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

Abstract

Background: Reducing 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.

Methods: We 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.

Results: Using 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.

Conclusions: It was predicted that reduced-dose efavirenz provides adequate exposure during pregnancy. These findings warrant prospective confirmation.

Fig. 1

Final structural model. Efavirenz is absorbed through three transit compartments into the liver compartment, based on four identical first-order rate constants. For the first pass through the liver, a fraction of the efavirenz amount is extracted and cleared, and the fraction of the amount remaining reaches the systemic circulation and becomes available for redistribution into the peripheral compartment. Efavirenz recirculates from the central compartment to the liver with a flow equivalent to liver plasma flow, and at each pass the liver extracts a further fraction. k_tr first-order rate constant, E_h fraction of efavirenz extracted, Q_h liver plasma flow, N number of transit compartments, CL_h hepatic clearance, Q intercompartmental clearance, V_h, V_c and V_p volume of ditribution of the liver, central and peripheral compartments, respectively

Fig. 2

Standard goodness-of-fit plots for the final model. a Observed concentration versus individual-predicted concentration around the line of unity. b Observed concentration versus population-predicted concentration around the line of unity. c CWRES versus population-predicted concentrations. d Conditional weighted residual versus time after dose. The dotted lines represent the 95% limits of the assumed CWRES distribution (i.e. 0 ± 1.96). CWRES conditional weighted residual

Fig. 3

pcVPC of the final model for efavirenz 600 mg stratified for pregnancy. The observations are indicated by the open circles. The median (continuous line) and 5th and 95th percentiles (dashed line) of the observations are shown, as well as the 95% confidence interval around the median (pink-shaded areas) and 5th and 95th percentiles (purple-shaded areas) of the simulated data. pcVPC prediction corrected visual predictive checks

Fig. 4

Simulated a total and b free concentrations following administration of efavirenz 400 mg once daily during the third trimester of pregnancy and for non-pregnant women, stratified by metabolizer status. The horizontal dotted lines represent the total and free efavirenz plasma target concentrations of a 0.7 mg/L and b 0.002 mg/L, respectively. EFV efavirenz, QD once daily. C₁₂ mid-dose concentration