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Dichloroacetate: population pharmacokinetics with a pharmacodynamic sequential link model.
P J Williams1, J R Lane, C C Turkel
1University of the Pacific, School of Pharmacy, Stockton, California, USA.
Journal of Clinical Pharmacology
|March 28, 2001
Summary
Dichloroacetate (DCA) reduces lactate levels. This study developed models to determine optimal DCA dosing for traumatic brain injury (TBI) patients in Phase III trials, finding TBI patient responses differ from healthy volunteers.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Neuroscience
Background:
- Dichloroacetate (DCA) is a small molecule known to reduce lactate concentrations.
- Traumatic brain injury (TBI) is a condition often associated with elevated lactate levels.
Purpose of the Study:
- To develop pharmacokinetic and pharmacodynamic models for Dichloroacetate (DCA).
- To determine an optimal Dichloroacetate (DCA) dose for a Phase III clinical trial in patients with traumatic brain injury (TBI).
Main Methods:
- Population pharmacokinetic and pharmacodynamic models were developed using NONMEM software.
- Pharmacokinetic data were analyzed using a physiologic two-compartment model.
- Pharmacodynamic data were analyzed using an indirect physiologic response model.
- Simulations were used to evaluate various dosing strategies.
Main Results:
- DCA clearance decreased significantly with multiple dosing (4.82 L/h to 1.07 L/h).
- Pharmacokinetics and pharmacodynamics of DCA in TBI patients could not be reliably predicted from data in normal volunteers.
- Population pharmacokinetic modeling and simulation proved effective for designing the Phase III trial.
Conclusions:
- Pharmacokinetic and pharmacodynamic modeling are essential for Dichloroacetate (DCA) dose determination in traumatic brain injury (TBI) patients.
- DCA dosing strategies require specific optimization for TBI populations.
- Modeling and simulation facilitated the design of a pivotal Phase III clinical trial for DCA in TBI.