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Pharmacokinetic Drug Interactions of Afatinib with Rifampicin and Ritonavir

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Abstract

Background and Objective

Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of advanced non-small cell lung cancer, metastatic head and neck cancer, and other solid tumours. As afatinib is a substrate for the P-glycoprotein (P-gp) pump transporter the three studies presented here investigated the pharmacokinetics of afatinib in the presence of a potent inhibitor (ritonavir) or inducer [rifampicin (rifampin)] of P-gp.

Methods

We conducted phase I, open-label, single-centre studies in healthy male volunteers who received a single once-daily oral dose of afatinib (20 or 40 mg) together with either ritonavir or rifampicin; two studies had a randomised, two- and three-way crossover design and the third was a non-randomised, two-period sequential study.

Results

When afatinib 20 mg was administered 1 h after ritonavir, afatinib geometric mean (gMean) maximum plasma concentration (C max) and area under the plasma concentration–time curve from time zero to infinity (AUC∞) increased by 38.5 and 47.6 %, respectively. Coadministration of ritonavir either simultaneously or 6 h later than afatinib 40 mg resulted in minimal increase in the afatinib gMean C max and AUC∞ (4.1 and 18.6 % for simultaneous administration with AUC∞ not completely within the bioequivalence limits; 5.1 and 10.8 % for timed administration within the bioequivalence limits). Administration of afatinib 40 mg in the presence of rifampicin led to reduction in C max and AUC∞ by 21.6 and 33.8 %, respectively. In all studies, P-gp modulation mainly affected the extent of absorption of afatinib; there was no change in the terminal elimination half-life. The overall safety profile of afatinib was acceptable.

Conclusion

Coadministration of potent P-gp modulators had no clinically relevant effect on afatinib exposure. Effects of potent P-gp inhibitors were minimal at higher afatinib doses and can be readily managed by the timing of concomitant therapy. As afatinib is not a relevant modulator or substrate of cytochrome P450 enzymes, the drug–drug interaction potential is considered to be low.

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Acknowledgments

These studies were sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. The studies were conducted at the Human Pharmacology Centre, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany (principal investigator, Mario Iovino). Boehringer Ingelheim was responsible for the design and conduct of all of the studies, and the collection and management of the data. The authors were responsible for the analysis and interpretation of the data and the preparation of the manuscript. All authors are employees of Boehringer Ingelheim and were fully responsible for all content and editorial decisions, and were involved at all stages of the manuscript development.

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Authors and Affiliations

  1. Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany

    Sven Wind, Thomas Giessmann, Arvid Jungnik, Tobias Brand, Kristell Marzin, Julia Bertulis & Peter Stopfer

  2. Biostatistics Europe, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany

    Julia Hocke

  3. Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany

    Dietmar Gansser

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  1. Sven Wind
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Correspondence to Sven Wind.

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Wind, S., Giessmann, T., Jungnik, A. et al. Pharmacokinetic Drug Interactions of Afatinib with Rifampicin and Ritonavir. Clin Drug Investig 34, 173–182 (2014). https://doi.org/10.1007/s40261-013-0161-2

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