A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400 mg in Pregnant Women

Abstract

BackgroundReducing the dose of efavirenz can improve safety, reduce costs, and increase access for patients with HIV infection. According to the World Health Organization, a similar dosing strategy for all patient populations is desirable for universal roll-out; however, it remains unknown whether the 400 mg daily dose is adequate during pregnancy.MethodsWe developed a mechanistic population pharmacokinetic model using pooled data from women included in seven studies (1968 samples, 774 collected during pregnancy). Total and free efavirenz exposure (AUC24 and C12) were predicted for 400 (reduced) and 600 mg (standard) doses in both pregnant and non-pregnant women.ResultsUsing a 400 mg dose, the median efavirenz total AUC24 and C12 during the third trimester of pregnancy were 91 and 87% of values among non-pregnant women, respectively. Furthermore, the median free efavirenz C12 and AUC24 were predicted to increase during pregnancy by 11 and 15%, respectively.ConclusionsIt was predicted that reduced-dose efavirenz provides adequate exposure during pregnancy. These findings warrant prospective confirmation.Electronic supplementary materialThe online version of this article (10.1007/s40262-018-0642-9) contains supplementary material, which is available to authorized users.

The association between cigarette smoking and efavirenz plasma concentration using the population pharmacokinetic approach

“…However, efavirenz is still widely used as the preferred first‐line antiretroviral agent in the middle‐ and low‐ income countries, including Malaysia 18 . Efavirenz dose of 400 mg daily was reported to reduce efavirenz toxicities, 12 and was noninferior to the usual 600‐mg daily dose in adult HIV‐positive patients 19–22 . Nevertheless, none of the previous studies evaluated the drug response of efavirenz dose reduction among HIV‐positive smokers.…”

Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy

“…Kreitchmann reported that C24 (24 h post-dose) concentrations during the second and third trimester were similar to the C24 concentrations seen in the ENCORE1 study with a 400 mg dose [23,27]. However, the increased variability due to CYP2B6's polymorphism could lead to the subtherapeutic, systemic exposure in extensive metabolisers, as predicted by PBPK studies [29,30].…”

HIV Clinical Updates: New Single-Tablet Regimens

“…31 Emerging data using the lower dose in pregnancy also suggest that adequate exposure is maintained along with reduced toxicities expected. 32,33 Research regarding the use of EFV 400 mg in patients with concomitant tuberculosis is still warranted.…”