Why Did The Fda Approve Efavirenz 800 Mg When Co-Administered With Rifampin?

Objectives: 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. Design/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 RIP reduced mean EFV exposure by similar to 30%. Population PK model provided acceptable predictive performance of central tendency and variability for EFV C-0, C-max and AUC. Simulations predicted that increasing EFV to 800 mg QD with RIP would result in EFV AUC and C-max similar to EFV 600 mg QD alone. EFV AUC and Cmax were similar to 2 times higher in subjects with reduced function CYP2B6 genotypes. However, the RIP 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. Conclusion: 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.