Pregnancy-Related Effects on Lamivudine Pharmacokinetics in a Population Study with 228 Women

Université Paris Descartes, Paris, France.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 11/2011; 56(2):776-82. DOI: 10.1128/AAC.00370-11
Source: PubMed


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.

Download full-text


Available from: Jean-Marc Tréluyer,
  • [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.
    Therapeutic drug monitoring 07/2012; 34(5):507-11. DOI:10.1097/FTD.0b013e318261c372 · 2.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antiretroviral therapy suppresses replication of HIV allowing restoration and/or preservation of the immune system. Providing combination antiretroviral therapy during pregnancy can treat maternal HIV infection and/or reduce perinatal HIV transmission. However, providing treatment to pregnant women is challenging due to physiological changes that can alter antiretroviral pharmacokinetics. Suboptimal drug exposure can result in HIV RNA rebound, the selection of resistant virus or an increased risk of HIV-1 transmission to the infant. Increased drug exposure can produce unwarranted maternal adverse effects and/or fetal toxicity. Subsequently, dose adjustments may be necessary during pregnancy to achieve comparable antiretroviral exposure to non-pregnant adults. For several antiretrovirals, systemic exposure is decreased during the last trimester of pregnancy. By 6-12 weeks postpartum, concentrations return to those prior to pregnancy. Also, the extent of antiretroviral placental transfer to the fetus and degree of antiretroviral excretion into breast milk varies within, and between, antiretroviral drug classes. It is necessary to consider the pharmacological characteristics of each antiretroviral when optimizing combination therapy during pregnancy to treat maternal HIV infection and prevent perinatal HIV transmission.
    Clinical Pharmacokinetics 10/2012; 51(10):639-59. DOI:10.1007/s40262-012-0002-0 · 5.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mother-to-child-transmission rates of HIV in the absence of any intervention range between 20 and 45%. However, the provision of antiretroviral drugs (ARVs) during pregnancy, delivery and breastfeeding can reduce HIV transmission to less than 2%. Physiological changes during pregnancy can influence ARV disposition. Associations between SNPs in genes coding for metabolizing enzymes, and/or transporters, and ARVs disposition are well described; however, relatively little is known about the influence of these SNPs on ARV pharmacokinetics during pregnancy and lactation as well as their effect on distribution into the fetal compartment and breast milk excretion. Differences in maternal, fetal and infant ARV exposure due to SNPs may affect the efficacy and safety of ARVs used to prevent mother-to-child-transmission. The aim of this review is to provide an update on the effect of pregnancy-induced changes on the pharmacokinetics of ARVs and highlight the potential role of pharmacogenetics.
    Pharmacogenomics 10/2012; 13(13):1501-22. DOI:10.2217/pgs.12.138 · 3.22 Impact Factor
Show more