Impact of genetic factors (CYP2C9, VKORC1 and CYP4F2) on warfarin dose requirement in the Turkish population.

Warfarin has a narrow therapeutic index and displays marked person-to-person variation in dose requirement. Functional polymorphisms at candidate genes can therefore offer utility as biomarkers to individualize warfarin treatment. The main objective of this study was to determine whether and to what extent variability in warfarin dose requirements was determined by polymorphisms in CYP2C9, VKORC1, CYP4F2 (rs2108622) and EPHX1 (rs2292566) in the Turkish population. Patients (n = 107) who had stable doses and international normalized ratio (INRs) at their last three consecutive visits were registered. Their demographic factors, concurrent medications, warfarin-related bleedings or thromboembolisms, smoking, alcohol intake and weekly green vegetable consumption were recorded. From a blood sample, DNA was isolated and genotyped by real-time PCR for polymorphisms of CYP2C9, VKORC1, CYP4F2 and EPHX1. A regression analysis was used to determine the independent effects of genetic and non-genetic factors on warfarin dose optimization. In our study, in addition to age, genetic variants of CYP2C9, VKORC1 and CYP4F2 were found to be significant predictor variables for the maintenance dose for warfarin, explaining 39.3% of dose variability. VKORC1 and CYP2C9 genotypes remain predictor variables of the warfarin dose, and we first found that CYP4F2 (rs2108622) contributes to dose variability in the Turkish population as well. These observations may be of benefit to future translation research with a view to global personalized medicine in regions hitherto understudied such as the Turkish population so as to rationalize initial warfarin dose and reduce the burden of frequent INR measurements.

Clinical relevance of bioequivalence acceptance criteria. The example of terbinafine.

OBJECTIVE: The present study was conducted with the aim of investigating which acceptance criteria for bioequivalence are relevant for orally applied antimycotics using terbinafine (CAS 78628-80-5) as an example. METHODS: A bioequivalence trial was performed in 18 healthy male volunteers with the aim of comparing a new generic product (tablets containing terbinafine hydrochloride, equivalent to 250 mg base) with the originator product. The trial was performed according to an open, cross-over design in one study centre. In each of the two study periods (separated by a wash-out of 14 days) a single dose of one 250 mg tablet (test or reference) was administered. Blood samples were taken up to 72 h post dose, the plasma was separated and the concentrations of terbinafine were determined by a liquid chromatography-mass spectrometry (LC-MS-MS) method with a quantification limit of 14 ng/ml. AUC0-infinity, AUC0-tlast, Cmax and tmax were calculated for both formulations and compared according to the currently valid CPMP Note for Guidance for the evaluation of Bioavailability and Bioequivalence. RESULTS: The parametric 90% confidence intervals for the primary target parameters were between 0.89 and 1.09 AUC0-tlast and between 0.71 and 0.95 for Cmax. The acceptance ranges prospectively defined in the protocol for this trial were fulfilled. In the light of the currently valid CPMP Note for Guidance, the question still arose whether the overall positive bioequivalence statement was clinically feasible. Taking into account the mechanism of action and the available efficacy and safety data on terbinafine, this question was answered positively. CONCLUSION: In the case of oral antimycotic agents and especially terbinafine, the bioequivalence acceptance range for Cmax can be expanded to 0.7-1.43, if the acceptance criteria for AUC are fulfilled.