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Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2003 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 56, no 2, 173-183 p.Article in journal (Refereed) Published
Abstract [en]


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.


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.


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.


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.

Place, publisher, year, edition, pages
2003. Vol. 56, no 2, 173-183 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-93718DOI: 10.1046/j.0306-5251.2003.01850.xPubMedID: 12895190OAI: oai:DiVA.org:uu-93718DiVA: diva2:167286
Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2011-10-07Bibliographically approved
In thesis
1. Models for Ordered Categorical Pharmacodynamic Data
Open this publication in new window or tab >>Models for Ordered Categorical Pharmacodynamic Data
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In drug development clinical trials are designed to investigate whether a new treatment is safe and has the desired effect on the disease in the target patient population. Categorical endpoints, for example different ranking scales or grading of adverse events, are commonly used to measure effects in the trials.

Pharmacokinetic/Pharmacodynamic (PK/PD) models are used to describe the plasma concentration of a drug over time and its relationship to the effect studied. The models are utilized both in drug development and in discussions with drug regulating authorities. Methods for incorporation of ordered categorical data in PK/PD models were studied using a non-linear mixed effects modelling approach as implemented in the software NONMEM. The traditionally used proportional odds model was used for analysis of a 6-grade sedation scale in acute stroke patients and for analysis of a T-cell receptor expression in patients with Multiple Sclerosis, where the results also were compared with an analysis of the data on a continuous scale. Modifications of the proportional odds model were developed to enable analysis of a spontaneously reported side-effect and to analyze situations where the scale used is heterogeneous or where the drug affects the different scores in the scale in a non-proportional way. The new models were compared with the proportional odds model and were shown to give better predictive performances in the analyzed situations.

The results in this thesis show that categorical data obtained in clinical trials with different design and different categorical endpoints successfully can be incorporated in PK/PD models. The models developed can also be applied to analyses of other ordered categorical scales than those presented.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 60 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 20
Pharmacokinetics/Pharmacotherapy, Pharmacodynamic, Modelling, Categorical data, NONMEM, Proportional odds model, Markov model, Differential drug effect model, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-6125 (URN)91-554-6394-0 (ISBN)
Public defence
2005-12-02, B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2011-07-08Bibliographically approved

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