Pharmacokinetics of fexofenadine: Evaluation of a microdose and assessment of absolute oral bioavailability
Introduction
Obtaining early information about the human pharmacokinetics (PK) of novel drugs is important for development success. Microdosing has been proposed as a means of obtaining early human PK information and is particularly useful where several drug candidates are available with conflicting animal and in vitro model PK data. In microdosing studies subpharmacologic doses (≤100 μg) of drug candidate are administered to human volunteers in order to obtain early PK data as an aid to decision making in drug candidate selection (Lappin and Garner, 2003). Regulatory guidelines for microdose studies require minimal preclinical safety evaluation, thus enabling data to be obtained earlier than Phase-I clinical trials, albeit at a low dose (ICH M3 Guidelines). There has been considerable debate about the utility of microdosing, mostly focused around the ability to predict PK at pharmacologically active doses (Bertino et al., 2007, Rowland, 2007). There is nevertheless, a growing body of evidence, but not yet conclusive, to support the value of microdosing (Lappin and Garner, 2008).
Among the questions that remain to be answered is: will an orally administered microdose reasonably predict PK at therapeutic doses for drugs that typify situations for which currently data are lacking, including those that are absorbed or eliminated predominantly by transporters (Beaumont and Smith, 2009). The study reported here partly addresses this question by comparing the PK of fexofenadine, following a microdose and a therapeutic dose in healthy male volunteers.
Fexofenadine, a H1-receptor antagonist used as an oral tablet in the treatment of allergic rhinitis and chronic idiopathic urticaria, undergoes minimal metabolism (Chen, 2007) and is frequently used as a probe substrate for the efflux transporter P-glycoprotein (P-gp). It is also a substrate for various uptake transporters, including human hepatic OATP1B3 (Shimizu et al., 2005). In the current study, fexofenadine was administered orally to human volunteers at doses of 100 μg or 120 mg in order to compare its PK obtained from a microdose to those from a therapeutic dose. In addition, to fully characterize fexofenadine, its disposition kinetics following intravenous (IV) administration was assessed, as its clearance, volume of distribution and absolute oral bioavailability are currently unknown.
In order to ensure adequate assay sensitivity for the microdose, fexofenadine was administered as the 14C-labelled drug and the ultra-sensitive method of accelerator mass spectrometry (AMS) was used to determine the plasma drug concentrations over time. The analytical sensitivity of AMS meant that only very low levels (7.4 kBq, 200 nCi) of radioactivity were administered to each subject, below those requiring regulatory approval for the administration of radioactivity to human subjects. In addition, inclusion of the 14C-isotopic label enabled the metabolism of fexofenadine following a microdose to be compared with that following a 120 mg dose.
Section snippets
Test substance and reagents
14C-Fexofenadine (2-[4-[1-hydroxy-4-[4-(hydroxy-[14C]-diphenyl-methyl)-1 piperidyl]butyl]phenyl]-2-methyl-propanoic acid) generously gifted by Sanofi-Aventis, Germany, was purified at Quotient BioResearch Ltd, UK. The specific activity was 3.46 MBq/mg and was supplied as a clear solution in ethanol with a certified radiochemical purity of 98.9% (radio-HPLC). Fexofenadine HCl (non-radiolabelled, used as a chromatographic standard) was obtained from Sigma–Aldrich Chemical Company, Dorset, UK with
Results
All subjects completed the study and treatments were well tolerated. On the basis of 14C content measured by AMS in samples of plasma taken just prior to each dose administration there was no evidence of carry-over from one dose period to the next. The limit of quantification (LOQ) for the AMS assay was 3 pg fexofenadime/mL plasma. Samples taken at 48 h were <LOQ.
Fig. 1 shows semilogarithmic plots of parent drug and total 14C concentrations over time following oral (Fig. 1A) and IV (Fig. 1B)
Discussion
Fexofenadine is a probe P-gp and OATP substrate and is neither an inducer nor inhibitor of transporter activity at therapeutic doses. Its limited absorption is at least partially controlled by P-gp and it is minimally metabolized based on urine and faecal recovery following oral administration of radiolabelled compound (Chen, 2007). Fexofenadine was chosen for study principally to explore whether a microdose of an essentially transport dependent substrate would predict the PK of a therapeutic
Conclusions
PK after an oral microdose of fexofenadine predicted well the PK observed at a 120 mg therapeutic dose (1200-fold dose range). This is the first published report of an IV dose of fexofenadine being given to human subjects, which allowed not only characterisation of the disposition kinetics of fexofenadine, but also its absolute oral bioavailability.
Acknowledgements
The work described in this paper was funded by the European Community as part of the Framework 6 Programme, grant number LSHG-CT-2005-018672 under the European Microdosing AMS Partnership Programme (EUMAPP – www.EUMAPP.com). The EUMAPP Steering Committee consisted of: R Colin Garner (Chairman), June Garner and Graham Lappin, Xceleron Ltd (UK); Roeline Jochemsen and Richard Weaver, Institut de Recherches Internationales Servier (France); Grzegorz Grynkiewicz, Pharmaceutical Research Institute
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