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 (100microg) of (14)C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100microg) of (14)C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C 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 (14)C. 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.

[1]  Malcolm Rowland,et al.  Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs , 2006, Clinical pharmacology and therapeutics.

[2]  W. Heizer,et al.  Influence of Gastrointestinal Site of Drug Delivery on the Absorption Characteristics of Ranitidine , 1992, Pharmaceutical Research.

[3]  L. K. Golightly,et al.  Second-Generation Antihistamines Actions and Efficacy in the Management of Allergic Disorders , 2012 .

[4]  Malcolm Rowland,et al.  Commentary on ACCP Position Statement on the Use of Microdosing in the Drug Development Process , 2007, Journal of clinical pharmacology.

[5]  B. Haehner‐Daniels,et al.  The effect of rifampin administration on the disposition of fexofenadine , 2001, Clinical pharmacology and therapeutics.

[6]  Dennis A Smith,et al.  Does human pharmacokinetic prediction add significant value to compound selection in drug discovery research? , 2009, Current opinion in drug discovery & development.

[7]  T. Kume,et al.  Effect of Oral Ketoconazole on Intestinal First-Pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys , 2007, Drug Metabolism and Disposition.

[8]  G R Wilkinson,et al.  OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[9]  H. Kusuhara,et al.  P-GLYCOPROTEIN PLAYS A MAJOR ROLE IN THE EFFLUX OF FEXOFENADINE IN THE SMALL INTESTINE AND BLOOD-BRAIN BARRIER, BUT ONLY A LIMITED ROLE IN ITS BILIARY EXCRETION , 2005, Drug Metabolism and Disposition.

[10]  H. Lennernäs,et al.  Transport Characteristics of Fexofenadine in the Caco-2 Cell Model , 2004, Pharmaceutical Research.

[11]  D. J. Pack,et al.  Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16 455) and its enantiomers in healthy male volunteers , 1998, Biopharmaceutics & drug disposition.

[12]  H. Greenberg,et al.  American College of Clinical Pharmacology Position Statement on the Use of Microdosing in the Drug Development Process , 2007, Journal of clinical pharmacology.

[13]  Kazuya Maeda,et al.  CONTRIBUTION OF OATP (ORGANIC ANION-TRANSPORTING POLYPEPTIDE) FAMILY TRANSPORTERS TO THE HEPATIC UPTAKE OF FEXOFENADINE IN HUMANS , 2005, Drug Metabolism and Disposition.

[14]  Gary M Pollack,et al.  Fexofenadine Brain Exposure and the Influence of Blood-Brain Barrier P-Glycoprotein After Fexofenadine and Terfenadine Administration , 2009, Drug Metabolism and Disposition.

[15]  L. Greos,et al.  Second-generation antihistamines: actions and efficacy in the management of allergic disorders. , 2005, Drugs.

[16]  M. Rowland,et al.  The use of isotopes in the determination of absolute bioavailability of drugs in humans , 2006, Expert opinion on drug metabolism & toxicology.

[17]  S. Davis,et al.  Alimentary tract andpancreas Transit ofpharmaceutical dosage forms through the , 1986 .

[18]  Chen Chen.  Some Pharmacokinetic Aspects of the Lipophilic Terfenadine and Zwitterionic Fexofenadine in Humans , 2007, Drugs in R&D.

[19]  Mikiko Shimizu,et al.  Lack of Dose-Dependent Effects of Itraconazole on the Pharmacokinetic Interaction with Fexofenadine , 2006, Drug Metabolism and Disposition.

[20]  Martin Cousineau,et al.  Altered oral bioavailability and pharmacokinetics of P-glycoprotein substrates by coadministration of biochanin A. , 2006, Journal of pharmaceutical sciences.

[21]  R. Colin Garner,et al.  Big physics, small doses: the use of AMS and PET in human microdosing of development drugs , 2003, Nature Reviews Drug Discovery.

[22]  R. C. Garner,et al.  The utility of microdosing over the past 5 years. , 2008, Expert opinion on drug metabolism & toxicology.

[23]  R. Colin Garner,et al.  The utility of microdosing over the past 5 years , 2008, Expert opinion on drug metabolism & toxicology.

[24]  J. Tillement.  The advantages for an H1 antihistamine of a low volume of distribution , 2000, Allergy.

[25]  M. Simpson,et al.  High-performance liquid chromatography accelerator mass spectrometry: correcting for losses during analysis by internal standardization. , 2008, Analytical biochemistry.

[26]  Yuichi Sugiyama,et al.  A Species Difference in the Transport Activities of H2 Receptor Antagonists by Rat and Human Renal Organic Anion and Cation Transporters , 2005, Journal of Pharmacology and Experimental Therapeutics.

[27]  R. C. Garner,et al.  A pharmacokinetic evaluation of five H(1) antagonists after an oral and intravenous microdose to human subjects. , 2009, British journal of clinical pharmacology.

[28]  K. Maeda,et al.  Involvement of Multiple Efflux Transporters in Hepatic Disposition of Fexofenadine , 2008, Molecular Pharmacology.

[29]  Yuichi Sugiyama,et al.  Microdose clinical trial: quantitative determination of fexofenadine in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.