Population pharmacokinetics of ospemifene and safety evaluation of pharmacokinetic alterations caused by intrinsic and extrinsic factorsâ©.
Int J Clin Pharmacol Ther
; 55(4): 339-347, 2017 Apr.
Article
de En
| MEDLINE
| ID: mdl-28128722
ABSTRACT
PURPOSE:
To develop a population pharmacokinetic (PPK) model to assess factors influencing ospemifene pharmacokinetics and to assess safety for pharmacokinetic alteration observed in drug development.METHOD:
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-1 for 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.â©.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tamoxifène
/
Modulateurs sélectifs des récepteurs des oestrogènes
/
Modèles biologiques
Type d'étude:
Prognostic_studies
Limites:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Middle aged
Langue:
En
Journal:
Int J Clin Pharmacol Ther
Sujet du journal:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Année:
2017
Type de document:
Article