Pharmacokinetics and pharmacodynamics of clomethiazole after oral and rectal administration in healthy subjects

CLINICAL THERAPEUTICS”NOL. 21, NO. 5,1999

Pharmacokinetics and Pharmacodynamics of Clomethiazole After Oral and Rectal Administration in Healthy Subjects Alexandra E. R&z, MS: Raymond G. Schlienger, PhD,’ Lilly Linder, MD,’ Wolf Langewitz, MD: and Walter E. Haefeli, MD’S ‘Division of Clinical Pharmacology, 2Division of Psychosomatics, Department of Internal Medicine, University Hospital, Basel, Switzerland, and 3Division of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany

ABSTRACT Clomethiazole, a sedative-hypnotic and anticonvulsant drug, has been successfully administered orally and intravenously, but in caseswhere either of these methods presents complications, rectal administration may represent a practical alternative. We sought to compare the single-dose pharmacokinetics and pharmacodynamics of clomethiazole after oral and rectal administration. Ten healthy adult volunteers were given 600 mg clomethiazole edisylate (corresponding to 390 mg clomethiazole base) in 2 capsules as a single oral or rectal dose in a double-masked, doubledummy, crossover fashion. Serum concentrations were measured up to 10 hours after administration using a specific highperformance liquid chromatography method. Computerized reaction-time measurement and visual analogue scales (VAS) were used to assess drug effects. Peak Accepted for pub/i&ion Printed in the USA. Reproduction in whole

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serum concentrations were significantly higher after oral administration (mean f SEM, oral 1.76 f 0.47 p,g/mL vs rectal 0.48 + 0.14 pg/mL; P = 0.03) and appeared earlier (55 +- 12 vs 89 f 11 min; P = 0.04). Area under the concentrationtime curve values were similar after administration by both routes (oral 116 + 20.6 vs rectal 105 + 36.0 p,g*min/mL), with a relative rectal bioavailability of 90% compared with oral administration. The objective pharmacodynamic effects on reaction time (increase of 104 f 26 vs 66 + 22 ms, oral vs rectal) and working speed (decrease of 132 + 38 vs 97 2 32 ms, oral vs rectal) were not significantly different. Subjective pharmacodynamic effects, as measured on the VAS, were comparable with both routes of administration. Clomethiazole was well tolerated, with a similar adverse effect profile for both routes of administration. The effects of rectal dosing of clomethiazole were similar to those of oral dosing but appeared to occur later. Our results suggest that rectal administration of a single 600mg clomethiazole edisylate dose bears no 829

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safety risk. Therefore, rectal administration could be considered when neither oral nor parenteral administration is possible and a later onset of effect is not critical. Key words: pharmacokinetics, pharmacodynamics, clomethiazole, oral administration, rectal administration, single dose, reaction time. INTRODUCTION Clomethiazole (chlormethiazole; 5-(2chloroethyl)-4-methylthiazole) is a sedative-hypnotic and anticonvulsant drug that has successfully been administered orally and parenterally for ethanol withdrawal,tA psychogeriatric disorders,5g6 anesthesia,‘,8 postcraniotomy seizures,9 and eclampsia.lO,l1 It is often used effectively in the elderly as a hypnotic?,12-14 However, particularly when administered to elderly patients, to patients with impaired liver function, and after overdose, intravenous administration of clomethiazole bears certain risks, such as development of respiratory insufficiency,15 tachycardia,15T16 thrombophlebitis,17 decreased mean arterial blood pressure, l5 and even cardiac arrest.16 Because of these potentially severe or even fatal cardiovascular and respiratory adverse reactions, close monitoring of the patient is required after intravenous administration of clomethiazole.‘* For the above reasons, oral administration of clomethiazole is preferred but may be difficult in patients who have problems with swallowing or difficulties in following instructions. It may even be impossible when patients are experiencing nausea and vomiting or convulsions or are uncooperative. Therefore, it would be convenient to have an alternative route without the risks of intravenous administration and with similar advantages to oral adminis830

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tration. The rectal route may represent such an alternative.” An important aspect of rectal drug delivery is the possibility of partially bypassing hepatic first-pass metabolism, because only the venous return of the proximal part of the rectum drains into the portal vein and subsequently into the liver, whereas the distal part of the rectum drains into the inferior vena cava.” Anecdotal evidence suggests that in elderly patients and patients with withdrawal syndromes, rectally administered clomethiazole could be similarly or even more effective than orally administered drug. Because of the extensive hepatic first-pass elimination after oral administration of clomethiazole?@23 we hypothesized that compared with oral dosing, rectal administration might lead to increased and earlier peak concentrations and to increased bioavailability due to partial reduction of first-pass loss. Because no data are available on the pharmacokinetics and pharmacodynamics of clomethiazole capsules after rectal administration, we compared the single-dose pharmacokinetics, pharmacodynamics, and safety of clomethiazole capsules after oral and rectal administration in healthy adult volunteers. SUBJECTS AND MATERIALS To be eligible for study participation, subjects had to have no history of renal, hepatic, or gastrointestinal disease. Findings on physical examination and routine laboratory tests had to be normal. All subjects gave written informed consent. The study was reviewed and approved by the ethical committee of the Department of Internal Medicine, University Hospital, Basel, and by the Swiss drug regulatory authorities (Intercantonal Office for the Control of Medicines, Beme).

A.E. R;iTZ ET AL. Study Design

Analytic Methods

This was a double-masked, doubledummy, randomized, crossover trial. All subjects received both study formulations orally and rectally in sequence at 2 study visits separated by sl week. The active compound was administered by 1 route of administration per study day, and the initial route of administration was randomly selected. On both study days, subjects received 2 capsules each of the verum* (equal to 600 mg clomethiazole edisylate, corresponding to 390 mg clomethiazole base) and placebo. Rectal administration was facilitated by lubricating the capsules with water. The volunteers were admitted to the hospital in the morning after an overnight fast. They had been asked to refrain from methylxanthine- and alcoholcontaining beverages for at least 12 hours before admission. Throughout the study, subjects remained in bed. A venous forearm cannula was inserted, and blood samples (10 mL) were obtained in plastic tubes before and at 13,23,33,43,53,60, and 90 minutes and 2,4,6,8, and 10 hours after drug administration. The blood was centrifuged at room temperature (3500 rpm for 7 minutes), and the serum was separated and stored at -7O”C, until analyzed. Reaction-time measurements were always performed before blood sampling to prevent any influence of stress or manipulation. Visual analogue scale (VAS) scores and measures of safety were recorded after each blood sample was obtained. Volunteers received a standardized meal consisting of a vegetarian sandwich 4 and 8 hours after drug administration.

Clomethiazole concentrations were determined using a specific high-performance liquid chromatography (HPLC) method (Praxis fiir Laboratoriumsmedizin Dr. Eberhard, Dortmund, Germany). Serum (0.5 mL) was mixed with 0.05 mL methanol containing 0.1 mg/mL methylphenylphenylhydantoin (Sigma, St. Louis, Missouri), as an internal standard and deproteinized with 0.5 mL acetonitrile. After mixing for 1 minute and centrifugation for 5 minutes at 10,000 rpm, the separated remnant fluid was mixed for 1 minute with 0.5 g of water-free sodium sulfate (Baker, Deventer, Holland), mixed for 1 minute, and centrifuged for another 5 minutes. Aliquots of 40 pL were injected into the HPLC system using a Waters M7 17-P autoinjector and a Waters M 510 pump (Waters Corporation, Milford, Massachusetts) with a Hyperchrome HPLC column, 250 X 4.6 mm (Bischoff Corporation, Lernberg, Germany) containing RP Multosphere@ 100, C 18,5 pm (Chromatographie Service, Langerwehe, Germany) as the stationary phase. The isocratic mobile phase consisted of 65% potassium hydrogenphosphate, 0.05 mol/L, pH = 2.3, and acetonitrile 35%, and a flow rate of 1.5 mL/min at room temperature was used. The compound was then identified at 254 nm using a Waters PDS-M99 l/M996 photodiode array detector combined with a Waters Millennium 20 10 workstation. Concentrations were determined using peak height ratios of internal standard to clomethiazole, with the internal standard referring to standard concentrations of 0,0.2,0.5, 1.O, and 2.0 pg/mL in serum with a linear range from 0 to 10 pg/mL and a detection limit of 0.05 p,g/mL referring to a signal-to-noise

*Trademark: Dietikon,

Distraneurin@ Switzerland).

(Astra

Pharmaceuticals,

831

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ratio of 2: 1. The standard clomethiazole formulation was purchased from Astra Pharmaceuticals (Wedel, Germany). Within-day and between-day coefficients of variation were 5.5% and 6.8%, respectively (N = lo), and the analytical recovery was 72.5% f 6. Safety Variables Systolic, diastolic, and mean arterial blood pressures and heart rate were measured at baseline and after each blood sample was obtained using an automated sphygmomanometer (Dinamap’” , Critikon Inc., Tampa, Florida). Blood pressure measurements were always performed in the supine position with the cuff placed around the upper left arm. Clinical symptoms or adverse effects were recorded based on observation and the spontaneous reports of volunteers. Pharmacokinetic

Variables

Such pharmacokinetic variables as maximum serum concentration (C,,,), time to maximum serum concentration (T,,,), lag time until first detection of clomethiazole in serum (T,,,), and area under the serum concentration-time curve (AUC) are expressed as continuous data. The AUC was calculated from 0 to 600 minutes using the linear trapeMJC,,,) zoidal rule. Pharmacodynamic

Variables

Objective Variables Subjects’ working speed and reaction time were tested using the programmable Bonn reaction-time device (BonnDet@), composed of a small box containing 10 light bulbs of 5 colors behind an opales832

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cent front panel, with 5 buttons in corresponding colors positioned below.24 This peripheral device is controlled by a microcomputer loaded with the provided software. The computer activates the lights based on a sequence of random numbers, with the constraint that no color is repeated in consecutive trials. The speed of stimulus release can be changed by means of a rheostat. The bulb lights up for the entire interstimulus period, whether the subject does or does not respond. For every stimulus-response sequence, the microcomputer registers the interstimulus interval as the working speed in milliseconds and the latency period between stimulus and response as the reaction time in milliseconds. A reaction is accepted as correct if the color of the light and the button pushed are identical. This test has been shown to be stable and reliable, with extremely low intrasubject variability in repetitive trials.24 In the present study, subjects were required to perform the test in approximately 6 minutes both at baseline and before each blood sample was obtained. In a run-in visit occurring within 2 weeks before the study, all volunteers performed the test 4 times to eliminate a learning effect. Subjective Variables Subjective pharmacodynamic variables were recorded by the investigators and the volunteers using a lo-cm VAS. At baseline and after each blood sample was obtained, volunteers were asked to answer the question “How do you feel?” using the VAS, which consisted of 4 components, each employing a scale ranging from 0 to 10: alert-drowsy; clearheaded-muzzy; very well-very ill; and well coordinated-clumsy.25

A.E. diTZ

ET AL.

Statistical Analysis

RESULTS

Results are given as mean * SEM. Pharmacokinetic and pharmacodynamic variables after oral and rectal administration were compared using the Wilcoxon signed rank test and analysis of variance (ANOVA), as appropriate. Nominal data were compared using the McNemar exact test for correlated proportions. Statistical significance was set at P < 0.05. The analysis was performed using StatView 4.5 1 software (Abacus Concepts Inc., Berkeley, California).

The study enrolled 10 healthy volunteers (5 males, 5 females) with a mean age of 28 years (range, 24 to 32 years) and a mean (+ SEM) weight of 68.1 + 3.6 kg (range, 58 to 91 kg).

i o.ol,,, 0

B

5 .P 5 e s u5i ,oz .P 2 G-E -0 0 E 2 rz

100

10 -

200 Time After

Pharmacokinetics Individual serum concentration-time curves for the 10 subjects after oral and rectal administration are shown in Figure 1. In

Oral

300 400 Administration

500 (min)

l-

0.1 _-- ___-__

0.01 0

I 100

I 200 Time

After

I 300 Rectal

/ 400 Administration

I 500

, 600

(min)

Figure 1. Clomethiazole serum concentration-time curves in 10 healthy volunteers after (A) oral and (B) rectal administration of 600 mg clomethiazole edisylate. The broken line represents the detection limit. 833

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1 subject, no clomethiazole was detectable after rectal administration. After oral administration, large intersubject variability in drug absorption was noted. Most subjects (6/10) had measurable serum concentrations of clomethiazole within the fist 30 minutes after oral administration, and peak concentrations (range, 1.25 to 4.81 &mL) were reached within the first hour; the 4 subjects with slower absorption had lower peak concentrations (range, 0.11 to 0.70 pg/mL). Serum concentration-time curves after rectal administration were less variable. Seven of 10 subjects had measurable concentrations within the first 30 minutes. C,, was significantly lower (by a factor of 3.7; P = 0.03) and peak concentrations occurred later (P =

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0.04) after rectal administration . The mean were similar for both Tlag and Auco4, routes of administration (Table I), with a calculated rectal bioavailability of 90% compared with oral administration. Mean serum concentration-time curves for oral and rectal administration are shown in Figure 2. The 2 curves were significantly different up until 53 minutes (P = 0.03). Pharmacodynamics Working speed significantly decreased and reaction time significantly increased compared with baseline after both oral and rectal administration (working speed: P = 0.01 and P = 0.005, respectively; reaction time: P = 0.007 and P = 0.01, respectively).

Table I. Pharmacokinetic values after oral and rectal administration of 600 mg clomethiazole edisylate* in 10 healthy volunteers.

c,,

Oral

Rectal

1.76 f 0.47

0.48 + 0.14 0.40 0.05-1.67

0.03

Q%fn-u

Mean (+ SEM) Median Range

1.55 0.11-4.81

0.04

Tm, (tin)

Mean (* SEM) Median Range

55 f 12 30.5

23-121

89e 11 93 34-124 0.65

Jag (tin)

Mean (+ SEM) Median Range AUC,, (pmin/mL) Mean (r SEM) Median Range

33 k 5 24

29 AT5 24

13-64

13-56

116 2 20.6 110.8

105 * 36.0

0.43

42.2-223

73.2 30.0-420

= maximumserumconcentration;T,,, = time to maximum serum dzztion; AUC Moo = area under the curve from 0 to 600 minutes. *Corresponding to 390 mg clomethiazole base. +I’ values for log-transformed data were analyzed by one-way analysis

C

834

concentration;

of variance.

T,,s = lag time until first

A.E. RATZ ET AL.

- - n

Oral - - Rectal

0.0 0

120

240

360 Time

480

600

(min)

Figure 2. Time course of mean (+ SEM) serum clomethiazole concentration after oral and rectal administration of a single dose of 600 mg clomethiazole edisylate in 10 healthy volunteers.

However, there were no statistically significant differences in effect between oral and rectal administration (Table II). The increase in reaction time was higher and the time to reach maximum effect on reaction time was shorter after oral administration, but the difference did not reach statistical significance (P = 0.06 and P = 0.07, respectively). Working speed and reaction time were correlated with Tmax after oral administration (working speed: rz = 0.77, P = 0.02; reaction time: r2 = 0.75, P = 0 .O1; Spearman rank correlation), whereas they were not correlated after rectal administration (working speed: r2 = 0.05, P = 0.79; reaction time: 1-2= 0.25, P = 0.11; Spearman rank correlation). There were significant increases compared with baseline values in all subjec-

tive variables assessed by VAS after oral and rectal administration (P < 0.01). Subjective variables expressed as changes from baseline were similar after oral and rectal application (Table III).

Safety All subjects reported subjective adverse effects after receiving clomethiazole by both routes of administration (Table IV). A total of 72 adverse effects were reported after oral use (range, 3 to 12 per person), in comparison with 62 after rectal use (range, 4 to 8). The majority of symptoms involved the nose (nasal irritation, including rhinorrhea, itching, burning, tingling, sneezing, and nasal congestion), the eyes (conjunctival irritation, with burning, tired eyes, 835

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Table II. Maximum change from baseline in working speed, reaction time, and time to maximum effect assessedby computerized device (BonnDet@)” in 10 healthy volunteers after oral and rectal administration of 600 mg clomethiazole edisylate.* Rectal (mean f SEM)

Oral (mean f SEM)

Decreasein working speed (ms) Increasein reaction time (ms) Time to maximum effect on working speed @in) Time to maximum effect on reaction time (min) *Corresponding to 390 mg clomethiazole ?Wilcoxon signed rank test.

132 + 38 104 f 26 57* 63*

11 12

P+

97 f 32 66 f 22

0.24 0.06

116 r 27 143 f 26

0.44 0.07

base.

Table III. Comparison of mean (2 SEM) differences between baseline values and maximum effect for 4 subjective variables assessedby lo-cm visual analogue scales* after oral and rectal administration of 600 mg clomethiazole edisylate+ in 10 healthy volunteers. Oral

Alert/drowsy (cm) Clearheaded/muzzy(cm) Very well/very ill (cm) Well coordinated/clumsy (cm)

4.7 f 1.0

3.1 f 1.1 3.5 f 0.5 2.9 + 0.7

Rectal 4.2 2.9 4.0 3.5

f f f f

1.1 1.1 0.7 1.0

P* 0.48 0.73 0.21 0.51

*Subjects were asked, “How do you feel?’ +Corresponding to 390 mg clomethiazole base. rWilcoxon signed rank test.

lacrimation, and itching), the head (itching and burning sensation of the forehead), and the central nervous system (CNS) (sedation, sleepiness, differences in general perception and color perception, visual flickering, dizziness, difficulty concentrating, and pressure and tension in the head). Three subjects reported rectal itching and buming, and 1 subject reported an increased urge to defecate after rectal administration. Compared with baseline values, the maximum recorded values for systolic and diastolic blood pressure and heart rate were significantly higher after both oral and rec836

tal administration of clomethiazole (P I 0.01). Although the increases in diastolic blood pressure and heart rate did not differ significantly between oral and rectal administration, the increases in systolic blood pressure and mean arterial pressure after oral administration were significantly greater than and approximately twice those seen after rectal administration (Table V).

DISCUSSION AND CONCLUSIONS The large interindividual variability in clomethiazole absorption after oral ad-

A.E. R;iTZ ET AL.

Table IV. Number of volunteers experiencing adverse effects after oral and rectal administration of 600 mg clomethiazole edisylate.* Symptom Nasal irritation Conjunctival irritation CNS effects Rectal irritation Other

Oral

Rectal

P+

9 10 8 0 3

10 9 8 4 3

NS NS NS NS NS

CNS = central nervous system. *Corresponding to 390 mg clomethiazole base. ‘McNemar exact test for correlated proportions.

Table V. Absolute and percentage increase in blood pressure and heart rate in 10 healthy volunteers after oral and rectal administration of 600 mg clomethiazole edisylate.* Oral (mean + SEM) Systolic blood pressure mm Hg % Diastolic blood pressure mm Hg % Mean arterial blood pressure mm Hg % Heart rate beats/min % *Corresponding to 390 mg clomethiazole ‘Wilcoxon signed rank test.

Rectal (mean f SEM)

P+

21+4 18 +4

10*4 8*3

0.05 0.06

13 *3 19k.5

15 *7 21 f 11

0.68 0.68

15 *4 17 *5

7*2 8*3

0.02 0.04

8+3 13 +5

11*3 16*5

0.41 0.33

base

ministration observed in our study is comparable to the results of previous studies.20,21Our data show that oral absorption of clomethiazole is highly erratic, with large intersubject differences in C,,,, T max,and bioavailability. Our study demonstrated that rectal dosing also results in erratic absorption and high intersubject

variability. Absorption was slower and less pronounced after administration by the rectal route, suggesting that rectal administration is not appropriate when an immediate effect is required. However, because the pharmaceutical composition of a rectal formulation may critically modify the absorption process,” absorption of 837

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rectal clomethiazole might be different when the drug is administered as a solution or gel formulation. In our study, bioavailability did not differ significantly between the 2 routes, but the power to detect a significant difference was insufficiently low (
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though the initial blood pressure response to the starting dose is not reported by those authors, it is possible that the agitated state itself might have been related to the increase in blood pressure. Therefore, the decrease in blood pressure during clomethiazole therapy may be caused by clinical improvement (less agitation) rather than by a direct blood pressure-lowering effect of clomethiazole. The findings of our study indicate that a single rectal dose of 600 mg clomethiazole edisylate is as effective as an equal oral dose and bears no safety risk in healthy young subjects. These data suggest that rectal use might be considered when oral or parenteral administration is impossible and a later onset of effect is not crucial. ACKNOWLEDGMENTS The authors wish to thank Astra Pharmaceuticals, Dietikon, Switzerland, for supplying the study drug and for financial support. The authors are indebted to Dr. H. Harhoff, Gemeinschaftspraxis fiir Laboratoriumsmedizin, Dortmund, Germany, for performing the HPLC analysis of clomethiazole and to Dr. Jiirgen Drewe for assistance in statistical analysis of the data.

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