Pharmacokinetics of fexofenadine: Evaluation of a microdose and assessment of absolute oral bioavailability

A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP). Fexofenadine was administered to 6 healthy male volunteers in a three way cross-over design. A microdose (100 μg) of 14C-drug was administered orally (period 1) and intravenously by 30 min infusion (period 2). In period 3 an intravenous tracer dose (100 μg) of 14C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120 mg). Plasma was collected from all 3 periods and analysed for both total 14C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine was collected and analysed for total 14C. Good concordance between the microdose and therapeutic dose pharmacokinetics was observed. Microdose: CL 13 L/h, CLR 4.1 L/h, Vss 54 L, t1/2 16 h; therapeutic dose: CL 16 L/h, CLR 6.2 L/h, Vss 64 L, t1/2 12 h. The absolute oral bioavailability of fexofenadine was 0.35 (microdose 0.41, therapeutic dose 0.30). Despite a 1200-fold difference in dose of fexofenadine, the microdose predicted well the pharmacokinetic parameters following a therapeutic dose for this transporter dependent compound.