TY - JOUR
T1 - Pharmacokinetics of fexofenadine
T2 - evaluation of a microdose and assessment of absolute oral bioavailability
AU - Lappin, Graham
AU - Shishikura, Yoko
AU - Jochemsen, Roeline
AU - Weaver, Richard John
AU - Gesson, Charlotte
AU - Houston, Brian
AU - Oosterhuis, Berend
AU - Bjerrum, Ole Jannik
AU - Rowland, Malcolm
AU - Garner, Colin
PY - 2010/5
Y1 - 2010/5
N2 - 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 (100μg) of 14C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100μg) of 14C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120mg). 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 13L/h, CLR 4.1L/h, Vss 54L, t1/2 16h; therapeutic dose: CL 16L/h, CLR 6.2L/h, Vss 64L, t1/2 12h. 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.
AB - 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 (100μg) of 14C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100μg) of 14C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120mg). 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 13L/h, CLR 4.1L/h, Vss 54L, t1/2 16h; therapeutic dose: CL 16L/h, CLR 6.2L/h, Vss 64L, t1/2 12h. 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.
U2 - 10.1016/j.ejps.2010.03.009
DO - 10.1016/j.ejps.2010.03.009
M3 - Journal article
C2 - 20307657
SN - 0928-0987
VL - 40
SP - 125
EP - 131
JO - Norvegica Pharmaceutica Acta
JF - Norvegica Pharmaceutica Acta
IS - 2
ER -
