Population Pharmacokinetics of Abacavir in Pregnant Women

Abstract

e For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy.A bacavir (ABC) is a potent nucleoside reverse transcriptase inhibitor administered to treat human immunodeficiency virus (HIV) infection and prevent its transmission. Currently, regimens containing ABC are still recommended as one of the first-line options for adults, including pregnant women (1). ABC pharmacokinetics in adults has been investigated previously (2-9), but only two limited studies (with small numbers of patients, no once-daily administration, and narrow ranges of age and gestational age) were focused on pregnant women (10, 11). During pregnancy, some physiological changes can affect the pharmacokinetics of a drug. Therefore, it is important to characterize these changes in a large population in order to use the drug safely and efficiently during pregnancy. Thus, plasma ABC concentrations in nonpregnant and pregnant women were analyzed using a population approach for the first time. The population pharmacokinetics parameters in HIV-infected nonpregnant and pregnant women were estimated, and the final model was used to determine if the current recommended doses produce efficient drug exposure in pregnancy.The HIV-infected pregnant (n ϭ 36) and nonpregnant (n ϭ 114) women had a median age of 35.7 years (range, 15 to 67 years) and a median body weight of 62.5 kg (range, 40 to 102 kg). The median gestational age at pharmacokinetics evaluation was 31 weeks (range, 9 to 41 weeks). A total of 266 samples were obtained from HIV-infected women. Among these samples, 16 were collected in pairs (maternal and cord blood samples). Women received orally an ABC-containing regimen: 300 mg twice daily (47.9%) or 600 mg once daily (52.1%). Blood samples for therapeutic-drug monitoring (TDM) were collected during a visit in the pharmacology unit of Hospital Cochin (Paris, France); therefore, the times elapsed between drug administration and sampling were variable. The pregnant women were enrolled at clinical sites of the ANRS-C01-French Perinatal Cohort (EPF). The mother of the child to be born provided signed informed consent. For the nonpregnant women, ethics committee approval and patient consent are not compulsory in France to use TDM data retrospectively. Plasma ABC concentrations were determined by high-performance liquid chromatography, as previously described (12). The limit of quantification (LOQ) was 0.02 mg/liter. The mean interassay precision for the lowest concentration of the quality controls was 10%. The data were analyzed using Nonmem software (version 6.2), and the first-order conditional estimation with interaction (FOCEI) method was applied (13). The 23 concentrations (8.6%) below the LOQ (BLQ) were replaced by the LOQ/2 ...

Pregnancy‐induced changes in the pharmacokinetics of caffeine and its metabolites

“…Typically 1‐2 samples per dosing interval are collected from each patient for PK analysis. Fauchet et al used a population PK approach to describe abacavir PK in HIV‐infected pregnant women (n = 36) with 1‐2 samples collected per patient . Zheng et al reported tacrolimus maternal blood concentrations using 1 sample per patient, which was collected at the time of delivery .…”

“…Fauchet et al used a population PK approach to describe abacavir PK in HIV-infected pregnant women (n ¼ 36) with 1-2 samples collected per patient. 17 Zheng et al reported tacrolimus maternal blood concentrations using 1 sample per patient, which was collected at the time of delivery. 18 Our study also adopted a sparse sampling strategy that allowed us to coordinate the study visit with regularly scheduled prenatal visits.…”

Equilibrative Nucleoside Transporter 1 (ENT1, SLC29A1) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta

“…Because the mRNA seems to correlate with ENT1 function, as evidenced in pharmacoresistance studies (Giovannetti et al, 2006;Marcé et al, 2006;Tsujie et al, 2007;Eto et al, 2013), we hypothesize that the observed placental mRNA variability might be reflected in protein/function level. Therefore, it may represent a potential reason for differences in reported cord-to-maternal blood concentration ratios (Chappuy et al, 2004;Best et al, 2006;Fauchet et al, 2014).…”

“…nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf). Transplacental transfer of abacavir in humans has been investigated only sparsely, and its cord-to-maternal-blood concentration ratio is variable, ranging from 62% to 163% at term (Chappuy et al, 2004;Best et al, 2006;Fauchet et al, 2014). The pharmacokinetics of antiviral drugs are frequently affected by the activity of drug transporters (Kis et al, 2010;Neumanova et al, 2014Neumanova et al, , 2015Neumanova et al, , 2016Ceckova et al, 2016).…”

Antiretroviral Pharmacokinetics in Pregnant Women

“…Among these women, 88% had a third‐trimester abacavir exposure similar to that reported in nonpregnant patients. A subsequent population pharmacokinetic analysis of abacavir, which included 266 samples from 36 pregnant and 114 nonpregnant women, also estimated that abacavir pharmacokinetics were unchanged during pregnancy and were not influenced by any studied covariate (age, body weight, pregnancy, and gestational age) . Based on these findings, no dosage adjustment of abacavir is recommended during pregnancy…”