Ryuji Kubota (1), Sayaka Matsumoto (1), Toshihiro Wajima (1)
(1) Clinical Pharmacology & Pharmacokinetics, Shionogi & Co., Ltd., Osaka, Japan
Objectives: To develop a population pharmacokinetic (PPK) model to assess influential factors on ospemifene pharmacokinetics; and to assess the potential risk of adverse event for the cases which may cause exposure increase.
Methods: A PPK model was constructed using pooled ospemifene concentrations. The followings were tested as covariates: age, race, body weight, BMI, albumin, ALT, bilirubin, and creatinine clearance. The expected changes in distributions of ospemifene exposures were assessed for the cases of administration to renal impairment subjects, administration to hepatic impairment subjects, co-administration with ketoconazole, or co-administration with fluconazole based on the Bayesian-estimated individual pharmacokinetic parameters. Safety information in a long-term safety trial was used to assess the potential changes in risks of adverse event regarding ospemifene exposure increase.
Results: A total of 7503 ospemifene serum concentrations from 1260 subjects were available for the PPK analysis. The PPK parameters estimates were 9.16 L/hr for CL/F, 34.3 L for V2/F, 16.4 L/hr for Q/F, 250 L for V3/F, and 0.522 hr-1 for ka based on the final model. The observed distribution in the long term safety study largely covered the expected distributions for administration to renal impairment subjects, administration to hepatic impairment subjects, and co-administration with ketoconazole, while insufficient exposure experience for co-administration with fluconazole. The incidence of adverse event was not associated with ospemifene exposure in the long-term safety study.
Conclusions: We have developed ospemifene PPK model. No relevant covariate was identified in the PPK analysis. The analyses support no dose adjustment for patients with renal impairment, patients with hepatic impairment or co-administration with CYP3A4 inhibitors, while caution should be executed for concomitant inhibition for CYP3A4 and CYP2C9.
Reference: PAGE 23 () Abstr 3074 [www.page-meeting.org/?abstract=3074]
Poster: Drug/Disease modeling - Other topics