Zusammenfassung Masterarbeit Jan-Frederik Schlender       

Physiologically-based Pharmacokinetic (PBPK) approach to evaluate Transporter-mediated Drug-Drug Interactions of Antihistaminic Drug Fexofenadine

In this thesis the impact of transporter-mediated DDI was evaluated by using a PBPK simulation approach. Regulatory agencies paid rising attention on transporters in the approval as well as in post-marketing procedures.

Therefore, fexofenadine was established to the SimCyp® simulator. As this project did not contain any in vitro or in vivo studies, literature data were collected regarding the demands of the SimCyp® simulation tools. The sustained amount of datasets was sparse. However, due to several in vivo studies an adequate plasma-concentration time profile was maintained for fexofenadine.

The sustained compound was investigated with five inhibitors, namely erythromycin, ritonavir, verapamil, ketoconazol, and cyclosporin. Inhibition values were obtained from literary in vitro studies or computed by the SimCyp® parameter estimation tool. Test runs with the inhibition values were conducted and showed a successful prediction within the 2-fold range.

DDI studies were conducted in healthy volunteers, obese and morbidly obese, North European Caucasian and in patients suffering from cirrhosis. The studies were performed with cross-over design. Single and multiple dose effects as well as wash-out effects were evaluated. The simulations resulted in 34% moderate (2-to 5-fold increase of AUC), 23% strong (AUC ratio >5-fold) and 43% weak (AUC ratio <2) DDIs.

The transporters` influence on the disposition of drugs was pointed out in this study. Nevertheless, the wide substrate specificity by various transporters and their extensive tissue presence cannot be predicted unambiguously. Due to our current understanding of transporters and despite the progress made for CYP-based DDI prediction, the in vitro techniques and the PBPK modeling based on those results are still in its infancy.

Most likely the FDA new draft guidance will adopt the ITC recommendations. Nevertheless, as each of the assays has its benefits and pitfalls, an appropriate design and interpretation of in vitro studies will be most challenging in case of transporter DDIs. In addition there must be an increased focus on tissue- instead of plasma-concentrations during DDI studies due to the ubiquitary abundance of transporters and their diverse performance. Therefore, the results obtained by these models must be interpreted with much care and caution.


As there is only a labelling due to P-gp mediated interactions for fexofenadine up to now, this study emphasized the need of further investigation for prospective OATP labeling. While no specific inhibitor and no standardized methods for OATP are available, recommendations will stay drug- and therapeutic-class specific. Additionally, there are needs to include renal transporters in a PBPK-model to evaluate the influence on fexofenadine’s pharmacokinetics. Depending on those study results, dosage adjustments could be necessary.

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