Pharmacokinetics of lopinavir/ritonavir and efavirenz in food insecure HIV-infected pregnant and breastfeeding women in Tororo, Uganda

Abstract

Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK), adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo, Uganda. In 2011, 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women, 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure, 26% lost weight ante-partum, and median BMI post-partum was only 20.2 kg/m(2) . Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall, drug exposure was reduced (LPV -33%, EFV -15%, ritonavir -17%) compared to well-nourished controls (P < 0.001), attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% (P < 0.001), whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure (P < 0.001), explaining 29% PK-variability. In conclusion, pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women, compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority.

Keywords: clinical research (CRE); infectious diseases (INF); pharmacodynamics (PDY); pharmacokinetics and drug metabolism; pharmacology (PHA).

Conflict of interest statement

Conflict of Interest

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: Dr. Havlir had support from National Institutes of Health, non-financial support from Abbott in the previous 3 years. Dr. Charlebois had support from National Institutes of Health – NICHD in the previous 3 years. Dr. Gandhi had support from National Institutes of Health in the previous 3 years. Dr. Aweeka had support from National Institutes of Health in the previous 3 years. The other authors report no support from any organisation for the submitted work

© 2013, The American College of Clinical Pharmacology.

Figures

Figure 1

VPC-based Simulations of LPV (a), RTV (b) and EFV (c) in ante and post partum, breastfeeding women. Black dots represent the concentrations (dried blood spot adjusted to represent plasma concentrations). The solid lines indicate the median of the observed data, the dark gray shaded area is the simulated median with uncertainty and the dotted lines are 90th percentiles of simulated data.

Figure 2

Association of apparent bioavailability (F1) and hair concentrations. Individual predictions of F1 of EFV (black dots), LVP (dark grey dots) and RTV (light grey dots) are shown. The association between F1 and hair concentrations was described using a linear function (straight black line). For comparison, the models without a measure of adherence are presented as a dotted lines (F1= 0.60, 0.67 and 0.85 for EFV, LPV and RTV respectively). EFV efavirenz, LPV lopinavir, RTV ritonavir

Figure 3

Predicted plasma concentration-time profiles for well nourished and malnourished pregnant and post pregnant women. Predicted plasma concentration-time profiles for EFV (a) and LPV (b) of well nourished women are (gray lines), and malnourished women (black lines). For LPV, plasma concentration-time profiles are shown for post-partum women (straight lines), after 35% dose increase during pregnancy (dotted lines). The dashed black lines show what would happen without dose adjustment in malnourished women during pregnancy.