title: Effect of rifampin on the pharmacokinetics, safety and tolerability of navitoclax (ABT-263), a dual inhibitor of Bcl-2 and Bcl-XL , in patients with cancer.
abstract: OBJECTIVE
  Navitoclax, a first-in-class small molecule Bcl-2 family inhibitor, is metabolized in vitro by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4. 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 CYP3A4 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.
  
  
  CONCLUSIONS
  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 (Cmax ) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: R S
authors.initials: RS
authors.lastname: Pradhan
authors.forename: L S
authors.initials: LS
authors.lastname: Rosen
authors.forename: A M
authors.initials: AM
authors.lastname: Graham
authors.forename: K D
authors.initials: KD
authors.lastname: Holen
authors.forename: H
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D012293:Rifampin / Q000494:pharmacology*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin; C528561:navitoclax
keywords: Bcl-2 inhibitor; CYP3A inducer; drug interaction; navitoclax; pharmacokinetics; rifampin