title: Pharmacokinetic drug interactions of afatinib with rifampicin and ritonavir.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany, sven.wind@boehringer-ingelheim.com.
authors.forename: Sven
authors.initials: S
authors.lastname: Wind
authors.forename: Thomas
authors.initials: T
authors.lastname: Giessmann
authors.forename: Arvid
authors.initials: A
authors.lastname: Jungnik
authors.forename: Tobias
authors.initials: T
authors.lastname: Brand
authors.forename: Kristell
authors.initials: K
authors.lastname: Marzin
authors.forename: Julia
authors.initials: J
authors.lastname: Bertulis
authors.forename: Julia
authors.initials: J
authors.lastname: Hocke
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gansser
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
mesh_terms: D000293:Adolescent; D000328:Adult; D000077716:Afatinib; D018592:Cross-Over Studies; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D011799:Quinazolines; D000077716:Afatinib; D019438:Ritonavir; D012293:Rifampin