DRUG DISPOSITION ____________________________________~

Clin. Pharmacokinet. 20 (4): 263-279, 1991 0312-5963/ 91/0004-0263/$08.50/0 © Adis International Limited. All rights reserved. CPKl430

Clinical Pharmacokinetics of Ketanserin Bengt Persson, Jos Heykants and Thomas Hedner Department of Medicine I and Clinical Pharmacology, Sahlgren's Hospital, Gothenburg, Sweden, and Department of Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutica, Beerse, Belgium

Contents 263 265 265 265 265 265 266 266 266 267 268 268 268 269 271 272 273 273 274 275 275 277 277 277 277 277

Summary

Summary I. Chemical and Physical Properties of Ketanserin 2. Analytical Methods of Measuring Ketanserin and its Metabolites in Biological Samples 2.1 High Performance Liquid Chromatography 2.2 Radioimmunoassay 3. Absorption and Bioavailability 3.1 Influence of Food and Gastric Acidity 4. Tissue Distribution and Plasma Protein Binding 4.1 Tissue Distribution 4.2 Plasma Protein Binding 5. Metabolism and Excretion 6. Plasma Concentrations and Half-Life of Ketanserin 6.1 Single-Dose Administration 6.2 Long Term Administration 6.3 Relationship Between Plasma Concentration and Therapeutic Efficacy 6.4 Relationship Between Plasma Concentration and Adverse Effects 7. Pharmacokinetics in Special Patient Groups 7.1 Elderly Patients 7.2 Hepatic Insufficiency 7.3 Renal Insufficiency 8. Drug Interactions 9. Implications of Ketanserin Pharmacokinetics for Clinical Use 9.1 Therapeutic Use 9.2 Adverse Events 9.3 Drug Interactions 9.4 Therapeutic Drug Monitoring

Ketanserin is a serotonin S2-receptor antagonist introduced for the treatment of arterial hypertension and vasospastic disorders. Plasma concentrations of ketanserin (and some metabolites) can be measured with high performance liquid chromatography using ultraviolet or fluorescence detection, or by radioimmunoassay. The methods are sensitive, accurate and specific. Following oral administration ketanserin is almost completely (more than 98%) and rapidly absorbed and peak concentrations in plasma are reached within 0.5 to 2 hours. It is subject to considerable extraction and metabolism in the liver (first-pass effect) and the absolute bioavailability is around

264

C/in. Pharmacokinet. 20 (4) 1991

50%. The compound is extensively distributed to tissues and the volume of distribution is in the order of 3 to 6 Ljkg. In plasma ketanserin binds avidly to plasma proteins, mainly albumin, and the free fraction is around 5%. Ketanserin is extensively metabolised and less than 2% is excreted as the parent compound. The major metabolic pathway is by ketone reduction leading to formation of ketanserin-ol which is mainly excreted in the urine. Ketanserin-ol, which by itself does not contribute to the overall pharmacological effect, is partly reoxidised into ketanserin, and it is likely that the terminal half-life of the parent compound is related to the slow ketanserin regeneration from the metabolite. Following intravenous administration plasma ketanserin concentrations decay triexponentially with sequential half-lives of 0.13, 2 and 14.3h. The terminal half-life is similar after oral administration. Following long term oral dosing (20 or 40mg twice daily) the pharmacokinetics remain linear and steady-state concentrations, which can be predicted from single-dose kinetics, are reached within 4 days. During long term treatment with the common dosage of 40mg twice daily, steady-state concentrations fluctuate between 40 I'gfL (trough) and 100 to 140 I'gfL (peak). The pharmacokinetic properties of ketanserin are predictable in a wide group of patients and there is no influence from the duration of treatment, age and sex of the patient or concomitant treatment with ,s-blockers or diuretics. There is no direct relationship between plasma concentrations of ketanserin and the antihypertensive effect in a group of patients. Side effects, including prolongation of the Q-T interval, are dose-dependent and, at least in the individual patient, related to peak plasma concentrations. In separate studies the pharmacokinetics of ketanserin were investigated in special patient groups, namely the elderly and patients with hepatic and renal insufficiency. In elderly patients over 65 years of age the pharmacokinetics were similar to those found in healthy subjects; if anything, the bioavailability and area under the plasma concentration-time curve tended to be higher in some patients. In patients with severe hepatocellular insufficiency, the bioavailability of ketanserin is markedly higher due to a reduced hepatic elimination; in spite of higher plasma concentrations the terminal half-life is not changed. In view ofthese observations a higher dosage than 20mg twice daily is not likely to be required. In patients with renal insufficiency, elimination of the metabolite ketanserin-ol is prolonged but adaptation to lower doses of ketanserin is probably not necessary since plasma concentrations of the parent compound are similar to those seen in patients with normal kidney function. Studies in vitro with ketanserin at concentrations normally seen in patients on long term therapy indicate that ketanserin does not displace other drugs from their protein binding sites in plasma. Conversely, the protein binding of ketanserin is not influenced by the coadministration of other highly bound drugs. There is no evidence that ketanserin induces or reduces hepatic enzyme systems, and it is therefore unlikely that ketanserin treatment will have clinically important effects on the metabolism of concurrently administered drugs, but formal interaction studies are lacking. Combined treatment with propranolol or cimetidine did not influence the pharmacokinetics of ketanserin. Furthermore, ketanserin did not appreciably alter the single-dose pharmacokinetics of digoxin and digitoxin or the steady-state concentrations of digoxin during long term therapy.

Ketanserin is a serotonin 5-HT2 receptor blocking agent with relatively weaker al-adrenoceptor and histamine HI-receptor blocking properties (Brogden & Sorkin 1990; Leysen et al. 1981). It reduces blood pressure by peripheral vasodilatation in a wide range of patient categories, and has been introduced as an antihypertensive agent (for review see Vanhoutte et al. 1988). In addition, it blocks platelet aggregation and improves haemor-

rheological properties, which may have therapeutic implications in vasospastic disorders such as Raynaud's syndrome and claudicatio intermittens. The pharmacokinetics of ketanserin have mainly been studied in healthy subjects and in hypertensive patients. This review summarises the current knowledge of the clinical pharmacokinetics of ketanserin, with emphasis on the clinical relevance. Throughout the review, citations of data on file re-

265

Clinical Pharmacokinetics of Ketanserin

monitoring or by fluorescence detection. All methods have acceptable characteristics oflinearity, reproducibility and accuracy, and the sensitivity limit is around I to 10 mg/L with UV monitoring and 0.1 to 0.2 myL with fluorescence detection. Hydroxylation

N-Dealkylation

Reduction

Fig. 1. Structural formula ofketanserin and major metabolic pathways.

fer to unpublished data held by Janssen Research Foundation Information Service, Beerse, Belgium.

1. Chemical and Physical Properties of Ketanserin Ketanserin [R41468, 3-(-2-[4-(-fluorobenzoyl)-Ipiperidinyl] ethyl)-2,4( 1H,3H)-quinazolinedione] (fig. 1) is a weak base (pKa = 7.50) with moderate lipophilicity (log P = 3.30 in the octanol-water system). Its solubility in water is 2.4% (24 giL). Ketanserin tartrate is used in all pharmaceutical formulations. All doses and concentrations in biological fluids are expressed as ketanserin base.

2. Analytical Methods of Measuring Ketanserin and its Metabolites in Biological Samples 2.1 High Performance Liquid Chromatography Several high performance liquid chromatography (HPLC) procedures have been described for the measurement of ketanserin and, in some cases, for the simultaneous determination of ketanserinol and/or 6-hydroxy-ketanserin in biological samples (whole blood, plasma, urine, tissues) [Davies 1983; Kacprowicz et al. 1983; Kurowski 1985a; Lindelauf 1983; Okonkwo et al. 1983; Simon & Somani 1982]. These methods employ the 4-chlorobenzoyl analogue (R46594) of ketanserin as internal standard. After extraction of an alkalinised sample with organic solvent systems, ketanserin and its metabolites are analysed using reversed-phase chromatographic conditions. The chromatographed compounds are quantified either by UV

2.2 Radioimmunoassay Ketanserin in plasma can also be assayed by a radioimmunoassay (RIA) procedure using antibodies raised in rabbits by repeated injections with a hapten chemically linked to bovine serum albumin (Woestenborghs et aI., data on file, No. 18427). The limit of sensitivity was 0.2 mg/L and, in plasma samples (n = 140) from subjects who had received single intravenous and oral doses, or repeated oral doses ofketanserin (Trenk et al. 1983), a very good correlation (r = 0.99) was found between HPLC and direct RIA (data on file, No. 31893).

3. Absorption and Bioavailability Orally administered ketanserin is rapidly absorbed and peak plasma concentrations are attained within 0.5 to 2h in both healthy volunteers (Heykants et al. 1986; Reimann et al. 1983; Trenk et al. 1983; Uji et al. 1988) [table I; fig. 2] and hypertensive patients (Fujita et al. 1988; Hedner et al. 1983; Hedner & Persson 1984; Persson et al. 1987; Waller et al. 1987a), irrespective of the dose or dosage form (Heykants et al. 1986). Using 14C_ labelled ketanserin in healthy volunteers Meuldermans et al. (1988a) concluded that the absorption is virtually complete, since only 0.2% of the oral dose was excreted as unchanged drug in faeces (fig. I, table II). Furthermore, the extent of the absorption of orally administered ketanserin is proportional to the dose within the clinically used dose range of 20 to 60mg (Heykants et al. 1986) [table III]. Following absorption from the gastrointestinal tract about half of the dose is extracted by the liver, and after oral administration the absolute bioavailability is in the order of 50% in both healthy volunteers (Heykants et al. 1986; Reimann et al.

Clin. Pharmacokinet. 20 (4) 1991

266

1983; Trenk et a!. 1983} and hypertensive patients (Persson et a!. 1987). Hence, ketanserin may be characterised as a drug with an intermediate extraction ratio and the elimination is partly dependent on hepatic blood flow, enzymatic activity and unbound drug. Since a moderate (20%) reduction in the extraction ratio would result in a 50% increase in the AUe for the same dose (Heykants et a!. 1986) the bioavailability was, predictably, higher in patients with hepatic insufficiency (Lebrec et a!. 1990) and in some elderly subjects (Kurowski 1985b). In healthy volunteers the bioavailability of a dose of ketanserin lOmg was identical with both intramuscular and intravenous modes of administration (Heykants et a!. 1986).

not influenced by the presence of food in the stomach [area under the concentration-time curve from time zero to 8h after administration (AUe(O_8)}: 425 ± 146 mg/L· h with a meal versus 428 ± 118 mg/L· h fasting] , in fasted subjects it was adversely affected by a reduction in gastric acidity, resulting in a 35% reduction in the mean AUe(O_8) value (275 ± 75 mg/L· h) [Heykants et a!., data on file, No. 22763}. However, antacids alone ('Maalox') when given 1.5h before and after ketanserin did not affect the rate and extent of ketanserin absorption (Van Velde et a!., data on file) [fig. 3, table IV].

4. Tissue Distribution and Plasma Protein Binding 4.1 Tissue Distribution

3.1 Influence of Food and Gastric Acidity As can be expected from the fast initial decline of plasma concentrations in the initial phase [fig. 2], after intravenous administration ketanserin is extensively distributed to the tissues. The volume of distribution at steady-state (Vss) was in the order of 3.3 to 6.2 L/kg in healthy volunteers (Heykants et a!. 1986; Reimann et a!. 1983; Trenk et a!. 1983) [table I], which agrees with values observed in hy-

The influence of a meal and gastric acidity on the absorption of ketanserin was investigated in 6 healthy subjects who in different phases of the study received a single oral dose of ketanserin 40mg (as a capsule) during fasting, with a meal and after pretreatment with cimetidine and sodium bicarbonate. Whereas the absorption of ketanserin was

Table I. Mean (± SD) pharmacokinetic parameters in healthy subjects after a single intravenous dose of ketanserin 10mg and single oral doses of ketanserin 20 or 40mg Parameter (units)

No. of subjects Cmax (I'g/L) t max (h) t'l2P (h) V•• (L/kg) Vd (L/kg) AUC(o-oo) (I'g/L • h)

Heykants et al. (1986)

Reimann et al. (1983)

10mg (IV)

10mg (IV)

10

14.3 ± 4.4 3.7 ± 0.96 9.7 ± 3.3 298 ± 36

F (%)

CL (L/h) Ae(O-48) (%)

33.9 ± 3.42 0.76 ± 0.43

40mg (soln) 10 198 ± 53 0.60 ± 0.24 17.8 ± 3.8

625 ± 99.6 50.4 ± 6.2 0.67 ± 0.36

6

12.4 ± 2.9 6.2 ± 1.9 6.9 ± 1.9 406 24.6 ± 3.72 3.0

40mg (tab) 6 193 ± 98 1.6 ± 1.4 12.8 ± 4.8

804 ± 221 49.3 ± 18.0

Trenk et al. (1983) 10mg (IV) 8

15.6 ± 6.2 3.3 ± 1.1 8.6 ± 3.1 385 ± 63 26.7 ± 4.8 0.49 ± 0.33

20mg (tab) 8 110 ± 28 0.66 ± 0.25 18.5 ± 5.1

393 ± 64.4 51.0 ± 6.0 0.36 ± 0.17

Abbreviations: Cmax = peak plasma drug concentration; tmax = time to Cmax; t'l2P = terminal half-life; V•• = volume of distribution at steady-state; Vd = volume of distribution; AUC(O-oo) = area under the plasma concentration-time curve from time zero to infinity; F = bioavailability; CL = total body clearance; Ae(O-48) = amount of drug excreted into urine from time zero to 48h after the dose.

267

Clinical Pharmacokinetics of Ketanserin

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Fig. 2. Mean plasma concentrations of ketanserin (0) and ketanserin-ol (e) following (a) intravenous doses of ketanserin IOmg and (b) oral doses of ketanserin 40mg (solution) to 10 healthy subjects (from Heykants et al. 1986, with permission).

pertensive patients (Persson et al. 1987). This may indicate that tissue binding of the drug is more extensive (99%) than binding to plasma protein (see below). However, there are no data available concerning the relative distribution in various tissues. 4.2 Plasma Protein Binding In a detailed study in plasma from healthy subjects the plasma protein binding of ketanserin and ketanserin-ol and their distribution in blood were studied by equilibrium analysis at 37"C using the specifically tritium-labelled compounds (Meuldermans et al. 1988b) [table V). In these subjects the

plasma protein binding, primarily to albumin, was 95%, which was higher than the blood cell binding (84%). In blood only 19% of the drug was distributed into the blood cells, which explains the blood/ plasma concentration ratio of 0.70. For ketanserin01 the plasma protein binding was 81 % and the blood/plasma concentration ratio 1.04. The binding of ketanserin to albumin was constant within a wide concentration range. It was not influenced by ketanserin-ol but was very dependent on small variations from the physiological pH (7.40) at the end of the equilibrium dialysis. The plasma protein binding of ketanserin has been assessed in several other studies comprising healthy subjects as well as hypertensive patients (Meuldermans et al. 1988b; Reimann et al. 1983; Trenk et al. 1983). The results vary to some extent but, taking into account the differences in methodology and most probably deviations from physiological plasma pH, the results largely agree and the free fraction of ketanserin in plasma may be estimated at 5%. However, a significant 50% increase of the free fraction to approximately 7.5% was observed in patients with hepatocellular and renal insufficiency (Barendregt et al. 1990; Lebrec et al. 1990; Meuldermans et al. 1988b). Since plasma protein binding is dependent on the albumin level, the increased free fraction in these patient groups may be explained by a reduction in that level. The influence of a number of drugs which are highly bound to plasma protein on the plasma protein binding of ketanserin, and vice versa, was investigated in vitro by adding high therapeutic concentrations of these drugs to a 100 mg/L concentration of ketanserin in human plasma (Meuldermans et al. 1988b). Various agents, each representing a major therapeutic class of highly bound drugs [such as imipramine, propranolol, phenytoin, furosemide (frusemide), hydrochlorothiazide, diazepam, cimetidine, indomethacin, sulfamethiazine and ketoconazole) did not influence the binding of ketanserin. The reverse was also true. These results suggest that clinically relevant interactions are unlikely on the plasma protein binding of either ketanserin or highly bound compounds. At high therapeutic concentrations of warfarin (100

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Clin. Pharmacokinet. 20 (4) 1991

~g/L) the binding of ketanserin decreased slightly (Meuldermans et al. 1988b). However, the presence of ketanserin conversely did not change the plasma protein binding of warfarin.

5. Metabolism and Excretion Ketanserin is extensively metabolised, and less than 2% is excreted as the parent compound (table II). Metabolism studies in animals and humans have shown that the drug is mainly metabolised by ketone reduction and N-dealkylation, and to some extent in humans by aromatic hydroxylation (Meuldermans et al. 1984, 1988a). The excretion of the metabolites is more abundant in the urine (68% of the dose) than in faeces (24% within 5 days) [table II]. The main metabolite in humans is reduced ketanserin, also called ketanserin-ol, which is also excreted partly as the ether glucuronide. The formation of ketanserin-ol is particularly involved in the first-pass metabolism of ketanserin, since the ratio of the AVC of ketanserin-ol to that of ketanserin after oral dosing (3.17 : 3.46) is twice that after parenteral administration (1.51: 1.63). Furthermore, the proportion ofa dose excreted as ketanserin-ol and its glucuronide almost equals that lost by first-pass metabolism (Heykants et al. 1986). Following oral administra-

tion of ketanserin in humans, peak plasma concentrations (Cmax ) of ketanserin-ol are reached within 1 to 2h and then decay monoexponentially and at a slower rate than the parent compound in the first 12h after dose administration (fig. 2). Thereafter, plasma concentrations decline at the same rate as those of ketanserin. This suggests that the terminal phase in the ketanserin curves represents oxidative regeneration of ketanserin from ketanserin-ol and that ketanserin-ol elimination is the slowest step, dictating the half-life ofketanserin (Heykants et al. 1986). This contention was supported by van Peer et al. (1986) who showed that administration of ketanserin-ol to humans results in the formation of ketanserin.

6. Plasma Concentrations and Half-Life of Ketanserin 6.1 Single-Dose Administration Following an intravenous injection of ketanserin in healthy volunteers, the decay in plasma drug concentrations can be described by a 3-compartment model with elimination from the central compartment and with sequential half-lives (t'l2) of O.13h (t'12,,), 2h (t'l2/1) and 14.3h (t'l2..,,) [Heykants et al. 1986]. These values are in agreement with other studies in healthy volunteers as well as in hyper-

Table II. Major metabolites of ketanserin in urine and faeces in 3 subjects after oral administration of [14C]ketanserin (from Meuldermans et al. 1988a, with permission) Metabolic pathway

Compound (R number)

Percentage of dose urine

Hydroxylation Reduction Hydroxylation plus reduction N-dealkylation Total a

Due to conjugates.

0-1 day (40.9%)

0-4 days (68.3%)

Ketanserin (R 41 468) 6-Hydroxy-ketanserin (R 49 285) Reduced ketanserin (R 46742) Reduced 6-hydroxy-ketanserin (R 56 566)

0.3 (+ 0.2)8 <0.1 (+ 0.1) 13.8 (+ 6.1) 0.9 (+ 1.0)

0.4 (+ 0.3) <0.1 (+ 0.1) 23.0 (+ 10.9) 2.7 (+ 0.7)

AcetiC acid derivative (R 53 309)

13.9(-)

21.7 (-)

28.9 (+ 7.3)

46.8 (+ 11.9)

faeces 0-5 days (23.6%)

0.2 2.2 9.2 5.9

17.5

269

Clinical Pharmacokinetics of Ketanserin

Table III. Mean (± SO) pharmacokinetic parameters of ketanserin in healthy subjects and different groups of patients after a single oral dose

AUC ratioa

Reference

3.5 ± 0.9 3.2 ± 0.7 3.2 ± 0.7

Heykants et al. (1986)

Study group (no.)

Dose (mg)

t max (h)

Cmax (I'g/L)

Healthy subjects (10) (10) (10) (8) (6)

20 40 60 20 40

(S) (S) (S) (T) (T)

0.70 ± 0.20 0.60 ± 0.24 0.53 ± 0.22 0.66 ± 0.25 1.6 ± 1.4

71 198 287 110 193

Elderly 59· 72y (21) (21) 67·77y (10)

40 (S) 40 (T) 20 (T)

0.52 ± 0.25 0.97 ± 0.58 0.95 ± 0.44

172 ± 46 104 ± 39 89 ± 44

15.4 ± 4.1 17.7 ± 7.3 18.7 ± 6.2

608 ± 143 520 ± 143 482 ± 104

3.2 ± 1.0

Gould et al. (1989)

Renal failure b nondialysis (6) dialysis (6)

40 (T) 40 (T)

0.8 ± 0.3 1.4 ± 0.7

127 ± 118 61 ± 51

28.8 ± 3.7 27.9 ± 5.6

632 ± 326 637 ± 481

8.3 ± 4.7 6.4 ± 3.5

Barendreg et al. (1990)

Cirrhosis (14) (8)

20 (T) 40 (T)

1.1 ± 0.8 2.5 ± 1.0

98 ± 46 158 ± 86

15.2 ± 4.9 11.9 ± 3.6

925 ± 359 1539 ± 802

0.65 ± 0.35 0.90 ± 0.50

Lebrec et al. (1990)

± ± ± ± ±

t,/2,8 (h)

26 53 129 29 98

16.5 17.8 16.9 18.5 12.8

AUC (0'00) (jtg/L' h)

± ± ± ± ±

3.3 3.8 3.2 5.1 4.8

279 625 935 393 804

± ± ± ± ±

59 100 180 64 221

Trenk et al. (1983) Reimann et al. (1983) Kurowski (1985)

a AUCketanserin.ol/ AUCketanserin. b Mean serum creatinine level: 699 I'mol/L. Abbreviations: S = solution; T = tablet; for other abbreviations. see table I.

tensive patients (Persson et al. 1987; Reimann et al. 1983; Trenk et al. 1983) [table I). After single oral administration in healthy volunteers (Heykants et al. 1986; Reimann et al. 1983; Trenk et al. 1983; Uji et al. 1988) [table I, fig. 2] and in hypertensive patients (Hedner et al. 1983; Persson et al. 1987; Waller et al. 1987) Cmax is reached within 0.5 to 2h and concentrations then decline biexponentially with a t,;, similar to those after intravenous or intramuscular administration. With regard to Cmax and AUC there is a dose-proportionality between 20, 40 and 60mg doses (Heykants et al. 1986). However, the terminal half-life is identical with all dosages (table III). 6.2 Long Term Administration For drugs exhibiting linear pharmacokinetics during long term intravenous infusion, steady-state is achieved after 5 times the terminal half-life, and steady-state concentrations (CSS) are directly related to the infusion rate (Ro) and inversely related

to plasma clearance (CL). [CSS = Ro/CL). To shorten the time to reach steady-state the body can be loaded with a bolus dose, which for ketanserin is usually in the order of 10mg (or 0.15 mg/kg). Using the plasma clearance value that Heykants et al. (1986) found in single-dose intravenous pharmacokinetics (34/L/h), the predicted CSS would be 59 ILg/L for an infusion rate of 2 mg/h and 118 1Lg/ L for an infusion rate of 4 mg/h. These values, in

Table IV. Mean (± SO) pharmacokinetic parameters of ketan· serin in 6 healthy subjects following administration of an antacid (aluminium hydroxide 220mg plus magnesium hydroxide 380mg) 1.5h before and after the dose (after Van Velde et al.. data on file) [cf. fig . 31

Subjects

Cmax (jtg/L)

tmax (h)

AUC(0-24) (jtg/L' h)

Controls Drug + antacid

86 ± 33 91 ± 43

1.3 ± 0.6 1.6 ± 0.9

574 ± 190 547 ± 112

Abbreviations: see table I.

270

Clin. Pharmacokinet. 20 (4) 1991

fact, agree closely with those found in practice, either in healthy subjects (Fagard et al. 1984; Reimann & Frolich 1983) or in patients with severe leg ischaemia (data on file, No. 43094). In the latter study by Dormandy and Walker, infusion in 14 patients was continued for 7 days. In 2 studies the pharmacokinetics following long term oral administration of ketanserin 20mg 2 and 3 times daily were assessed in healthy subjects (Trenk et al. 1983; Uji et al. 1988). Steady-state after multiple dosing was achieved within 3 to 5 days. The average CSs agreed well with the concentration predicted from the single dose pharmacokinetic studies (according to the formula CSs = F X dose/CL X dose interval, where F is the bioavailability). Thus, with ketanserin there is no unusual drug accumulation due to time-dependent nonlinear changes in pharmacokinetics. Information about the fluctuations between peak and trough plasma concentrations of ketanserin under steadystate conditions is available from several clinical studies in hypertensive patients (fig. 4, table VI) [Hedner et al. 1983; Hedner & Persson 1984; McGourty et al. 1985; Persson et al. 1987; Waller et al. 1987a). As in healthy volunteers the measured CSs in patients (median age 64 years) was in

100

o

4

Time

8 (h)

Fig. 3. Influence of an antacid (aluminium hydroxide 220mg) and magnesium hydroxide 380mg) on the absorption of ketanserin in 6 healthy subjects: • = drug plus antacid; o = controls; arrows indicate administration of the antacid I. 5 hours before and after the dose of ketanserin (from Van Velde et aI., data on file) [cf. table IV].

Mean (± SO) plasma protein binding of ketanserin and ketanserin-ol and distribution in blood of healthy male subjects (data from Meuldermans et al. 1988b)

Table V.

Parameter

Ketanserin (n = 6)

Ketanserin-ol (n = S)

Plasma protein binding (%) Blood plasma ratiO Distribution (%) in blood to plasma water plasma protein blood cells Binding to blood cells (%)

9S.1 ± 0.36 0.70 ± 0.01

81 .2 ± 0.74 1.04 ± O.OS

3.8 77.2 19.0 83.8

11.7 41 .9 46.3 81 .3

± ± ± ±

0.18 2.3 2.2 0.48

± ± ± ±

0.24 2.S 2.6 0.83

good agreement with that predicted from singledose pharmacokinetics in young and middle-aged healthy subjects, indicating that the pharmacokinetics of ketanserin remain linear during long term treatment in various patient groups. Although C max was similar (range 102 to 158 ~g/L) for the 3 dosage schedules (40mg once, twice and thrice daily), trough concentrations (13 to 60 ~g/L) and average CSs (33 to 89 ~g/L) were clearly dose-related. There are a number of studies from which plasma concentration data under steady-state conditions are available. In most studies patients were treated with ketanserin alone (Andren et al. 1983; Hedner et al. 1983, 1984) or in combination with ,a-blockers or diuretics (data on file, No. 43319; Hedner & Persson 1984). Blood sampling in most of these studies occurred at irregular time intervals with respect to the last dose of ketanserin. If the analysis is restricted to the commonly used dosage schedules (i.e. 20 to 40mg twice daily) and only values obtained either 1 to 3h (around peak time) or 10 to 14h (trough) after intake are used, the plasma concentration data are in agreement with those found in the studies in which blood sampling occurred at regular intervals after dosing, and with those predicted from single-dose pharmacokinetics (table VII). Thus, again it may be concluded that steady-state plasma concentrations ofketanserin are related to dose and frequency of administration. In addition to the dose-plasma concentration relationship, regression analysis was also applied

Clinical Pharmacokinetics of Ketanserin

271

by De Dier and coworkers to assess whether plasma concentrations of ketanserin were affected by either duration of treatment, sex, age or bodyweight of patients (data on file, No. 43319). The analyses indicated that there was no change in steady-state plasma concentrations in patients treated with ketanserin 40mg 2 or 3 times daily for up to 2 years. Furthermore, there was no significant effect of the patient age (median 59 years, range 26 to 82 years) [fig. 5], sex (173 male/93 female) [fig. 5] or bodyweight (median 75, range 44 to 115kg). Since ketanserin significantly reduced the blood pressure in most hypertensives it appears that the blood pressure reduction per se did not change the pharmacokinetics of ketanserin. 6.3 Relationship Between Plasma Concentration and Therapeutic Efficacy Several studies in groups of patients have been unable to identify a clear interindividual relationship between plasma ketanserin concentrations and the blood pressure reduction (data on file, No. 43319; Donnelly et al. 1987; Hedner et al. 1986) [fig. 6]. There may be a correlation between plasma concentrations and the decrease of blood pressure in individual patients, i.e. during long term treat-

500

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Ii:

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Fig. 4. Mean (± SEM) steady-state plasma concentrations of ketanserin (0) and ketanserin-ol (e) in 6 hypertensive patients

receiving ketanserin 40mg twice daily. Abbreviations: C~ax = peak concentration; C~in = trough concentration (after Hedner & Persson 1984) [cf. table VI).

Table VI. Mean (± SEM) steady-state plasma concentrations of ketanserin and ketanserin-ol in 6 hypertensive patients receiving ketanserin 40mg twice daily (after Hedner & Persson 1964) [cf. fig. 4] Parameter

Ketanserin

Ketanserin-ol

CSS (!,g/L)

66 ± 10 792 ± 124 50.4 ± 3.24

210 ± 25 2518 ± 305

AUC(O_12) ("gIL· h) CLpo (L/h)

Abbreviations: CSs = concentration at steady-state; AUC(0-12) = area under the concentration-time curve from time zero to 12h after the dose; CLpo = total body clearance after oral administration.

ment the antihypertensive effect during the day may correspond to plasma concentration (Donnelly et al. 1988; Persson et al. 1987). In conclusion, it may be stated that there is no direct relationship between plasma ketanserin concentrations and ther-apeutic effect. Nevertheless, it is obvious that plasma concentrations are of prime importance to therapeutic effect: in patients responding to ketanserin therapy, plasma concentrations ranged between 15 and 140 ~g/L (Hedner et al. 1983). The relative contribution of the S2-serotonergic and al-adrenoceptor antagonistic properties to the antihypertensive effect of ketanserin is poorly understood (Robertson 1990; Vanhoutte et al. 1988). Clearly, the plasma concentrations found when ketanserin is administered in a therapeutic dose range are well above those required to block 5-HT2-receptor-mediated events on the vascular wall and in platelets in vitro and in vivo (van Nueten et al. 1981). This observation supports the view that the antihypertensive effect does not depend on a peripheral S2-serotonergic receptor blockade alone. Apart from essential hypertension, ketanserin treatment has been assessed in a variety of clinical disorders such as intra- and postoperative hypertension, hypertensive crisis in carcinoid syndrome, eclampsia and cerebrovascular disease, migraine, pulmonary embolism and peripheral vascular diseases such as Raynaud's syndrome and claudicatio intermittens (for review see Vanhoutte et al. 1988).

272

Clin. Pharmacokinet. 20 (4) 1991

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glucuronide by biliary excretion). Although plasma concentrations ofketanserin-ol are equal to or (from 4 hours after dosing) higher than those of the parent compound, the contribution ofketanserin-ol to the overall pharmacological effect is small since ketanserin-ol has an approximately IOOO-foid lower affinity for the arterial 5-HT2 receptor than ketanserin (Frenken & Kaumann 1984; Heykants et al. 1988).

70

Fig. 5. Individual plasma ketanserin concentrations and corresponding age of patients treated with oral ketanserin 40mg twice daily (n = 116): • = male, 0 = female (from De Dier et aI., data on file).

The intravenous and oral dosages used have usually been the same as those discussed above. Apart from the use of ketanserin in hypertensive emergencies and in patients with peripheral obliterative disease, there is no information about the pharmacokinetics in these patient categories and even less on the relationship between plasma concentration and therapeutic efficacy. Since the biotransformation ofketanserin in humans results in relatively minor modifications of the chemical structure of the parent compound, it is conceivable that the pharmacodynamic properties of the major metabolites could contribute to the pharmacological activity of ketanserin. After reviewing the available literature it can be stated that, although 6-hydroxy-ketanserin has a pharmacological profile and potency similar to that of the parent drug (Heykants et al. 1988), its contribution to the overall in vivo pharmacological effect in humans is negligible since the metabolite is not detectable in plasma (~ 10 ~g/L) after oral administration of ketanserin 40mg (Meuldermans et al. 1988a). This may be due to the relatively small contribution of aromatic hydroxylation to the overall biotransformation of ketanserin in humans (table II) and to the rapid and efficient elimination of this metabolite from the body (most likely as its

6.4 Relationship Between Plasma Concentration and Adverse Effects

The most common adverse effects with ketanserin treatment are sedation and dry mouth. There are no data on the direct relationship between side effects and measured plasma concentrations, but they are clearly dose-dependent and (at least in the individual patient) related to peak plasma concentrations, since they primarily occur I to 2h after the dose, i.e. at the time of Cmax (Hedner & Persson 1984; Hedner et al. 1983, 1984). Furthermore, side effects are more abundant after intravenous administration (usually lOmg) which initially leads

Table VII. Effect of different dose regimens on mean (± SEM) near peak (samples taken 1-3h after last dose) and near trough (samples taken 10-14h after last dose) plasma concentrations of ketanserin at steady-state in various patient categories (data from Hedner et al. 1983, 1984; Persson et al. 1987; Woittiez et al. 1986; data on file)

Dose regimen (mg)

20 tid 400d bid tid

Near peak

Near trough

n

C (llg/ L)

n

C (1l9/L)

74 19 235 309

52.8 ± 3.3 86.1 ± 13.9 94.6 ± 3.5 132 ± 4.3

3 10 47 36

26.6 26.8 41.1 53.0

± ± ± ±

9.5 5.2 3.0 4.9

= number of observations; C = concentration; tid = 3 times daily; od = once daily; bid twice daily.

Abbreviations: n

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Clinical Pharmacokinetics of Ketanserin

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serin (40mg twice daily) and QT prolongation in patients with renal insufficiency. At an average plasma ketanserin concentration of 50 ~g/L the QT time was increased by 9%. In a prospective, randomised trial of221 patients with ketanserin 80mg daily or placebo the QT time was prolonged by more than 30 msec in 30% of the patients taking the drug (Zehender et al. 1989). In no patient, however, did the QTc exceed 500 msec. Since side effects appear to be related to dose per intake rather than total daily dose, single doses of ketanserin larger than 40mg are generally not recommended.

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7. Pharmacokinetics in Special Patient Groups 7.1 Elderly Patients

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to higher Cmax values than those reported for the common oral dosages (Jennings & Opie 1987; Milei et al. 1987; Reimann et al. 1983). To date, treatment with ketanserin has been associated with only one potentially serious side effect. In several placebo-controlled studies ketanserin has caused a slight and dose-dependent prolongation of the QT interval (Aldariz et al. 1986; Cameron et al. 1987; Stott et al. 1986), which has clinical implications with respect to the development of ventricular arrhythmias. Donnelly et al. (1988) reported that after long term administration of ketanserin 40mg twice daily QT prolongation (by around 10% or on average 32 msec) occurred, particularly with Cmax , Proppe and Manthei (1989) found a direct relationship between plasma concentrations of ketan-

A large proportion of the hypertensive patients in whom steady-state plasma concentrations are available were 65 years of age or more. From these data it may be concluded that the pharmacokinetics of ketanserin do not differ widely between elderly and younger patients (fig 5). Two studies were set up to study in detail its pharmacokinetics in the elderly (table III). In the study by Kurowski (1985b) 21 healthy volunteers with an average age of 65 years (range 59 to 72) were treated with ketanserin 10mg intravenously and 40mg orally (both as tablet and solution) and then with 40mg twice daily for 2 months. In another study (Gould et al. 1990) 9 hypertensive patients (mean age 72, range 67 to 77) were treated with ketanserin 20mg twice daily for II days and plasma concentrations of ketanserin and ketanserin-ol were assayed after ingestion of the first tablet as well as during steady-state conditions. When compared with the data from studies in younger and middle-aged hypertensive patients and healthy volunteers (table III), the results indicate that the pharmacokinetics of ketanserin in the elderly are very similar to those in younger patients. The elimination half-lives were similar in all studies (I6h). As in relatively younger

274

Clin. Pharmacokinet. 20 (4) 1991

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patients and in healthy volunteers, CSs in the elderly was predictable from single-dose pharmacokinetics, indicating that the pharmacokinetics of ketanserin are linear and that no undue accumulation of drug occurs. If anything, the absolute bioavailability of orally administered ketanserin may be higher in some elderly patients. This may be due to a reduced first-pass metabolism, which in turn may be related to a reduced liver blood flow and/or to diminished activity of the liver enzymes involved in the first-pass metabolism of ketanserino Furthermore, the t'l2 of ketanserin-ol may be prolonged in comparison with at least that seen in younger volunteers, which may be related to a reduced renal clearance of the metabolite. Nevertheless, from a pharmacokinetic point of view there appears to be no need for a dose adjustment in elderly patients. Although views are divergent, several researchers have suggested that the antihypertensive effects of ketanserin are age-related, i.e. the decrease in blood pressure with ketanserin treatment is greater in patients over the age of 60 years (DeCree et al. 1985; Doyle 1988; Rosendorff & Murray 1986). However, it is unlikely that the purported greater antihypertensive efficacy of ketanserin in elderly

patients is due to altered pharmacokinetics (Gould et al. 1990; Hedner et al. 1988).

7.2 Hepatic Insufficiency

The pharmacokinetics of ketanserin were studied in 26 patients with moderate hepatic insufficiency due to cirrhosis (Lebrec et al. 1990) and compared with data obtained in healthy subjects (Heykants et al. 1986). The patients received single oral or intravenous doses ofketanserin and in some cases the coefficient of hepatic extraction was directly measured by the simultaneous plasma sampling of hepatic and peripheral venous blood. Following oral doses of ketanserin 20 or 40mg, the AUC(O-oo) was 2 to 4 times higher than in hypertensive patients or healthy volunteers (table III). Since the elimination half-life of ketanserin was similar to or shorter than that in comparable patient groups, the higher AUC was related to a reduced first-pass metabolism resulting from both a reduced hepatic extraction and a decreased liver blood flow. In addition, the volume of distribution (V d) was smaller than in healthy subjects; how-

275

Clinical Pharmacokinetics of Ketanserin

ever, since the rate of absorption was also decreased, Cmax values were not different from controls. These data demonstrate that the bioavailability of ketanserin is increased in patients with hepatic insufficiency, which was predictable for a drug with a hepatic extraction ratio of 50% (Heykants et al. 1986). These findings should be taken into account when ketanserin is prescribed in patients with impaired hepatocellular activity.

7.3 Renal Insufficiency

Four studies involving a total of 55 patients were designed to study the pharmacokinetics of ketanserin in patients with renal disease (Barendregt et al. 1990; Onoyama et al. 1988; Proppe et al. 1989; Zazgomik et al. 1986). The degree of renal impairment ranged from moderate (mean serum creatinine level 230 ~mol/L; Onoyama et al. 1988) to severe (mean serum creatinine level 699 ~mol/L; Barendregt et al. 1990) and 15 patients required regular haemodialysis. Following single (20mg) or repeated oral doses (20 or 40mg twice daily), plasma and urinary concentrations of ketanserin and ketnaserin-ol were assessed for up to I year (Proppe et al. 1989). As expected, the renal excretion of the metabolite ketanserin-ol was reduced, resulting in increases in the plasma concentrations and AUC of the metabolite (table VIII, fig. 7). However, the rate of accumulation is then probably slowed by an increased biliary excretion as the glucuronide.

The terminal half-life of ketanserin depends on the elimination rate of ketanserin-ol and, particularly in severe renal insufficiency, may be prolonged. Nevertheless, both C max and trough CSs values, even after 12 months' treatment, are similar to those found in healthy volunteers. As in hepatocellular insufficiency, the plasma protein binding of ketanserin appears to be reduced in renal insufficiency, resulting in up to a 30% increase in the free fraction (Meuldermans et al. 1988b). Despite this, neither plasma ketanserin nor ketanserin-ol was removed by haemodialysis (Zazgomik et al. 1986). In conclusion, plasma concentrations of ketanserin at steady-state were not greatly influenced by renal insufficiency. Whether the observed increase in the free ketanserin fraction has any significant influence remains to be seen. However, dose adjustments in the normal range of ketanserin 20 to 40mg twice daily are probably not necessary in patients with renal impairment.

8. Drug Interactions A drug interaction occurs when either the pharmacokinetics or the pharmacodynamics of the drug are altered by administration of another agent. This review is limited to the former and does not discuss potential pharmacodynamic interactions such as the increased risk of cardiac arrhythmias when ketanserin is combined with potassium-losing diuretics or drugs affecting heart muscle repolarisa-

Table VIII. Mean (± SO) pharmacokinetics of ketanserin and ketanserin·ol in 9 patients with renal insufficiency (creatinine clearance

< 19 ml/min)

after a single dose of ketanserin 40mg (data from Barendregt et al. 1990) [cf. fig. 7)

Ketanserin Ketanserin-ol

a

Ratio of the AUCs: 7.0 ± 6.0.

Abbreviations: see table I.

tmax (h)

Cmax ) (pg/L)

t\l2jj (h)

1.2 ± 0.7 1.7 ± 1.0

110 ± 104 101 ± 47

29.4 ± 4.7 40.7 ± 9.3

712 ± 428

3434 ± 1061

276

tion (antiarrhythmics). Concurrent administration of 2 or more drugs can influence the absorption, tissue distribution (e.g. plasma protein binding), metabolism (e.g. induction or inhibition) or excretion of drugs. It has been noted above (section 3.1) that pretreatment with cimetidine (which reduces gastric acidity) and antacids in combination results in a decreased oral absorption of ketanserin. On the other hand, ketanserin in therapeutic plasma concentrations did not significantly change the plasma protein binding of highly bound drugs in vitro. Ketanserin 20 to 40mg twice daily for 8 weeks had no effect on indices of hepatic enzyme induction in hypertensive humans (Waller et ai. 1987b). Furthermore, the pattern of urinary and faecal excretion of radioactively labelled ketanserin to rats during long term administration did not change (Meuldermans et ai. 1984). These observations suggest that ketanserin is unlikely to have any clinically important effects on the metabolism of concurrently administered drugs, but in vivo studies in patients are lacking. Since ketanserin by itself has been reported by some to slightly increase the bleeding time (Longstaff et ai. 1985), interaction studies with anticoagulants are warranted. Detailed interaction studies have been performed with cimetidine, propranolol, digoxin and digitoxin. The influence of ketanserin on the pharmacokinetics of propranolol was addressed in 3 well performed studies (Ochs et ai. 1987; Trenk et ai. 1985; Williams et ai. 1986), which varied in design but generally employed placebo controls and crossover design and allowed assessment of interactions following single doses as well as of long term treatment in a normal dose range. The results clearly show that propranolol does not influence the pharmacokinetics of ketanserin. The same conclusion can be drawn from clinical studies by Hedner et ai. (1984), who found similar steady-state concentrations in hypertensive patients treated with ketanserin alone or in combination with ~-blocking agents. In the study of Ochs et ai. (1987), treatment with ketanserin tended to impair the oral clearance of propranolol, leading to higher serum propranolol Cmax , but the differences were not significant.

Clin. Pharmacokinet. 20 (4) 1991

The influence of ketanserin on the pharmacokinetics of digoxin was evaluated in 10 healthy volunteers who received a single dose of digoxin 1.25mg by intravenous infusion before and during treatment with ketanserin 40mg twice daily beginning 7 days before administration (Ochs et ai. 1985). The same researchers also assessed the pharmacokinetics of intravenous digitoxin 1mg during treatment with ketanserin in a similar manner. Plasma concentrations of digoxin and digitoxin were measured for up to 72 hours and 14 days, respectively, after administration. Ketanserin caused a slight but nonsignificant prolongation of the digoxin elimination half-life and a reduction in clearance of digitoxin, and also a small increase in Vd. In another study (Janchen et aI., data on file) in 12 hypertensive patients with heart failure, trough concentrations of acetyldigoxin (dose: 0.2mg twice daily) were assessed during treatment with ketanserin 40mg twice daily. Subsequently, treatment with acetyldigoxin was started at least 2 months before the study and continued throughout. Trough concentrations of digoxin were assessed during concomitant treatment with placebo, ketanserin and placebo (each for I week). The respective mean (± SD) plasma concentrations of digoxin were 0.86 ± 0.50,0.86 ± 0.53 and 0.75 ± 0.55 j.£g/L, indicating that treatment with ketanserin did not influence the CSs of digoxin. Furthermore, the CSs values of ketanserin (42 ± 31 j.£g/L) were similar to those reported for treatment with ketanserin alone. The findings of these investigations suggest that ketanserin has no meaningful influence on the pharmacokinetics of digoxin and digitoxin, but since 2 of the studies were of single-dose administration more investigations are necessary. In addition to its typical histamine H2-blocking effects (reduction in gastric acidity), cimetidine is known to inhibit the oxidative metabolism of a number of drugs. Since ketanserin is mainly eliminated by hepatic metabolism and undergoes firstpass extraction by the liver, a study was undertaken by Kirch and co-workers to investigate whether cimetidine affects the pharmacokinetics of ketanserin (data on file, No. 40194). The plasma concentration time-course following a single oral

277

Clinical Pharmacokinetics of Ketanserin

dose ofketanserin 40mg was measured in 7 healthy volunteers after concomitant treatment with cimetidine 400mg 3 times daily for 7 days. The mean AUC(O-oo) (614.5 ± 147.7 vs 573.6 ± 136 ~g/L· h) and t'h/l (15.5 ± 2.7 vs 17.0 ± 4.2h) for ketanserin alone or in combination with cimetidine, respectively, did not differ significantly, indicating that cimetidine did not affect the first-pass metabolism and the elimination of ketanserin.

9. Implications of Ketanserin Pharmacokinetics for Clinical Use 9.1 Therapeutic Use The recommended dosage of ketanserin is 20 to 40mg once or twice daily. Within this dose range the absorption is not influenced by food and the pharmacokinetics are predictable and remain linear in patients regardless of sex, weight, age and duration of treatment. There is no evidence that peripheral vascular disease or hypertension have direct effects on the pharmacokinetics of ketanserino Although elimination of the metabolite is reduced in patients with severe renal insufficiency, CSs is not changed and from a pharmacokinetic point of view a dose adjustment does not appear to be necessary in this group. To date the only known clinical condition requiring dose reduction is hepatic insufficiency, which increases the bioavailability of ketanserin.

9.2 Adverse Events The side effects of ketanserin are predictable and probably due to the pharmacological properties of the drug. Although the interindividual variability is large the side effects, including QT prolongation, are clearly dose-related and particularly associated with Cmax . Thus, they are related to dose per intake rather than total daily dose. In hypertensive patients at least, the incidence of adverse events rises sharply with a dose increase from 40 to 60mg. In contrast, the incidence is moderate and similar with a 40mg dosage regardless of once, twice or 3 times daily regimens.

9.3 Drug Interactions Apart from the possible reduced absorption during concomitant treatment with H2-blockers and antacids in combination, it is unlikely that ketanserin will have any clinically meaningful pharmacokinetic drug interactions related to, for example, altered liver metabolism or displacement from plasma protein binding sites. However, besides concurrent treatment with l3-blockers, diuretics, digitalis and cimetidine, formal studies are lacking. The possibility of prolonged bleeding time during concomitant administration of ketanserin also needs further investigation. 9.4 Therapeutic Drug Monitoring Therapeutic drug monitoring is important for drugs with a narrow therapeutic range, steep concentration-response curve and plasma concentration-related toxicity. Since the interindividual sensitivity to both therapeutic efficacy and adverse events with ketanserin treatment varies to a large extent, there is no meaningful plasma concentrations range, so that plasma concentration monitoring of ketanserin is unlikely to be helpful.

References Aldariz AE, Romero H, Baroni M, Baglivo H, Esper RJ. QT prolongation and torsade de pointes: ventricular tachycardia produced by ketanserin. Pace 9: 836-841, 1986 Andren L, Svensson A, Dahl6f B, Eggertsen R, Hansson L. Ketanserin in hypertension: early clinical evaluation and dosefinding study ofa new 5-HT2 receptor antagonist. Acta Medica Scandinavica 214: 125-130, 1983 Barendregt JNM, van Peer A, van der Hoeven JG, Oene JC, Tjandra YI. Ketanserin pharmacokinetics in patients with renal failure. British Journal of Clinical Pharmacology, in press, 1990 Brogden RN, Sorkin EM. Ketanserin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease. Drugs 40: 903-949, 1990 Cameron HA, Ramsay LE. Ketanserin in essential hypertension: a double-blind, placebo-controlled study. Postgraduate Medical Journal 61: 583-586, 1985 Cameron HC, Waller PC, Ramsay LE. The effect of ketanserin on the QT interval. British Journal of Clinical Pharmacology 23: 630P, 1987 Davies CL. Determination of ketanserin in plasma by reversedphase high-performance liquid chromatography. Journal of Chromatography 275: 232-233, 1983 De Cree J, Hoing M, De Ryck M. Symoens J. The acute anti-

278

hypertensive effect of ketanserin increases with age. Journal of Cardiovascular Pharmacology 7 (Supp!. 7): sI26-sl27, 1985 Donnelly R, Elliot HL, Meredith PA, Hughes DMA, Reid JL. Ketanserin concentration-effect relationships in individual hypertensive patients. British Journal of Clinical Pharmacology 26: 61-64, 1988 Donnelly R, Elliot HL, Meredith PA, Reid JL. Acute and chronic ketanserin in essential hypertension: antihypertensive mechanisms and pharmacokinetics. British Journal of Clinical Pharmacology 24: 599-606, 1987 Doyle AE. Why are the antihypertensive effects ofketanserin agerelated? Journal of Cardiovascular Pharmacology 12 (SuppI8): sI24-s13l, 1988 Fagard R, Cattaert A, Lijnen P, Staessen J, Vanhees L, et a!. Responses of the systemic circulation and of the renin-angiotensin-aldosterone system to ketanserin at rest and exercise in normal man. Clinical Science 66: 17-25, 1984 Frenken M, Kaumann AJ. Interaction of ketanserin and its metabolite ketanserinol with 5HT2 receptors in pulmonary and coronary arteries of calf. Naunyn-Schmiedeberg's Archives of Pharmacology 326: 334-339, 1984 Fujita T, Ito Y, Noda H, Isaka M. Antihypertensive effect and pharmacokinetics ofKJK-945 (ketanserin tartrate) at single dose on essential hypertension. Journal of Clinical Therapeutics and Medicine 4 (Supp!. I): 21-33, 1988 Gould SE, Silas J, Hosie J. Could the increased antihypertensive efficacy of ketanserin in the elderly be due to altered pharmacokinetics. Cardiovascular Drugs and Therapeutics 4 (Supp!. I): 87-90, 1990 Hedner T, Andersson OK, Winther K, Persson B. Are there reasons to believe that the antihypertensive effects of serotonin (S2) antagonists are age-related? Journal of Cardiovascular Pharmacology 12 (Supp!. 8): 132-140, 1988 Hedner T, Persson B. Ketanserin in combination with ~-adren­ ergic receptor blocking agents in the treatment of essential hypertension. British Journal of Clinical Pharmacology 18: 765771, 1984 Hedner T, Persson B, Berglund G. Ketanserin, a novel 5-hydroxytrpytamine antagonist: monotherapy in esssential hypertension. British Journal of Clinical Pharmacology 16: 121-125, 1983 Hedner T, Persson B, Berglund G. Experience with ketanserin, a serotonin (S2) antagonist, in longterm treatment of essential hypertension. Clinical and Experimental Hypertension A6: 743751, 1984 Hedner T, Pettersson A, Persson B. Blood pressure reduction and pharmacokinetics of ketanserin in hypertensive patients. Journal of Hypertension 4 (Supp!. I): s91-s93, 1986 Heykants J, Michiels M, Woestenborghs R, Awouters F, Leysen JE, et a!. Pharmacokinetic evaluation of the in vitro and in vivo pharmacological profile of the major metabolites. of ketanserin in the rat. Arzneimittelung-Forschung 38: 785-788, 1988 Heykants J, van Peer A, Woestenborghs R, Gould S, Mills J. Pharmacokinetics of ketanserin and its metabolite ketanserin01 in man after intravenous, intramuscular and oral administration. European Journal of Clinical Pharmacology 31: 343350, 1986 Jennings AA, Opie LH. Effects of intravenous ketanserin on severely hypertensive patients with double-blind crossover assessment of central side-effects. Journal of Cardiovascular Pharmacology 9: 120-124, 1987 Kacprowicz AT, Shaw PG, Moulds RFW, Bury RW. Determination of ketanserin in human plasma by high-performance liquid chromatography. Journal of Chromatography 272: 417420, 1983 Kurowski M. Simultaneous determination of ketanserin and ketanserinol in biological fluids using ion-pair liquid chromatography and fluorimetric detection. Journal of Chromatography 341: 208-212, 1985a

Clin. Pharmacokinet. 20 (4) 1991

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