Effect of Pregnancy on Unbound Raltegravir Concentrations in the ANRS 160 RalFe Trial

Abstract

A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration (C_trough) decreased significantly in the evening (28%); however, the median total C_trough in the morning, unbound C_trough in the morning, and unbound C_trough in the evening showed a nonsignificant decrease of 16%, 1%, and 15%, respectively, during pregnancy compared to the postpartum period. This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound C_trough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered clinically relevant. (This study has been registered at ClinicalTrials.gov under identifier NCT02099474.).

Keywords: HIV; population pharmacokinetics; pregnant women; raltegravir; unbound concentrations.

FIG 1

Population pharmacokinetic model of unbound, total, and glucuronide RAL concentrations. In this model, C_U-RAL, C_T-RAL, and C_RAL-G represent the unbound, total, and glucuronide-RAL concentration in plasma. The parameters estimated were the transit/absorption constant rate (K_TR), apparent elimination clearance of unbound RAL (CL_U/F), apparent volume of distribution of unbound RAL (V_U/F), transfer from unbound RAL to RAL-GLU (CL_met/V_met), elimination rate constant of RAL-GLU (K_e-met), N_HSA, number of drug binding sites in each molecule of HAS (C_BOUND = N_HSA·C_U·[HSA]), and the number of RAL binding sites in HSA. [HSA] is the concentration of HSA in plasma.

FIG 2

Observed raltegravir unbound concentration, total concentration and glucuronide concentration (from left to right) and population median predictions (dashed curve for the nonpregnant women and solid curve for the pregnant women) for each fraction obtained from the pharmacokinetic model proposed. The points and the full curve represent the concentration obtained during pregnancy, and the crosses and dashed curve represent the concentration obtained during postpartum. The horizontal lines correspond to 35 and 22 ng/ml for total raltegravir and 6 and 3.7 for unbound raltegravir.

FIG 3

Visual predictive check (VPC) plots for evaluation of the pharmacokinetic model of raltegravir unbound fraction (left), total fraction (center), and glucuronide fraction (right). The lines show the 5th, 50th, and 95th percentiles of observed data. The areas represent the 90% confidence interval around the simulated percentiles. Blue-filled circles stand for observed concentrations of RAL for each fraction.