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Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies
Author(s) -
Jorga Karin,
Fotteler Bärbel,
Banken Ludger,
Snell Paul,
Steimer JeanLouis
Publication year - 2000
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2000.00113.x
Subject(s) - pharmacokinetics , medicine , pharmacology , population , population pharmacokinetics , environmental health
Aims To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under‐ or over‐exposure to this catechol‐ O ‐methyltransferase (COMT) inhibitor. Methods Four hundred and twelve patients participated in three multicentre, parallel, double‐blind, placebo‐controlled, dose‐finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. Results The pharmacokinetic model which best described the data was a two‐compartment open model with first‐order absorption and possibly a lag‐time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10–20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4.5–5 l h −1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half‐life in patients of approximately 5–8 h. Conclusions Using sparse concentrations and mixed effect‐effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under‐ or over‐exposure to tolcapone.