title: Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers.
abstract: OBJECTIVE
  To evaluate the effect of a potent cytochrome P450 3A4 (CYP3A4) inhibitor, ketoconazole, and separately the effect of food on PF-04449913 pharmacokinetics in healthy volunteers.
  
  
  METHODS
  This was an open-label, two-sequence, three-period, three-treatment, single-dose, crossover study. Subjects were randomized to receive single doses of 200 mg PF-04449913 after an overnight fast or after consuming a high-fat meal during Period 1 or 2, with a washout period of at least 8 days. In Period 3, all subjects received ketoconazole (400 mg/day) (days 1-7) and a co-administered single 200-mg PF-04449913 dose (day 4).
  
  
  RESULTS
  Geometric mean ratio of PF-04449913 in the presence of ketoconazole versus PF-04449913 alone was 2.40 [90% confidence interval (CI) 2.15, 2.68] for area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) and 1.40 (90% CI 1.24, 1.58) for peak plasma concentration (C max). The geometric mean ratio for fed state compared with fasted state for AUC(0-inf) was 0.87 (90% CI 0.78, 0.97) and for C max was 0.66 (90% CI 0.56, 0.78). PF-04449913 was well tolerated, and all adverse events were mild to moderate.
  
  
  CONCLUSIONS
  PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for expected PF-04449913 exposures after co-administration of a strong CYP3A4 inhibitor in patients with cancer who routinely receive antifungal azoles. While a high-fat meal decreased PF-04449913 exposure, the differences in plasma exposure under the two conditions were not considered clinically meaningful.
authors.affiliation: Pfizer Inc, 10555 Science Center Dr, San Diego, CA, 92121, USA, Naveed.Shaik@Pfizer.com.
authors.forename: M Naveed
authors.initials: MN
authors.lastname: Shaik
authors.forename: Robert R
authors.initials: RR
authors.lastname: LaBadie
authors.forename: Dan
authors.initials: D
authors.lastname: Rudin
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Levin
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001682:Biological Availability; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004032:Diet; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072086:Smoothened Receptor; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D001562:Benzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C000592580:glasdegib; D007654:Ketoconazole