title: Population pharmacokinetics of ospemifene and safety evaluation of pharmacokinetic alterations caused by intrinsic and extrinsic factors .
abstract: OBJECTIVE
  To develop a population pharmacokinetic (PPK) model to assess factors influencing ospemifene pharmacokinetics and to assess safety for pharmacokinetic alteration observed in drug development.
  
  
  METHODS
  A PPK model was constructed using pooled ospemifene concentrations. Covariates considered before start of the analysis were: age, race, body weight, BMI, albumin, alanine amino-transferase, bilirubin, and creatinine clearance. The expected distribution of ospemifene concentration was derived for the 4 cases in phase-1 studies that increased ospemifene exposure: administration to severe renal impairment subjects (case 1), administration to moderate hepatic impairment subjects (case 2), coadministration with ketoconazole (case 3), or coadministration with fluconazole (case 4). Safety information in a long-term safety trial was used to assess the potential changes in risk of adverse events with ospemifene-exposure increase.
  
  
  RESULTS
  The PPK parameter estimates were 9.16 L/h for CL/F, 34.3 L for V2/F, 16.4 L/h for Q/F, 250 L for V3/F, and 0.522 h-1for ka, based on the final model. Distributions of estimated AUC in a phase-3 study largely covered the expected distribution for case 1, case 2, or case 3, but did not overlap the expected distribution for case 4. The incidences of adverse events were not associated with ospemifene exposure in the long-term safety study.
  
  
  CONCLUSIONS
  We developed an ospemifene PPK model and identified no relevant covariate in the PPK analysis. The drug appears safe to use in renal impairment, moderate hepatic impairment, and when coadministered with ketoconazole. Ospemifene should not be administered with fluconazole. .
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kubota
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wajima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000009:adverse effects; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000009:adverse effects; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D019338:Polypharmacy; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D015725:Fluconazole; C119141:Ospemifene