Prediction of the exposure to a 400-mg daily dose of efavirenz in pregnancy: is this dose adequate in extensive metabolisers of CYP2B6?

Abstract

Purpose: A daily dose of 400 mg of efavirenz (EFV) was recently shown to be 'not therapeutically inferior' to a 600-mg daily dose, while providing the added advantage of reduced toxicity risk and cost saving on chronic therapy. However, to our knowledge, the 400-mg dose has not been tested in pregnant women, although significant increases in clearance (CL/F) of EFV have been reported, particularly in CYP2B6 extensive metabolisers (EM).

Methods: This study used PBPK modelling to predict the exposure to a 400-mg dose in pregnant women, in CYP2B6 extensive metabolisers (EM), intermediate metabolisers (IM) and poor metabolisers (PM). The PBPK model was verified using available clinical pharmacokinetic data for a 600-mg dose of EFV in pregnancy and applied to the prediction of the pharmacokinetics of a 400-mg daily dose in pregnancy.

Results: Results predicted about a 2-fold increase in drug CL/F in the third trimester of pregnancy (T3) when compared with CL prior to pregnancy, which was as expected from clinical observations with the 600-mg dose. _.Consequently, about 57% of EM may have sub-therapeutic concentrations of EFV in T3.

Conclusion: The recommended reduction in efavirenz dose from 600 to 400 mg may not provide therapeutic drug levels in EM patients during their T3 of pregnancy, which could lead to therapeutic failure. Clinical trials to evaluate the effectiveness of a 400-mg dose of EFV in T3, especially in EM patients, are needed.

Keywords: CYP2B6; Efavirenz; PBPK simulation; Pharmacokinetics; Phenotypes; Pregnancy.