title: The effect of multiple doses of rifampin and ketoconazole  on the single-dose pharmacokinetics of ridaforolimus.
abstract: OBJECTIVE
  Ridaforolimus is an inhibitor of the mammalian target of rapamycin protein, with potent activity in vitro and in vivo. Ridaforolimus is primarily cleared by metabolism via cytochrome P450 3A (CYP3A) and is a P-glycoprotein (P-gp) substrate. Since potential exists for ridaforolimus to be co-administered with agents that affect CYP3A and P-gp activity, this healthy volunteer study was conducted to assess the effect of rifampin or ketoconazole on ridaforolimus pharmacokinetics.
  
  
  METHODS
  Part 1: single-dose ridaforolimus 40 mg followed by rifampin 600 mg daily for 21 days and singledose ridaforolimus 40 mg on day 14. Part 2: single-dose ridaforolimus 5 mg followed by ketoconazole 400 mg daily for 14 days and single-dose ridaforolimus 2 mg on day 2.
  
  
  RESULTS
  Part 1: the geometric mean ratios (GMRs) (90% confidence interval [CI]) for ridaforolimus area under the concentration-time curve to the last time point with a detectable blood concentration (AUC₀-∞) and maximum blood concentration (Cmax) (rifampin + ridaforolimus/ ridaforolimus) were 0.57 (0.41, 0.78) and 0.66 (0.49, 0.90), respectively. Both time to Cmax (Tmax) and apparent halflife (t₁/₂) were similar. Part 2: the GMRs (90% CI) based on dose-normalized AUC₀-∞ and Cmax (ketoconazole + ridaforolimus/ridaforolimus alone) were 8.51 (6.97, 10.39) and 5.35 (4.40, 6.52), respectively. Ridaforolimus apparent t₁/₂ was *1.5-fold increased for ketoconazole ? ridaforolimus; however, Tmax values were similar.
  
  
  CONCLUSIONS
  Rifampin and ketoconazole both have a clinically meaningful effect on the pharmacokinetics of ridaforolimus.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Stroh
authors.forename: John
authors.initials: J
authors.lastname: Palcza
authors.forename: Jacqueline
authors.initials: J
authors.lastname: McCrea
authors.forename: Sabrina
authors.initials: S
authors.lastname: Marsilio
authors.forename: Sheila
authors.initials: S
authors.lastname: Breidinger
authors.forename: Deborah
authors.initials: D
authors.lastname: Panebianco
authors.forename: Amy
authors.initials: A
authors.lastname: Johnson-Levonas
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
authors.forename: Keith
authors.initials: K
authors.lastname: Orford
authors.forename: Gail
authors.initials: G
authors.lastname: Murphy
authors.forename: Nancy
authors.initials: N
authors.lastname: Agrawal
authors.forename: Michele
authors.initials: M
authors.lastname: Trucksis
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C515074:ridaforolimus; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; D012293:Rifampin; D020123:Sirolimus