Evaluation of universal versus genotype-guided efavirenz dose reduction in pregnant women using population pharmacokinetic modelling

Objectives: Lack of data on the pharmacokinetics of efavirenz in pregnant women at the 400mg reduced dose currently prevents universal roll-out. Population pharmacokinetic modelling was used to explore pharmacokinetic endpoints at 200, 400 and 600mg daily doses in pregnant women stratified by CYP2B6 metabolic status. Methods: The analysis was based on 252 plasma efavirenz concentrations from 77 pregnant women (77 sparse, 175 intensive) who received antiretroviral regimens containing 600mg of efavirenz. The model was developed using NONMEM (R). The effect of genetics was investigated and concentration-time courses at steady-state were simulated for individuals (n = 1000 each) classified as CYP2B6 slow, intermediate and fast metabolizers at 200, 400 and 600mg daily doses. Results: At a 400mg reduced dose, predicted mean (90% CI) mid-dose efavirenz concentration (C-12) was 2.24 mu g/mL (0.89-4.18) in pregnant women classified as slow metabolizers, compared with 0.87 mu g/mL (0.34-1.64) in intermediate metabolizers and 0.78 mu g/mL (0.30-1.47) in fast metabolizers. C-12 was below the 0.47 mu g/mL threshold determined within the ENCORE 1 trial in 10% at 400 mg, 4.6% at 600mg and 3.4% with genotype-guided dosing. The 4.0 mu g/mL toxicity threshold was exceeded in 4.6% at 400 mg, 13.5% at 600mg and 5.2% with genotype-guided dosing. Conclusions: These data provide context for the ongoing debate about reduction in efavirenz dose to 400mg during pregnancy and should be interpreted alongside the lower toxicity expected with the lower dose. Additional research is required to investigate genotype-guided dose reduction in pregnant women.