Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients.
OBJECTIVE
This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach.


METHODS
One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM.


RESULTS
Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect.


CONCLUSIONS
The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.
Zingmark
Per-Henrik
PH
AstraZeneca R & D Södertälje, Sweden. per-henrik.zingmark@astrazeneca.com
Ekblom
Marianne
M
Odergren
Tomas
T
Ashwood
Tim
T
Lyden
Patrick
P
Karlsson
Mats O
MO
Jonsson
E Niclas
EN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002719:Chlormethiazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism
D006993:Hypnotics and Sedatives; D002719:Chlormethiazole