Deciphering ADME genetic data using an automated haplotype approach.

OBJECTIVE: To investigate the utility of statistical tools in translating Affymetrix Drug Metabolizing Enzyme and Transporter (DMET) Assay single-nucleotide polymorphisms (SNPs) into common consensus star alleles. METHODS: DMET SNP data from clinical trials in different ethnicities were pooled for analyses. Three different statistical methods, PHASE, Bayesian, and expectation-maximization (EM), were first assessed by comparing the consistency of calling CYP2D6 alleles among 1108 Asians and 55 Caucasians. Subsequently, the performance of EM in deriving haplotype calls was evaluated against the Affymetrix Translation Table for CYPs 2B6, 2C19, 2C9, and 3A4/5 in 582 Asians, 296 Caucasians, and 369 Africans. Selected DNA samples were sequenced to verify the EM-predicted haplotype calls. RESULTS: PHASE, Bayesian, and EM methods showed a similar CYP2D6 star allele call rate. The EM method, with a 0.99 posterior probability cutoff, was chosen for further evaluation because of its low false-positive call rate. Haplotype calls obtained with the EM method were consistent with the Affymetrix Translation Table more than 95% of the time for all five CYPs, except for the CYP2B6 calls in the African descents (83%). In addition, the EM method was superior to the Translation Table-only approach in resolving complex haplotype patterns, identifying novel haplotypes in CYP2B6 and CYP3A5, and determining genotype calls in the presence of missing SNP data. CONCLUSION: A statistical method such as EM could be used to augment the translation of DMET assay SNP data into star alleles, especially for complex genes, to facilitate full utilization and interpretation of clinical pharmacogenetics data.

The effect of commonly used vehicles on canine hematology and clinical chemistry values.

Drug metabolism and pharmacokinetic (DMPK) studies are an important phase in drug discovery research. Compounds are administered via the intravascular or extravascular routes to animals to calculate various pharmacokinetic parameters. An important step in this process is dissolving the novel compound in a safe vehicle. This procedure is particularly challenging for compounds that must be administered intravenously, as the solution must be clear before injection. There are no published guidelines on which vehicles, or combination of vehicles, are acceptable in a particular species, nor are there published data on the effects these vehicles have on clinical chemistry or hematology parameters, particularly in dogs. In this study, 9 vehicles commonly used at sanofi-aventis USA (propylene glycol, polyethylene glycol 400, glycofurol, hydroxypropyl Beta-cyclodextrin, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, ethyl alcohol, and saline) were tested for adverse clinical reactions (such as vomiting or diarrhea) and for their effect on hematology and clinical chemistry parameters. Each vehicle was administered to a group of 8 Beagles by slow intravenous infusion, and blood was collected prior to infusion and at 24 h and 7 d postinfusion. Of 8 dogs given propylene glycol, 2 developed mild gastrointestinal signs (vomitus, diarrhea) after their infusions. None of the vehicles tested induced significant hematology or serum clinical chemistry abnormalities, nor were significant clinical signs noted after administration. We conclude that at the dose, route, and manner described, all of the vehicles tested in this study are clinically safe to use and have no acute effects on hematology or serum chemistry parameters.