Investigating the determinants of efavirenz pharmacokinetics after long term treatment with and without rifampicin among Tanzanian HIV/TB and HIV patients

Background: The extent of pharmacokinetic interaction between rifampicin and efavirenz is still uncertain. Aim : We investigated the determinants of efavirenz pharmacokinetics after long term antiretroviral therapy (ART) with and without rifampicin co-treatment. Patients and methods: We recruited patients on efavirenz based ART alone (arm1, n=20) and patients on efavirenz/rifampicin based HIV/Tuberculosis co-treatment (arm2, n=34). Intensive blood sampling (at around 0, 1, 3, 6, 12, 16 and 24 hours after taking efavirenz) was performed 16 weeks after initiation of ART and repeated in arm2 patients (n=31) 8 weeks after completion of Tuberculosis treatment. Data were analyzed by nonlinear mixed effects modelling. Treatment arms, sampling occasions, demography, clinical, laboratory and single nucleotide polymorphisms data were tested as potential covariates for the model parameters. Results: The patients had median age and weight of 42 years (IQR, 36-50) and 48 Kilograms (IQR, 43-60) respectively. The proportion of CYP2B6*1/*1 and CYP2B6*6/*6 genotypes were 38.2% and 23% respectively. Efavirenz pharmacokinetics was described by 1 compartment model. The estimated population values for absorption rate constant (Ka) and apparent volume of distribution (V/F) were 1.5h -1 (95%CI, 0.9-2.1) and 696L/70Kg (95%CI, 551-841) respectively. CYP2B6 genetic polymorphism was the only determinant of efavirenz oral clearance (CL/F) being highest in patients with CYP2B6*1/*1 genotype (22.8 L/h/70kg; 95%CI, 16.4-29.2) and 58% (95%CI, 41-75) lower in patients with CYP2B6*6/*6 genotypes. Regardless of genotype, the ratio of efavirenz clearance, arm1 to arm2, during and after co-treatment were 1.2 (95%CI, 0.80 -1.60) and 1.1(95%CI, 0.76-1.46) respectively. Conclusion: Our results support the hypothesis that after long term efavirenz treatment the magnitude of its auto induction of metabolism and cellular transport is comparable to that due efavirenz/rifampicin co-treatment. The CYP2B6 genetic polymorphism but not rifampicin co-treatment should be taken into account when adjusting for efavirenz dosage during both ART and HIV/TB co treatment.