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

Graham Lappin; Yoko Shishikura; Roeline Jochemsen; Richard John Weaver; Charlotte Gesson; Brian Houston; Berend Oosterhuis; Ole Jannik Bjerrum; Malcolm Rowland; Colin Garner

doi:10.1016/j.ejps.2010.03.009

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

Graham Lappin, Yoko Shishikura, Roeline Jochemsen, Richard John Weaver, Charlotte Gesson, Brian Houston, Berend Oosterhuis, Ole Jannik Bjerrum, Malcolm Rowland, Colin Garner

86 Citations (Scopus)

Abstract

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, CL_R 4.1L/h, V_ss 54L, t_1/2 16h; therapeutic dose: CL 16L/h, CL_R 6.2L/h, V_ss 64L, t_1/2 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.

Original language	English
Journal	European Journal of Pharmaceutical Sciences
Volume	40
Issue number	2
Pages (from-to)	125-31
Number of pages	6
ISSN	0928-0987
DOIs	https://doi.org/10.1016/j.ejps.2010.03.009
Publication status	Published - May 2010

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title = "Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability",

abstract = "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.",

author = "Graham Lappin and Yoko Shishikura and Roeline Jochemsen and Weaver, {Richard John} and Charlotte Gesson and Brian Houston and Berend Oosterhuis and Bjerrum, {Ole Jannik} and Malcolm Rowland and Colin Garner",

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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

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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.

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ER -

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

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