Pregnancy-related effects on lamivudine pharmacokinetics in a population study with 228 women

Abstract

The aim of this study was to describe lamivudine (3TC) pharmacokinetics (PK) in HIV-infected nonpregnant and pregnant women and their fetuses. Samples were collected according to therapeutic drug monitoring from 228 women treated with lamivudine and retrospectively analyzed by a population approach. The samples were also collected from cord blood and amniotic fluid at birth. Lamivudine pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. Mean population parameter estimates (intersubject variability) for women were an absorption rate constant of 1.04 h(-1), an elimination clearance rate of 23.6 (0.266) liters · h(-1), a central volume of distribution of 109 (0.897) liters, an intercompartmental clearance rate of 6.7 liters/h, and a peripheral volume of distribution of 129 liters. A fetal compartment was linked to maternal circulation by mother-to-cord (or fetus) and cord-to-mother rate constants of 0.463 h(-1) and 0.538 h(-1), respectively. The amniotic fluid compartment was connected to the fetal compartment with an elimination rate constant of 0.163 h(-1) and a fixed-constant swallowing flow. The placental transfer expressed as fetal-to-maternal area under the concentration-time curve (AUC) ratio was 0.86, and the lamivudine amniotic fluid accumulation, expressed as the amniotic fluid-to-fetal AUC ratio, was 2.9. Pregnant women had a 22% higher apparent clearance than nonpregnant and parturient women; however, this increase did not lead to subexposure and should not require a dosage adjustment.

Fig 1

Population pharmacokinetic model for the simultaneous prediction of lamivudine concentrations in the mother, cord, and amniotic fluid. A two-compartment model with first-order absorption and elimination best described maternal data. For concentrations in cord blood, an effect compartment is linked to the maternal plasma compartment by a first-order process. Amniotic fluid concentrations were linked to the fetal compartment via the fetal swallowing flow and fetal elimination rate constant. k_a denotes the absorption rate constant, CL denotes the maternal elimination clearance from the central compartment, V_c denotes the volume of the central maternal compartment, Q denotes the maternal intercompartmental clearance, V_p denotes the volume of the peripheral maternal compartment, k_MF denotes maternal-to-fetal rate constant, k_FM denotes the fetal-to-maternal rate constant, and k_eF denotes the fetal elimination rate constant.

Fig 2

Individual women's lamivudine clearances (liter/h) as a function of gestational age (weeks).

Fig 3

(Left) Observed and model-predicted lamivudine concentrations versus time in nonpregnant women (open circles and thin line) and pregnant women (filled circles and thick line). (Middle) Observed (open circles) and predicted (line) concentrations in cord blood. (Right) Observed (open circles) and predicted (line) concentrations in amniotic fluid. Asterisks indicate concentrations lower than the LOQ.

Fig 4

Evaluation of the final model by comparison between the 5th (dash line), 50th (solid line), and 95th (dashed line) percentiles obtained from 1,000 simulations and the observed data (open circles) for lamivudine concentrations in women (left) and cord blood (right). Asterisks indicate concentrations lower than the LOQ.