follow-up studies have been published with respect to this suggested relationship and mechanism of action. 3.2 Diciofenac Pharmacokinetics and Disease States 3.2. 1 Renal Insufficiency
Many patients with rheumatic disorders have some degree of renal function impairment and elderly patients with poor renal function are especially susceptible to the induction of renal failure by NSAIDs. Studies with single intravenous doses of I4C-Iabelled diclofenac in 5 patients with varying degrees of renal impairment indicated that the AUC is markedly increased only when the creatinine clearance is 0.18 Llh or less, but the AUC for unchanged diclofenac sodium was not influenced by renal function.l I8I ] In severe renal impairment, steady-state concentrations of the total conjugated metabolites for 2 daily doses of 50mg can be expected to be 4 times higher than in individuals with normal renal function. The excretion of diclofenac and its metabolites in urine decreased in direct proportion to the reduced glomerular filtration rate.l I8I ] In individuals with impaired renal function, urinary excretion of diclofenac, 3'-hydroxy, 5'-hydroxy and 3'hydroxy-4'-methoxy diclofenac accounted for less than 1% of the oral dose and the excretion of 4'hydroxy represented 2.4% of the dose. A comparison of 4'-hydroxy excretion in individuals with normal and impaired renal function were approximately 31 and 4%, respectively.l40] The binding of diclofenac to serum proteins may be lower in patients with severe renal failure. The reduced binding may increase Vd and increase the clearance of the drug. Unfortunately, the unC1in. Pharmacokinet. 1997 Sep; 33 (3)
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Clinical Pharmacokinetics of Diclofenac
bound clearance of diclofenac was not determined, although, in theory this may decrease with renal impairment. It is also possible that there was a reduced absorption or a compensatory increases biliary excretion and the excretion of the drug in faeces. However, no studies have assessed these pharmacokinetic possibilities. In addition, there is no information published indicating whether or not diclofenac is dialysable. 3.2.2 Hepatic Insufficiency
The influence of chronic hepatic impairment on diclofenac pharmacokinetics has not been completely delineated. As diclofenac undergoes significant hepatic metabolism, there may be important pharmacokinetic variations in patients with hepatic disorders (Le. hepatitis, cholestasis, cirrhosis and ascites). Albumin, globulin and the total protein decrease in patients with hepatic disease, which could increase the free fraction of diclofenac. The pharmacokinetics of diclofenac in patients diagnosed with chronic hepatitis or cirrhotic hepatitis after oral administration of a single dose of diclofenac 250mg showed a significant delay of absorption in cholestatic patients (tmax = 1.25 hours), which may have been because of their fasting state as compared with the control group. However, they had no other pharmacokinetic differences compared with patients who had normal liver function.[73] In the majority of these patients elimination was diminished due to a decrease in metabolic capacity for the drug. Unfortunately, the degree of plasma protein binding was not determined in these patients, which may have been significantly reduced. Patients with hepatic impairment, specifically with Laennec's cirrhosis and alcoholic cirrhosis, have shown diminished intrinsic clearance of diclofenac, which suggests that both conjugation and demethylation are affected. However, the urinary excretion of metabolites was equivalent to that in healthy individuals. Oral clearance of diclofenac was not reduced after a single dose in liver cirrhosis as compared with healthy individuals. A study of 10 patients with hepatic impairment demonstrated that the pharmacokinetics of a sin© Adis International Limited. All rights reserved.
gle oral dose of diclofenac was not significantly changed. One report of a patient with reduced liver metabolic activity demonstrated an increased AUe value for diclofenac, which coincides with altered hepatic uptake processes in humans showing quantitatively similar losses of unbound diclofenac clearance. [181] The clinical sequelae of higher unbound diclofenac concentrations to either efficacy or toxicity has not been determined. However, a significant negative correlation between serum bilirubin concentration and serum protein binding of diclofenac has been demonstrated.l 181 ] 3.2.3 Rheumatic Disorders
The effect of rheumatoid arthritis on the pharmacokinetics of diclofenac has not been extensively studied. One report in a middle-aged patient with rheumatoid arthritis suggests that total plasma concentrations were much lower in patients with rheumatoid arthritis, but there was no change in AUe and terminal t[/2~.[64] There is no information available on unbound diclofenac concentrations where peak values may be significantly higher in the active phase of arthritis. Fluctuations in serum albumin due to disease processes with corresponding protein binding changes may have pharmacokinetic and pharmacodynamic consequences. In addition, disease states such as rheumatoid arthritis may affect the capacity of the liver to metabolise diclofenac, possible through the effects of inflammatory mediators, hepatic uptake of unbound drug or modulation of intrahepatic processes. There was very little difference between the plasma protein binding in patients with arthritis when compared with healthy individuals.l 141 ] Plasma exchange is sometimes used as a therapeutic modality for patients suffering from systemic disease associated with polyarthritis nodosa or hepatitis B etc. The effects of plasma exchange in patients with histologically proven polyarteritis nodosa demonstrated that between 14 to 17% of the diclofenac was removed during each session. Plasmaphoresis clearance ranged between 23 to 51 % of the plasma clearance for diclofenac. Pharmacotherapy of diclofenac in patients undergoing plasma exClin. Pharmacokinet. 1997 Sep: 33 (3)
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change should be administered after the end of each session. [182,159] 3.3 Influence of Age on Diclofenac Pharmacokinetics
Therapeutic regimens in paediatric patients are based on extrapolation of pharmacokinetic data in adults. The recommended dosage in children is 2 to 3 mg/kg. The single intravenous dose pharmacokinetics of diclofenac given pre-operatively in children after S and IS minute infusions show a 2-fold increase in clearance and a S-fold higher Vd with similar terminal tl/2B when compared with adults,l89] Unfortunately, there is no information available on plasma protein binding in this age group; therefore, some children may require more frequent doses to maintain clinical response. The pharmacokinetic parameters for children over 2 years of age with juvenile rheumatoid arthritis corresponded to adult values after a single enteric-coated 2Smg tablet. The youngest patient (2 years old) had a lower elimination rate (2.2S%) in urine over 12 hoursP4] In another study, children with juvenile rheumatoid arthritis were treated daily with diclofenac suppositories. The maximum concentrations of diclofenac were attained O.S hours after drug administration and no evidence of accumulation was evident after 16 days of treatment,l183] The administration of single or multiple doses of entericcoated diclofenac SOmg tablets to fasted female patients less than 21 years of age and fasted female patients over 62 years of age showed no significant differences with respect to mean Cmax or urinary excretion patterns.[58,63] However, the amount of unchanged diclofenac excreted in urine over the first few hours post-dose was greater for younger patients,l63] In a more recent study,l65] the mean maximum plasma concentration and AUC were increased 4and 2-fold, respectively, in elderly (mean 76 years) compared with non-elderly (mean 47 years) patients with osteoarthritis. Fluctuations in serum albumin levels and changes in the severity of disease could alter the pharmacokinetics of highly bound drugs. In addition, the normal aging process © Adis International Limited. All rights reserved.
Davies & Anderson
can affect the capacity of the liver to metabolise diclofenac. 4. Pharmacokinetic Drug Interactions 4,1 Effect of Other Drugs on the Pharmacokinetics of Diclofenac
There is considerable information regarding the effects of other drugs on the pharmacokinetics of diclofenac. Sometimes combinations of NSAIDs are used in the treatment of chronic arthropathies. Aspirin (acetylsalicylic acid) when given at therapeutic doses concurrently with diclofenac causes a significant lowering of diclofenac plasma concentrations and a reduction in AUC,l57,67,69] Pre-treatment with aspirin for 6 days did not reduce this effect any further,l67] The displacement of diclofenac from protein binding sites, a transient increase in Vd and increased plasma clearance is the underlying pharmacokinetic explanation for these changes,l69] This may be a concern because of the potential for self-prescribing of aspirin by patients already receiving NSAIDs. In patients with rheumatoid arthritis, diclofenac either alone or in combination with aspirin, was superior to aspirin alone for pain and morning stiffness. Thus, there was no evidence of an enhanced therapeutic effect or toxicity and no apparent clinical manifestations of this pharmacokinetic interaction.[I84] To improve analgesia, combinations of centrally and peripherally acting analgesics are of particular interest in the treatment of chronic cancer pain. The concomitant administration of codeine with diclofenac, either as a suppository or a tablet, did not affect the relative bioavailability of diclofenac,ll 10,1 17] Diclofenac administered ISOmg daily with 400mg of the analgesic floctafenine for 1 week did not show any interference with protein binding. The plasma concentrations of diclofenac were slightly reduced but no pharmacokinetic interaction was detectableP2] Daily administration of diclofenac sodium and paracetamol (acetaminophen) to healthy volunteers for 16 days did not show any significant differences in AUC,ln] Additionally, for prophyClin. Pharmacokinet. 1997 Sep; 33 (3)
Clinical Pharmacokinetics of Diclofenac
laxis and treatment of gastric and duodenal ulcers, gastroprotective agents are sometimes coadministered with NSAIDs to counteract the adverse gastrointestinal adverse effects of this class of drugs. Sulglicotide coadministered with diclofenac did not interfere with the bioavailability of diclofenac)81] A gastroprotective formulation of diclofenac and sucralfate did not show any differences in AVC, however, an earlier and greater Cmax was observed)81] This contrasts with a more recent study demonstrating that short term pretreatment of healthy male volunteers with sucralfate decreased potassium diclofenac AVC and Cmax without affecting t max )114] The concomitant administration of aluminum hydroxide or magnesium hydroxide antacid combinations may delay the absorption of diclofenac but does not affect the total amount of the drug absorbed)185] Another study demonstrated that magnesium hydroxide-containing antacids had no effect on the rate or extent of absorption; however, the average plasma concentration was about 50% higher at 40 to 90 minutes after administration and the C max occurred about 0.5 hours earlier when the drug was taken with magnesium hydroxide)93] This effect could be attributed to the premature dissolution of the enteric-coated tablet in a local basic pH environment. Volunteers who received diclofenac alone and concomitantly with an antacid containing aluminum hydroxide and magnesium hydroxide did not show any difference in mean cumulative urinary excretion. In several individuals the elimination of diclofenac was delayed after intake of the antacid. The rate of absorption may also be retarded under such conditions.l7 2] NSAIDs are sometimes coadministered with histamine (H2) receptor antagonists for healing and reducing the incidence of gastroduodenal ulceration. A single dose of diclofenac 75mg given with 2 doses of ranitidine demonstrated only a slight increase in diclofenac Cmax when compared with the administration of diclofenac alone. The increase in gastric pH did not appear to influence the oral absorption of enteric-coated diclofenac.[98] The influence of 2 dose ranitidine treatment on enteric© Adis International Limited. All rights reserved.
205
coated diclofenac products showed no differences in Cmax , however, there was a slightly reduced bioavailability evident. [105] In addition, a combination tablet of diclofenac and misoprostol demonstrated no pharmacokinetic interaction between diclofenac and misoprostol. The bioavailability of diclofenac from the combination tablet was similar to that seen when the 2 drugs are given separately)96] However, caution must be taken when extrapolating this to other prostaglandin analogues. Single and repeated pre-medication with nocloprost (a prostaglandin analogue) influenced the pharmacokinetics of diclofenac. An acceleration of absorption rates, decrease in AVC and an apparent increase in total body clearance was evident, however, this only reached significance after single dose pre-medication and was not apparent upon multiple dose administration.[I03] Interestingly, a pilot study comparing placebo, misoprostol 200~g, diclofenac sodium 50mg and their combination with diclofenac concluded that misoprostol had a small analgesic effect and could potentiate the analgesic effect of diclofenac when used in combination. The potentiation of analgesia was specific for diclofenac as it was not apparent in a parallel study using ibuprofen.[l13] NSAIDs are often coadministered with diseasemodifying antirheumatic drugs such as methotrexate and cyclosporin for the management of patients with rheumatoid arthritis. NSAIDs are occasionally coadministered with cyclosporin in severe or refractory patients with rheumatoid arthritis. Several reports suggest a potential nephrotoxic interaction between cyclosporin and diclofenac, which clinically manifests as an increase in plasma creatinine, serum potassium and blood pressure.[l86] A single oral dose of cyclosporin administered alone and on day 8 of multiple oral doses of diclofenac 50mg demonstrated a significant increase in diclofenac Cmax and AVC with extensive variability))3] A recent study in patients with refractory rheumatoid arthritis (n = 20) investigating the effect of cyclosporin on the pharmacokineticspharmacdynamics of diclofenac during combination therapy demonstrated a 104% increase in the Clin. Pharmacokinet. 1997 Sep: 33 (3)
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AUC with a significant rise in baseline serum creatinine. There was no change in t l/ 2, and the authors attributed the increase in AUC to an increase in systemic exposure due to a reduction in first pass metabolism. There was no apparent correlation with the pharmacokinetic changes and effect on serum creatinine or blood pressure; however, it may be advisable to start diclofenac and cyclosporin combination therapy at the lower end of the therapeutic dose range.! 112] Since diclofenac is administered as the salt of a weak acid, pH may affect the pharmacokinetic parameters, however, the simultaneous administration of several alkaline antirheumatic drugs, including gold keritinate, penicillamine, chloroquine, azathioprine, prednisolone, cefadroxil and doxycycline did not result in any appreciable changes in the pharmacokinetics of diclofenac.[7S,187] The coadministration of triamcinolone diacetate 40mg with a single dose of intramuscular diclofenac did not show any significant pharmacokinetic changes except for a 20% increase in the mean C max of diclofenac.l 16] This increase in Cmax may be due to a slight increase in the rate of absorption. Rheumatic disease may also be associated with type II hyperlipidaemias, for which patients may receive cholestipol resin or cholestyramine. Pharmacokinetic changes in diclofenac adsorption due to colestipol resin and cholestyramine result in a reduction in AVC by 33 and 62%, and Cmax by 58 and 75%, respectively.[I08] In vitro studies indicate that diclofenac has no significant effect on the serum protein binding of salicylic acid, tolbutamide, prednisolone, acenocoumarol or warfarin.l S2 ,139] The in vitro binding of diclofenac to serum is not affected by benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin and sulphamethazoleP] 4.2 Effect of Diclofenac on the Pharmacokinetics of Other Drugs
The short term administration of diclofenac and aspirin showed an effect on salicylic acid plasma profiles. After 2 weeks of the diclofenac regimen, aspirin administration over a 6-day period demon© Adis International limited. All rights reserved .
Davies & Anderson
strated lower average steady-state salicylic acid plasma concentrations with a more rapid cumulative urinary excretion of total salicylate.l69] Concomitant diclofenac administration with intravenous tolbutamide in patients with maturity onset diabetes mellitus showed no significant difference in blood glucose levels, insulin levels or any demonstrable effect on plasma tolbutamide concentrations.!S] No appreciable effect on drug or carbohydrate requirements is necessary for patients with diabetes mellitus treated with diclofenac, including insulin, sulphonylurea or biguanide therapy.f188] Furthermore, fasting blood sugar and urinary sugar excretion was not affected upon diclofenac administration in patients with diabetes mellitus plus rheumatic disease stabilised on glibenclamide.f 1791 NSAIDs may potentiate the effect of oral anticoagulants by displacing them from protein binding sites or altering their metabolism. A 4 times daily dose of diclofenac 25mg showed no statistically significant differences in prothrombin times when compared with placebo in hospitalised patients receiving acenocoumaroPS,189] Patients on long term phenprocoumon therapy following myocardial infarction or thrombophlebitis administered diclofenac sodium 25 to 50mg 3 times daily for 14 days showed only minor changes in prothrombin times and anticoagulant requirements.[1 90] Diclofenac does not appear to affect plasma coagulation as assessed by thrombin and partial thromboplastin time during thromboembolism prophylaxis treatment with heparin/dihydroergotamine in patients with total hip replacements, and diclofenac can be safely coadministered in such patients for anti-inflammatory analgesic properties.l 191 ] NSAIDs are often coadministered with disease modifying anti-rheumatic drugs such as methotrexate, cyclosporin and sulphasalazine for the management of patients with rheumatoid arthritis. However, a severe and occasionally fataL interaction between diclofenac and indomethacin with methotrexate has been documented.l 192 ] This toxicity is postulated to be due to: Clin. Pharmacokinet. 1997 Sep; 33 (3)
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• a consequence of the displacement of methotrexate from plasma proteins • altered hepatic metabolism of methotrexate • altered renal prostaglandin synthesis resulting in a decrease in glomerular filtration rate and methotrexate clearance • competition for renal tubular secretion between NSAIDs and methotrexate. The mechanism of this interaction between diclofenac and methotrexate still remains a matter of speculation. Another possibility is that since the 7-hydroxy metabolite of methotrexate and diclofenac are highly protein bound, displacement of 7 -hydroxy-methotrexate (MTX) by diclofenac would increase the concentration of the 7 -hydroxyMTX eligible for renal filtration, which could promote renal damage. Several studies of methotrexate disposition kinetics with coadministered diclofenac have been published with conflicting results. A decreased oral clearance of methotrexate when diclofenac was concomitantly administered to adults with rheumatoid arthritis has been reported with a trend towards a reduced renal c1earance.l 192 ] Conversely, no alterations of methotrexate kinetics in patients with rheumatoid arthritis treated with methotrexate and diclofenac have been found.l 193 ] There were, however, apparent methotrexate/ diclofenac interactions in individual patients on NSAIDs and variability in the renal clearance of methotrexate.l 194j Moreover, an alteration in the Vd of methotrexate was evident after diclofenac administration. However, the small number of patients, wide variability and limited sensitivity for detection may also account for these differences. Several reports suggest a potential nephrotoxic interaction between cyclosporin and diclofenac; however, this does not appear to be a pharmacokinetic interaction as whole blood trough concentrations of cyclosporin did not show marked changes when diclofenac was introduced or withdrawn.l 195 ] In addition, another study has also demonstrated that the mean pharmacokinetic parameters of cyclosporin were unchanged during coadministration with diclofenacP 31 Conversely, I case report © Adis International Limited, All rights reserved,
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showed that steady-state cyclosporin concentrations decreased by 30% after commencing diclofenac therapy and that changes in cyclosporin whole blood concentrations appeared to follow rather than precede changes in serum creatinine.[ 1961 In addition, the single dose pharmacokinetics of sulfasalazine in rheumatoid patients with and without steady-state diclofenac 50mg 3 times daily demonstrated large variations in sulphasalazine, sulphapyridine and acetylsulphapyridine concentrations. The only significant effect of diclofenac therapy was to reduce the tmax of the sum total of sulphapyridine and acetylsulphapyridine.l 197 ] Diclofenac may decrease the renal clearance of lithium, which may cause an increase in serum lithium concentrations and overdose.[198] Thus, careful monitoring and titration of lithium dosage is required in patients who receive diclofenac and lithium concurrently. After an 8-day pre-treatment of digoxin to steady-state concentrations in healthy volunteers, the administration of diclofenac increased plasma digoxin concentrations 72 hours post-dose, which returned to normal after 2-days upon discontinuation of diclofenac.l 1991 Although no clinical signs of toxicity were noted, digoxin intoxication correlates with plasma concentrations and careful monitoring of patients receiving these drugs concomitantly is advised. NSAIDs are sometimes coadministered with H2 receptor antagonists for healing and the reducing incidence of gastroduodenal ulceration. A single dose of diclofenac 75mg with 2 doses of ranitidine demonstrated only a slight decrease in the Cmax of ranitidine when compared with the control group. In addition, a combination tablet of diclofenac and misoprostol demonstrated no pharmacokinetic interactions between diclofenac and misoprostol. The bioavailability of misoprostol from the combination tablet was similar to that seen when the 2 drugs are given separately.[961 Diclofenac sodium does not enhance the hypoglycaemic effect of tolbutamide, biguanide or glibenclamide in patients with diabetes mellitus. Diclofenac 150mg daily had no appreciable effect on [14C]aminopyrine breath tests in 19 paClin, Pharmacokinet, 1997 Sep; 33 (3)
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tients. [5,200] This indicates that diclofenac does not influence hepatic demethylation capacity and is also unlikely to interact with other drugs that are metabolised by this pathwayPOI] A case report describing acute renal failure in a patient receiving diclofenac and triamterene has been reported.[202] The effectiveness of hydrochlorothiazide was reduced after the addition of diclofenac to the therapy, and lead to bodyweight gain; however, there was no attenuation of blood pressure by diclofenac in patients with essential hypertensionP03]
5. Conclusions The therapeutic and toxicological relevance of diclofenac pharmacokinetic data requires further study. There is limited information on the concentration-effect relationships of diclofenac. A relationship between anti-inflammatory effect, analgesic effect and the plasma concentrations of the drug has yet to be established. Future research should try and delineate the pharmacodynamic role of the metabolite profiles, formulation-dependent gastrointestinal toxicity, unbound drug concentrations and the importance of the enterohepatic recirculation on the pharmacokinetic and pharmacodynamic data. Since many patients may not respond to a certain NSAID, and toxicological profiles between NSAIDs may differ, there is a continued need for safe and effective therapeutic alternatives.
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Correspondence and reprints: Dr Neal M. Davies, Faculty of Medicine University of Calgary, Department of Pharmacology and Therapeutics, Calgary, Alberta, T2N 4Nl, Canada. e-mail:
[email protected]
Clln. Pharmacokinet. 1997 Sep; 33 (3)
