Taimour Langaee1, Richard Wagner2, Lloyd P Horne3, Lee Ann Lawson3, Cecilia Becker2,4, Mohamed Shahin1, Petr Starostik3, Peter W Stacpoole4. 1. 1 Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida , Gainesville, Florida. 2. 2 Medosome Biotec, LLC , Alachua, Florida. 3. 3 Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , Gainesville, Florida. 4. 4 Department of Pathology, College of Medicine, University of Florida , Gainesville, Florida.
Abstract
AIMS: Dichloroacetate (DCA) represents the first targeted therapy for pyruvate dehydrogenase complex deficiency; it is metabolized by glutathione transferase zeta1 (GSTZ1). Variation in the GSTZ1 haplotype is the principal variable influencing DCA kinetics and dynamics in humans. We aimed to develop a sensitive and rapid clinical genetic screening test for determining GSTZ1 haplotype status in individuals who would be treated with DCA, and then apply the test for the investigation of the plasma pharmacokinetics (PK) of DCA as a function of GSTZ1 haplotype. MATERIALS AND METHODS: DNA samples from 45 healthy volunteer study participants were genotyped for three functional GSTZ1 single nucleotide polymorphisms (rs7975, rs7972, and rs1046428) by TaqMan®. Prior studies showed that subjects with at least one EGT haplotype (EGT carrier) metabolized DCA faster than EGT noncarriers. The clinical genetic test for GSTZ1 was developed and validated at our CLIA-certified Clinical Laboratory. Four fast metabolizer EGT carriers and four slow metabolizer EGT noncarriers were selected to complete a standard PK study. Each participant received a single oral dose of 25 mg/kg of DCA (IND 028625) for 5 days. RESULTS: The EGT haplotype carrier group demonstrated significantly faster metabolism of DCA and higher rates of plasma DCA clearance after 5 days of drug exposure compared with EGT noncarriers (p = 0.04). CONCLUSIONS: These preliminary data establish the validity and practicality of our rapid genotyping/haplotyping procedure for genetic-based DCA dosing to mitigate or prevent adverse effects in patients treated chronically with this drug.
AIMS: Dichloroacetate (DCA) represents the first targeted therapy for pyruvate dehydrogenase complex deficiency; it is metabolized by glutathione transferase zeta1 (GSTZ1). Variation in the GSTZ1 haplotype is the principal variable influencing DCA kinetics and dynamics in humans. We aimed to develop a sensitive and rapid clinical genetic screening test for determining GSTZ1 haplotype status in individuals who would be treated with DCA, and then apply the test for the investigation of the plasma pharmacokinetics (PK) of DCA as a function of GSTZ1 haplotype. MATERIALS AND METHODS: DNA samples from 45 healthy volunteer study participants were genotyped for three functional GSTZ1 single nucleotide polymorphisms (rs7975, rs7972, and rs1046428) by TaqMan®. Prior studies showed that subjects with at least one EGT haplotype (EGT carrier) metabolized DCA faster than EGT noncarriers. The clinical genetic test for GSTZ1 was developed and validated at our CLIA-certified Clinical Laboratory. Four fast metabolizer EGT carriers and four slow metabolizer EGT noncarriers were selected to complete a standard PK study. Each participant received a single oral dose of 25 mg/kg of DCA (IND 028625) for 5 days. RESULTS: The EGT haplotype carrier group demonstrated significantly faster metabolism of DCA and higher rates of plasma DCA clearance after 5 days of drug exposure compared with EGT noncarriers (p = 0.04). CONCLUSIONS: These preliminary data establish the validity and practicality of our rapid genotyping/haplotyping procedure for genetic-based DCA dosing to mitigate or prevent adverse effects in patients treated chronically with this drug.
Authors: Dan Dan Tian; Samuel K Bennett; Lucy A Coupland; Kathryn Forwood; Yadanar Lwin; Niloofar Pooryousef; Illa Tea; Thy T Truong; Teresa Neeman; Philip Crispin; James D'Rozario; Anneke C Blackburn Journal: Pharmacol Res Perspect Date: 2019-10-08