SHORT

C O M M U N I C A T I O N S

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses E. W. Wuis, M.J.M. Dirks, T.B. Vree and E. Van der Kleijn Introduction The g a m m a - a m i n o b u t y r i c acid (GABA) agonist baclofen is a centrally acting muscle relaxant, which is used in the t r e a t m e n t of spasticity. Once initiated, t h e r a p y with this drug is often continued for a prolonged period of time. Until now, pharmacokinetic studies with baclofen h a v e mostly dealt with single doses in h e a l t h y subjects [1-4]. Multiple-dose studies in patients are essential in order to obtain pharmacokinetic information in the s a m e circumstances in which the drug is routinely used. In a multiple-dose study in elderly patients receiving baclofen in a fixed dosage schedule, the investigation had to be discontinued as most patients developed severe drowsiness [5]. In this communication we report the results of a pharmacokinetic study of baclofen in spastic patients, while they were being t r e a t e d with individualized oral dosages.

Methods Patients The subjects were 6 neurological in-patients (4 males and 2 females) with spasticity of spinal or cerebral origin. Their m e a n (+ SD) age and body weight were 52 years (+ 6) and 83 kg (+ 13), respectively. None was overtly incontinent for urine. Only 1 p a t i e n t was without any co-medication; a v a r i e t y of drugs was t a k e n by the other patients. Full details are given in Table 1. The patients were t r e a t e d with oral racemic baclofen (Lioresal | tablets, Ciba-Geigy, Arnhem, the Netherlands) in doses v a r y i n g between 30 and 80 m g daily given at 6-h or 8-h intervals (Table 2). The duration of baclofen medication varied a m o n g the patients, but was such to h a v e caused steady-state in each p a t i e n t for the particular dosage r e g i m e n reported.

Keywords Baclofen Clearance Patients Pharmacokinetics ~E.W. Wuis (correspondence), M.J.M. Dirks, Dr. T.B. Vree and Prof. Dr. E. Van der Kleijn: Department of Clinical Pharmacy, University Hospital Nijmegen Sint Radboud, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.

12(2) 1990

Sampling procedure Serial 2-3 ml venous blood samples were collected in heparinized tubes at p r e d e t e r m i n e d t~mes for the period of a dosage interval. P l a s m a was separated by centrifugation (1,500 g) and stored at - 2 0 ~ until analysed. U r i n e was collected on spontaneous voiding in portions equalling the dosage intervals for a period of 3-4 intervals. The total volume and pH of each urine specimen was m e a s u r e d and 10 ml samples were stored at - 2 0 ~ until analysed. The total number of urine specimens obtained from the 6 patients was 21. Analysis of plasma and urine Racemic baclofen in p l a s m a and urine was m e a s u r e d by high pressure liquid chromatography (HPLC) with fluorimetric detection [6]. The m i n i m u m detectable concentration was 0.02mg.1-1. H i g h u r i n a r y baclofen concentrations were determined, using the rapid directUV method [7]. P l a s m a protein binding in a number of p l a s m a samples was m e a s u r e d at room t e m p e r a t u r e by filtration t h r o u g h E M I T | Free level filters (Syva, Pale Alto, USA). No nonspecific binding to the filters was found. Creatinine both in p l a s m a and urine was m e a s u r e d by an a u t o m a t e d Jaff~ method. Analysis of data M i n i m u m (Css(min)) and m a x i m u m (C~s(max)) p l a s m a concentrations, and the time to reach the m a x i m u m (tmax) were obtained from the data at the sampling times. The fluctuation in the p l a s m a concentration was expressed as Cs~(maJ Cs~(min)"100%. F r o m the a r e a u n d e r the curve during a dosage interval ~ (AUC~(~)), which was calculated by the linear trapezoidal rule, the average steady-state p l a s m a concentration

Wuis EW, Dirks MJM, Vree TB, Van der Kleijn E. Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses. Pharm Weekbl [Sci] 1990;12(2):71-4. Abstract The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30-80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (• 0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml .min -1 (_+ 44), plasma protein binding 35% (_+ 6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (• 16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects. Accepted 23 February 1990.

P h a r m a c e u t i s c h Weekblad Scientific edition

71

(C~,(av)) was computed according to Css(av)= AUC~(Jr. The total body clearance (CL/f) was obtained according to CL/f = D/AUC,~(~) in which f i s the fraction of the dose systemically available and D the dose per dosage interval. Apparent renal clearance (CLR) values were computed from the renal excretion rate in each urine sample divided by the average steady-state plasma concentration. Creatinine clearances (CLcR) were similarly obtained. From the total volume of urine collected, the fraction of systemically available drug excreted unchanged into the urine (fe) was calculated. The nonrenal clearance (CLNR) was obtained according to CLNR = (CL/D (1-fe). Data are expressed as mean ( i SD). Statistical significance was tested by the paired t-test; P < 0 . 0 5 was t a k e n to indicate significance. Results Figure 1 depicts the plasma baclofen concent r a t i o n - t i m e curves following m u l t i p l e oral doses in 6 spastic patients during the dosage interval period. The values obtained for the pharmacokinetic parameters are listed in Table 2. Individual mean values are given for the apparent renal clearance of baclofen and for the creatinine clearance. The C L R w a s high and was not significantly different from the CLcR when all re-

hal clearance values from the 6 patients (n = 21) were examined. No correlation between urine flow [overall mean value 1.2 ml. min -1 (• 0.6)] or pH [overall mean value 6.3 (• 1.0)] and the C L R w a s discerned. The average plasma protein binding was 35% (• 6) as determined in 12 samples from different patients with total baclofen plasma concentrations varying from 0.10 to 0.40 mg. 1-1. Discussion The pharmacokinetic parameters of baclofen found in this study with spastic patients treated with multiple oral doses are in good agreement with the results obtained in the earlier mentioned single-dose studies in healthy subjects. Only in elderly patients (aged 69-81 years) were maximum concentrations after dosing reported at later times [5]. With both dosage regimens (q6h and q8h), the fluctuation in the plasma concentration was great - ranging from slightly less t h a n 200% to just over 400% - though consistent with a mean half-life of 7 h as reported previously in healthy subjects [3 4]. The half-life was not determined in the present study, because this would have implied abrupt withdrawal of the drug risking seizures, hallucinations, and dyskinesias [8 9]. The clinical relevance of the wide fluctuation in the plasma concentration is

Table 1

Characteristics of the patients Patient

Age/gender

Body weight (kg)

Clinical diagnosis

Co-medication

A B C

49/M 47/F 60/M

107 82 80

spinal cord injury; back pain multiple sclerosis multiple sclerosis

D

52/F

71

E

58/M

77

F

46/M

80

normal pressure hydrocephalus; radicular syndrome; lumbago; hypothyroidism cerebrovascular insufficiency; polyneuropathy; epilepsy; dementia multiple sclerosis

lactulose, methenamine mandelate vitamins B co-trimoxazole, phenprocoumon, triamterene, vitamin B1 oxazepam, thyroxine sodium phenytoin

Table 2

Pharmacokinetic parameters of baclofen in spastic patients following multiple oral doses Patient

A B C D E F Mean SD

72

Daily dose

40 40 80 30 60 75

r (h)

tmax (h)

C~(max) 9100 %

6 6 6 8 8 8

3.0 1.1 2.0 2.1 2.0 1.1 1.9 0.7

188 209 354 220 256 439

C~(av) fe (mg. 1-1)

0.180 0.180 0.336 0.171 0.191 0.220

Clearance (ml-min -1)

CL/f

CL R

CLcR

CLNR

0.90 0.74 0.53 0.46 0.57 0.71

154 154 165 122 218 237

139 115 103 56 143 169

144 121 94 56 97 146

15 40 78 65 95 68

0.65 0.16

175 44

121 39

II0 34

60 29

Pharmaceutisch Weekblad Scientific edition

12(2) 1990

Figure 1 Plasma baclofen concentrationtime curves following multiple oral doses q6h (A) or q8h (B) for the period of the dosage interval in 6 spastic patients

31asrna conc (mg/I) O. 7

A

0.8

baclofen q6h

05

0.7

31asma c o n c (rag/I) B

0.8

baclofen q8h

0.5

0.4

V pat. A (40 rng) O pat,. B (40 rag] [80 mg]

0.3

0.4 0.3

0.2

0.2

o.1

Q1

o

2

4

O

T

I

I

I

I

0

2

4

6

8

time after a close (tn}

not known. Therapeutic concentrations are considered to be 0.08-0.4 mg. 1-1 [10], while concentrations of over 0.8 mg. 1-1,have been associated with toxicity [11 12]. Cerebrospinal fluid levels may possibly reflect the concentration at the site of action of this centrally acting muscle relaxant better than plasma [13]. Liquor obtained from 3 patients in the present study, however, failed to give detectable baclofen concentrations (assayed as plasma), making it unsuitable as a sampling medium. The apparent renal clearance of baclofen was found to be equal to the creatinine clearance. This relationship was established using renal clearance values derived from data not solely obtained during the elimination phase. The altered bladder function of patients with spasticity (see below) precludes short sampling intervals, while chronic dosing further restricts sampling possibilities. However, it can be assumed that, like the findings in healthy subjects in whom ample urine sampling during elimination revealed an identical relationship [4], the variation in baclofen's renal clearance is closely related to the variation in the creatinine clearance. The influence of the renal function on the pharmacokineric pattern of baclofen is most clearly seen in patients D and F with almost equal nonrenal clearance values (Table 2). The difference in total body clearance can be explained completely by the difference in creatinine clearance. Thus, the 2.5-fold difference in dose is not reflected in the average steady-state plasma concentrations, which were 0.171 and 0.220 mg.1-1, respectively. The nearly equal plasma concent r a t i o n - t i m e curves of patients D and E (Fig. 1B) with a 2-fold difference in dose, can also be ascribed for the greater part to the differences in renal function. These findings may explain the earlier reported toxicity of baclofen with normal doses in patients with renal impairment [11 14 15), and are in agreement with a case of intoxication where a previously effective dose led to 12(2) 1990

Pharmaceutisch Weekblad Scientific edition

time after a close (h}

unacceptably high plasma concentrations after both the creatinine clearance and the renal clearance had dropped considerably [unpublished observation]. The present study also demonstrates the practical difficulties of urine sampling in spastic patients in whom dysfunction of voiding is frequently present [16]. Reduced voluntary control and altered reflex activity imply that the short sampling intervals one may need for pharmacokinetic purposes will often not be feasible, while the volume of a portion may be compromised. Very likely there was some inaccuracy in the portions collected in patients C and E. When their renal clearance values were computed differently (by multiplying fe by CL/D, the values were smaller (87 and 124 m l . m i n -1) though reasonably close to the listed values.

Conclusion The results of this baseline study suggest that the pharmacokinetics of multiple-dose baclofen in spastic patients will not differ greatly from those previously reported after single doses in healthy subjects, the renal function being a prominent variable. It remains to be established how the separate enantiomers of the clinically used racemic mixture will behave, but it is anticipated that the observed relationship between the renal clearance of baclofen and the creatinine clearance will not be stereoselective [4 17].

Acknowledgements The authors thank the neurologists of the Institute for Neurology (Prof. Dr. B.P.M. Schulte) for kind permission to sample the patients and the nursing staff members for help with the sampling.

References 1 Kochak GM, Rakhit A, Wagner WE, Honc F, Waldes L, Kershaw RA. The pharmacokinetics of baclofen derived from intestinal infusion. Clin Pharmacol Ther 1985;38:251-7. 73

2 Peterson GM, McLean S, Millingen KS. Food does not affect the bioavailabilityofbaclofen. Med J Aust 1985; 42:689-90. 3 Krauss D. Untersuchungen zur Razemat- und Enantiomerenkinetik von Baclofen und seinen Fluoranalogons [Disssertation]. Frankfurt am Main: Goethe-Universit~it, 1988. 4 Wuis EW, Dirks MJM, Vree TB, Van der Kleijn E. Plasma and urinary excretion kinetics of orally administered baclofen in healthy subjects. Eur J Clin Pharmacol 1989;37:181-4. 5 Hulme A, MacLennan WJ, Ritchie RT, John VA, Shotton PA. Baclofen in the elderly stroke patient its side effects and pharmacokinetics. Eur J Clin Pharmacol 1985;29:467-9. 6 Wuis EW, Dirks RJM, Vree TB, Van der Kleijn E. High-performance liquid chromatographic analysis of baclofen in plasma and urine of man after precolumn extraction and derivatization with o-phthaldialdehyde. J Chromatogr 1985;337:341-50. 7 Wuis EW, Van Beijsterveldt LEC, Dirks RJM, Vree TB, Van der Kleijn E. Rapid simultaneous determination of baclofen and its -/-hydroxy metabolite in urine by high-performance liquid chromatography with ultraviolet detection. J Chromatogr 1987;420: 212-6. 8 Garabedian-Ruffalo SM, Ruffalo RL. Adverse effects secondary to bacl0fen~wi'thdrawal. Drug Intell Clin Pharm t985;19:30~1-6.

74

9 Harrison SA, Wood Jr CA. Hallucinations after preoperative baclofen discontinuation in spinal cord injury patients. Drug Intell Clin Pharm 1985;19:747-9. 10 Young RR, Delwaide PJ. Drug therapy. Spasticity. II. N Engl J Med 1981;304:96-9. ' 11 Seyfert S, Kraft D, Wagner I K. Baclofen-Dosis bei Haemodialyse und Niereninsuffizienz. Nervenarzt 1981;52:616-7. : 12 Anderson P, Noh~r H, Swahn CG. Pharmacokinetics in baclofen overdose. Clin Toxicol 1984;22:11-20. 13 Penn RD, Savoy SM, Corcos D, et al. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517-21. 14 Dahlin PA, George J. Baciofen toxicity associated with declining renal clearance after ~buprofen. Drug Intell Clin Pharm 1984;18:805-8. 15 Hormes JT, Benarroch EE, Rodriguez M, Klass DW. Periodic sharp waves in baclofen-induced encephalopathy. Arch Neurol 1988;45:814-5. 16 Pedersen E. How spasticity affects bowel and bladder function. In: Feldman RG, Young RR, Koella WP, eds. Spasticity. Disordered motor control. Chicago: Year Book Medical Publishers, 1980:57-69. 17 Wuis EW, Dirks MJM, Termond EFS, Vree TB, Van der Kleijn E. Comparison of the pharmacokinetics of intravenously administered rac-baclofen and its (-)(R)- and (+)-(S)-enantiomers in dogs. Int J Clin Pharm Res 1989;10:239-46.

P h a r m a c e u t i s c h W e e k b l a d Scientific e d i t i o n

12(2) 1990