ESTIMATION OF ORAL BIOAVAILABILITY OF A LONG HALF-LIFE DRUG IN HEALTHY-SUBJECTS

Purpose. To estimate and compare the oral bioavailability of a drug (B MS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two- period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is propo sed to calculate the oral bioavailability of BMS-187745 which has a lo ng half-life; incomplete data points were available to characterize it s elimination phase. The plasma concentration-time data obtained follo wing IV infusion of parent drug, and after administration of either PO 1 or PO2 treatment were fitted simultaneously with systemic pharmacoki netic parameters shared by both the oral and IV routes of administrati on. Results. The best simultaneous fittings of the plasma concentratio n-time data were obtained by using a biexponential pharmacokinetic mod el with a first-order absorption rate constant. The mean bioavailabili ty (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasona ble, ranging from 38-40%. In contrast, F calculated by the model-indep endent AUC method exhibited high CV, ranging from 111-120%. Conclusion s, The oral bioavailability values estimated by the proposed model wer e more reasonable compared to those calculated by the model-independen t AUC method. The proposed approach may be useful for estimating bioav ailability of long half-life drugs when incomplete data points are ava ilable to characterize their elimination phase.