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

Abstract

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.

Effects of Multiple Doses of Dichloroacetate on GSTZ1 Expression and Activity in Liver and Extrahepatic Tissues of Young and Adult Rats

“…Given the greater proportion of liver to body weight in juveniles, the hepatic metabolism of DCA is predicted to be augmented within this age group. This is consistent with the higher clearance of DCA observed in young populations (Shroads et al, 2008;Mangal et al, 2018), as children may retain a higher capacity for the GSTZ1-catalyzed metabolism of DCA, due to relative liver size.…”

“…For example, the chronic use of DCA in adults can lead to development of reversible peripheral neuropathy (Kaufmann et al, 2006;Stacpoole et al, 2019). However this effect is seldom clinically symptomatically observed in children (Stacpoole, 2011;Abdelmalak et al, 2013), who metabolize DCA more quickly after multiple doses than adults (Shroads et al, 2008;Mangal et al, 2018). In people, DCA metabolism is independent of sex (Stacpoole et al, 1998).…”

Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate

“…Evidence of hypoglycemia, liver involvement, and muscle weakness were also noted but not in all three siblings. The lactic acidosis, with all three siblings responding well to the classical treatment with dichloroacetate, although this can have variable success in children (45), is likely to be explained by the inefficient respiration on pyruvate that we found using the patient-derived cells, but as of today, we have no explanation for the clinical presentation with low serum methionine. It should be noted that methionine can be an important source of reducing power through synthesis of glutathione, which is used in mice upon conditional deletion of Txnrd1 in hepatocytes with or without concomitant deletion of Txn (46,47).…”

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

“…Sodium dichloroacetate treatment may help stabilize PDC escaping PDH deficiency, which leads to differences in mitochondrial activity from chronic DCA exposure. Sodium dichloroacetate reactivates PDC and consequently promotes oxidative metabolism in the mitochondria: the metabolism of pyruvate shifts from glycolysis towards oxidative phosphorylation, lowering lactate production, and this has been exploited in lactic acidosis treatment [4,25,26].…”