Premium
Effect of rifampin on the pharmacokinetics, safety and tolerability of navitoclax ( ABT ‐263), a dual inhibitor of Bcl‐2 and Bcl‐X L , in patients with cancer
Author(s) -
Yang J.,
Pradhan R. S.,
Rosen L. S.,
Graham A. M.,
Holen K. D.,
Xiong H.
Publication year - 2014
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12193
Subject(s) - pharmacokinetics , pharmacology , dosing , cmax , tolerability , medicine , chemistry , adverse effect
Summary What is known and objective Navitoclax, a first‐in‐class small molecule Bcl‐2 family inhibitor, is metabolized in vitro by the hepatic microsomal cytochrome P450 ( CYP ) enzymes CYP 3A4. Drugs that affect CYP3A4 may therefore have an impact on the pharmacological profile of navitoclax. This study evaluated the effects of co‐administration of a potent CYP 3A4 inducer rifampin on the pharmacokinetic and safety profiles of navitoclax. Methods This open‐label, fixed‐sequence, 2‐period study was performed in twelve subjects with non‐haematologic or haematologic malignancy that was relapsed or refractory to standard therapy. A 7‐day washout period separated the two treatment periods. On Study Day 1 and Day 8, subjects received a single 250 mg oral dose of navitoclax. Rifampin 600 mg was administrated once daily ( QD ) on Study Day 4 through Day 10. Blood samples for navitoclax assay were collected prior to dosing (0 h) and at a series of time points through 72 h after dosing on Study Day 1 and Day 8. Results and discussion Co‐administration of a single 250 mg dose of navitoclax with 600 mg QD doses of rifampin had a negligible effect on the maximum plasma concentration (C max ) of navitoclax [ratio of geometric least square means: 0·84 (90% CI : 0·61–1·16)] but moderately decreased the area under the plasma concentration–time curve ( AUC ) of navitoclax [ratio of geometric least square means: 0·59 (90% CI : 0·44–0·80)]. Rifampin did not affect the half‐life of navitoclax. Co‐administration of rifampin did not appear to significantly change the safety profile of navitoclax in the limited number of patients evaluated in this study. What is new and conclusion Co‐administration navitoclax with rifampin moderately decreased navitoclax AUC , which could be partly due to the induction effect of rifampin on CYP3A4. Further assessment on the mechanism of drug interaction is warranted.