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.