A Pilot Study of Rapid Haplotyping Procedure for Personalized Dosing of Dichloroacetate (DCA) in Healthy Volunteers

Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a rare disease of mitochondrial energy failure with the life of expectancy of affected children severely truncated. Treatment of PDCD remains a serious, unmet challenge. Dichloroacetate (DCA) represents the first targeted therapy for PDCD by stimulating residual PDC activity. Cumulative experience with DCA has revealed dose accumulation in a subset of the population. This can be abated through personalized dosing of DCA, assigned by haplotype variation in the gene encoding glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate. Haplotype variations in GSTZ1 influence the kinetics and dynamics of chronically administered DCA. A single dose of DCA has a bioavailability approaching unity and is widely distributed throughout the body. The plasma half-life (t ½) is ~1 hr in drug-naïve subjects. Gender does not influence DCA kinetics or metabolism. The major route of biotransformation is via dehalogenation to glyoxylate by glutathione transferase zeta 1 (GSTZ1). DCA is a mechanism-based inhibitor of GSTZ1, so repeated administration results in increased plasma t ½ and decreased clearance.

Inclusion criteria

• Healthy as outline in the physical exam and blood tests
• Non smoker

Exclusion criteria

• Cannot comprehend or refuse to sign the informed consent form;
• Febrile or have other clinical signs of infection;
• Pregnant or are nursing;
• In females, cannot or refuse to use contraception or avoid unprotected intercourse during the study;
• Uncontrolled hypertension (BPs > 160 mmHg or BPd > 100 mmHg) on conventional medication;
• Anemic (hematocrit < 35% in males; < 35% in females;
• Serum creatinine ≥ 1.3 mg/dl, TSH > 4.5 mIU/ml; a transaminase (ALT or AST) > 2 x ULN, total bilirubin > 1.2 mg/dl or fasting glucose ≥ 110 mg/dl.
• History of psychosis, seizures or diabetes mellitus or be receiving anti-psychotic, anti-epileptic or blood glucose-lowering medication.