Dichloroacetate: Population pharmacokinetics with a pharmacodynamic sequential link model

Citation
Pj. Williams et al., Dichloroacetate: Population pharmacokinetics with a pharmacodynamic sequential link model, J CLIN PHAR, 41(3), 2001, pp. 259-267
Citations number
30
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
JOURNAL OF CLINICAL PHARMACOLOGY
ISSN journal
00912700 → ACNP
Volume
41
Issue
3
Year of publication
2001
Pages
259 - 267
Database
ISI
SICI code
0091-2700(200103)41:3<259:DPPWAP>2.0.ZU;2-N
Abstract
Dichloroacetate (DCA) is a small molecule that reduces ambient concentratio ns of lactate in man. It was the purpose of this study to develop pharmacok inetic and pharmacodynamic models for determination of a dose for a pivotal Phase III clinical trial of DCA in patients with traumatic brain injury (T BI). Population pharmacokinetic and pharmacodynamic models were developed f or DCA using NONMEM(R) software. The pharmacokinetic data were fit to a phy siologic two-compartment model, and the pharmacodynamic data were fit to an indirect physiologic response model. Simulations were employed to evaluate various dosing strategies for consideration in a pivotal Phase III clinica l trial of DCA. For the pharmacokinetic model, it was discovered that the c learance of DCA decreased on multiple dosing from 4.82 L/h to 1.07 L/h and that the pharmacokinetics and pharmacodynamics in TBI patients could not be predicted from normal volunteers. Population pharmacokinetic modeling and simulation of the expected effects of several dosing strategies were useful procedures for designing a Phase III trial. Journal of Clinical Pharmacolo gy, 2001;41:259-267 (C) 2001 the American College of Clinical Pharmacology.