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.