title: Why did the FDA approve efavirenz 800 mg when co-administered with rifampin?
abstract: OBJECTIVE
  Literature reports regarding the efficacy of efavirenz (EFV) 600 mg with rifampin (RIF) are not consistent. Evaluation of a drug-drug interaction (DDI) study and supportive semi-mechanistic population pharmacokinetic (PK) analyses were undertaken to help delineate this issue.
  
  
  METHODS
  DDI study and supportive semi-mechanistic population PK analyses were provided by BMS. Population PK analysis was based on six studies with intensive EFV PK sampling. An ACTG study with sparse PK sampling was used for model evaluation. Simulations compared EFV exposure at various doses in combination with RIF to EFV exposures at 600 mg once daily (QD). Effects of CYP2B6 genotypes on the magnitude of EFV-RIF interaction were also explored.
  
  
  RESULTS
  In DDI study, co-administering EFV 600 mg QD and RIF reduced mean EFV exposure by ~ 30%. Population PK model provided acceptable predictive performance of central tendency and variability for EFV C0, Cmax, and AUC. Simulations predicted that increasing EFV to 800 mg QD with RIF would result in EFV AUC and Cmax similar to EFV 600 mg QD alone. EFV AUC and Cmax were ~ 2 times higher in subjects with reduced function CYP2B6 genotypes. However, the RIF effect was consistent across all genotypes. EFV dose adjustment to 800 mg QD did not increase the risk of overexposure compared to 600 mg EFV QD within each genotype.
  
  
  CONCLUSIONS
  Dose adjustment based on matching systemic exposure was recommended to mitigate the potential for sub-therapeutic EFV exposures. Our review did not reveal any safety concerns in subjects receiving EFV 800 mg QD with RIF.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Chan-Tack
authors.forename: Pravin
authors.initials: P
authors.lastname: Jadhav
authors.forename: Shirley
authors.initials: S
authors.lastname: Seo
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Robertson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kraft
authors.forename: Mary E
authors.initials: ME
authors.lastname: Singer
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Struble
authors.forename: Vikram
authors.initials: V
authors.lastname: Arya
mesh_terms: D000480:Alkynes; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000009:adverse effects; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D048588:Benzoxazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D060085:Coinfection; D003198:Computer Simulation; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D004334:Drug Administration Schedule; D017277:Drug Approval; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D005838:Genotype; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010641:Phenotype; D019338:Polypharmacy; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000480:Alkynes; D000904:Antibiotics, Antitubercular; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz; D012293:Rifampin