Healthy
Conditions
Brief summary
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.
Detailed description
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.
Interventions
Dichloroacetate (DCA) 25 mg/kg oral solution will be administered daily for 5 days.
OTHERGSTZ1 haplotyping
One teaspoon of blood is collected by standard phlebotomy. Cheek cells are collected by standard brushing. Samples will be analyzed at two independent laboratories to validate methods for GSTZ1 haplotype analysis.
Sponsors
Medosome Biotec LLC
Food and Drug Administration (FDA)
University of Florida
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
SCREENING
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GSTZ1 haplotype frequency | Baseline Visit | The TagMan-based genotyping technology will be used for GSTZ1 haplotype analysis from both blood and cheek samples. Haplotype variations in GSTZ1 influence the kinetics of chronically administered investigational medication DCA. The coding region of the GSTZ1 gene contains three functionally important non-synonymous single nucleotide polymorphisms (SNPs) that give rise to five major GSTZ1 haplotypes: KRT (Z1A), KGT (Z1B), EGT (Z1C), EGM (Z1D), and KGM (Z1F). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration (Cmax) of Dichloroacetate (DCA) | -10, 0, 5, 10, 20, 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 30 hours post dose | After 5 days of oral DCA administration, blood samples will be collected at the specified times for Peak Plasma Concentration (Cmax) analysis. |
Countries
United States
Outcome results
None listed