A Pilot Study of Rapid Haplotyping Procedure for Personalized Dosing of Dichloroacetate (DCA) in Healthy Volunteers
A Pilot Study of Rapid Haplotyping Procedure for Personalized Dosing of Dichloroacetate (DCA) in Healthy Volunteers
The purpose of this study is to identify and analyze the frequency of GSTZ1 haplotypes in a
 healthy adult population and determine the pharmacokinetics of Dichloroacetate (DCA)
 metabolism based on haplotype analysis.

 The DCA drug is the first targeted treatment for Pyruvate Dehydrogenase Complex Deficiency
 (PDCD).

 This pilot study, focuses on developing a high throughput, sensitive and accurate screening
 test for determining glutathione transferase zeta 1 (GSTZ1) haplotype status in individuals
 who would be treated with DCA.
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.