Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children.

Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children. Accordingly, a semimechanistic pharmacokinetic-enzyme turnover model was developed in a step-wise approach: (1) a population pharmacokinetic model for adults was developed; (2) the adult model was scaled to children using allometry and physiology-based scaling; and (3) the scaled model was externally qualified, updated with clinical data, and optimal doses were projected. A 2-compartment model accounting for saturable clearance and GSTZ1 enzyme turnover successfully characterized the DCA PK in adults and children. DCA-induced inactivation of GSTZ1 resulted in phenoconversion of all subjects into slow metabolizers after repeated dosing. However, rate and extent of inactivation was 2-fold higher in subjects without the wild-type EGT allelic variant of GSTZ1, resulting in further phenoconversion into ultraslow metabolizers after repeated DCA administration. Furthermore, DCA-induced GSTZ1 inactivation rate and extent was found to be 25- to 30-fold lower in children than in adults, potentially accounting for the observed age-dependent changes in PK. Finally, a 12.5 and 10.6 mg/kg twice-daily DCA dose was optimal in achieving the target steady-state trough concentrations (5-25 mg/L) for EGT carrier and EGT noncarrier children, respectively.