title: Clinical assessment of potential drug interactions of faldaprevir, a hepatitis C virus protease inhibitor, with darunavir/ritonavir, efavirenz, and tenofovir.
abstract: BACKGROUND
  Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients.
  
  
  METHODS
  In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated.
  
  
  RESULTS
  Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined.
  
  
  CONCLUSIONS
  No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut.
authors.forename: John P
authors.initials: JP
authors.lastname: Sabo
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut.
authors.forename: Jens
authors.initials: J
authors.lastname: Kort
authors.affiliation: Buffalo Clinical Research Center, New York.
authors.forename: Charles
authors.initials: C
authors.lastname: Ballow
authors.affiliation: University Hospital Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.affiliation: University Hospital Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.affiliation: PAREXEL International GmbH, Berlin, Germany.
authors.forename: Rainard
authors.initials: R
authors.lastname: Fuhr
authors.affiliation: Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland.
authors.forename: Birgit
authors.initials: B
authors.lastname: Girlich
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut.
authors.forename: Michael
authors.initials: M
authors.lastname: Schobelock
authors.affiliation: Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Feifel
authors.affiliation: Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lang
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Boehringer Ingelheim Ltd, Burlington, Ontario, Canada.
authors.forename: Mabrouk
authors.initials: M
authors.lastname: Elgadi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000480:Alkynes; D000621:Aminoisobutyric Acids; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use; D060085:Coinfection; D003521:Cyclopropanes; D000069454:Darunavir; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D000068698:Tenofovir; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000480:Alkynes; D000621:Aminoisobutyric Acids; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009842:Oligopeptides; D063065:Organophosphonates; D011480:Protease Inhibitors; D011804:Quinolines; D013449:Sulfonamides; D013844:Thiazoles; C552340:faldaprevir; D000068698:Tenofovir; D011392:Proline; D007930:Leucine; D000225:Adenine; C098320:efavirenz; D019438:Ritonavir; D000069454:Darunavir
keywords: HCV; HIV; antiretrovirals; drug–drug interactions; faldaprevir