title: A clinical drug-drug interaction study to evaluate the effect of a proton-pump inhibitor, a combined P-glycoprotein/cytochrome 450 enzyme (CYP)3A4 inhibitor, and a CYP2C9 inhibitor on the pharmacokinetics of vismodegib.
abstract: OBJECTIVE
  The Hedgehog pathway inhibitor vismodegib exhibits pH-dependent solubility, and in vitro studies have shown that vismodegib is a substrate of P-glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The objective of this four-arm parallel study in healthy subjects was to evaluate the effect of the proton-pump inhibitor rabeprazole, the P-gp/CYP3A4 inhibitor itraconazole, and the CYP2C9 and 3A4 inhibitor fluconazole on vismodegib steady-state pharmacokinetics.
  
  
  METHODS
  Cohorts included a control arm (n = 22), in which vismodegib 150 mg was administered once daily (QD) for 7 days, and 3 arms in which vismodegib was co-administered QD for 7 days with rabeprazole 20 mg (including a 4-day lead-in; n = 24); itraconazole 200 mg (n = 22); or fluconazole 400 mg (n = 22).
  
  
  RESULTS
  Area under the vismodegib concentration-time curve from zero to 24 h (AUC0-24h) at steady state was lower with concomitant rabeprazole administration relative to vismodegib alone [geometric mean ratio (GMR), 86.2 (associated 90 % confidence interval [CI], 76.1, 97.7)]. There was no effect of itraconazole on steady-state exposure of vismodegib [GMR, 96.4 (90 % CI 84.9, 109.6)]. Co-administration with fluconazole increased vismodegib steady-state AUC0-24h [GMR, 130.9 (90 % CI 115.2, 148.7)]. Co-administration of rabeprazole, itraconazole, and fluconazole had similar effects on the exposure of unbound vismodegib and total vismodegib.
  
  
  CONCLUSIONS
  The results of this study suggest that vismodegib can be administered with acid-reducing agents and P-gp and CYP inhibitors without the risk of a clinically meaningful pharmacokinetic drug-drug interaction. CLINICALTRIALS.
  NCT01772290.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. vmalhi@gmail.com.
authors.forename: Vikram
authors.initials: V
authors.lastname: Malhi
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Colburn
authors.affiliation: F. Hoffmann-La Roche, Ltd., Welwyn Garden City, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Williams
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.|Denali Therapeutics, South San Francisco, CA, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Chandra
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.|Theravance Biopharma, South San Francisco, CA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D064750:Rabeprazole / Q000008:administration & dosage / Q000494:pharmacology*; D012995:Solubility
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000813:Anilides; D065688:Cytochrome P-450 CYP2C9 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; C538724:HhAntag691; D054328:Proton Pump Inhibitors; D011725:Pyridines; D017964:Itraconazole; D064750:Rabeprazole; D015725:Fluconazole
keywords: CYP inhibitors; Clinical drug–drug interaction; Clinical pharmacology; P-glycoprotein inhibitor; Pharmacokinetic; Proton-pump inhibitor