Maternal-Fetal Transfer and Amniotic Fluid Accumulation of Nucleoside Analogue Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pregnant Women

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 ...

supporting

confidence: 71%

“…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.…”

mentioning

confidence: 99%

Population Pharmacokinetics of Abacavir in Pregnant Women

Fauchet

Tréluyer

Préta

et al. 2014

“…The concordance between the results obtained with the ex vivo placental perfusion model and the cord-to-maternal plasma (C:M) ratios has already been shown for various antiretroviral agents of the nucleoside reverse transcriptase inhibitor and protease inhibitor classes. Indeed, the results obtained with the perfused cotyledon model and suggesting a relatively high and low placental transfer for nucleotide reverse transcriptase inhibitors and protease inhibitors, respectively, are in accordance with those obtained in vivo using matched maternal and umbilical cord blood samples collected at the time of delivery (21,25,27,(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). Nevertheless, despite the in vivo/ex vivo concordance reported in the literature, our results should be confirmed in vivo with calculation of ratios in paired maternal and cord blood samples.…”

Section: Discussionsupporting

confidence: 35%

Placental Transfer of Maraviroc in an Ex Vivo Human Cotyledon Perfusion Model and Influence of ABC Transporter Expression

Vinot

Gavard

Tréluyer

et al. 2013

f Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfused ex vivo for 90 min with maraviroc (600 ng/ ml) either in the maternal-to-fetal (n ‫؍‬ 10 placentas) or fetal-to-maternal (n ‫؍‬ 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ؎ 3.0 and 0.26 ؎ 0.07, respectively, whereas the mean CLI was 0.52 ؎ 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and ABCC2, ABCC10, and ABCC11 placental gene expression levels (P < 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by in vivo data obtained from paired maternal and cord blood samples.

“…A degree of assurance can be gained from the low rates of virologic failure and vertical HIV transmission among pregnant women stable on LPV/r-based regimens, with many achieving full viral suppression at the time of delivery and in certain cases being able to deliver vaginally. It is also likely that a substantial prophylactic benefit to the fetus occurs through coadministered nucleoside analogues, which are known to achieve high concentrations in the placenta (8) and female genital tract (11). In the current study (with ϳ63% treatment-naive patients), despite a reduction in LPV exposure during the third trimester in both cohorts, LPV concentrations were adequate (Ͼ1,000 ng/ml) in the majority of women studied.…”

Section: Discussionmentioning

confidence: 80%

Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Else

Douglas

Dickinson

et al. 2012

Lopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC 0 -12 ) and maximum concentration were ϳ15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.A ntiretroviral therapies (ARTs), with the exception of zidovudine, are unlicensed for use in pregnancy. However, they are widely used, in accordance with national and international guidelines, both for maternal treatment and for the prevention of HIV mother-to-child transmission (MTCT). Multiple physiological changes which can impact the pharmacokinetics (PKs) of these agents occur during pregnancy; therefore, studies in pregnancy are required to ensure appropriate dosing and avoid unnecessary toxicity or treatment failure. Protease inhibitors (PIs) are widely used during pregnancy for both treatment and prevention of MTCT due to their efficacy, lack of CD4 count-dependent toxicity, and short half-lives (t 1/2 s). However, plasma concentrations of certain protease inhibitors have repeatedly been shown to be significantly reduced during the third trimester, with some concerns over efficacy (37).Lopinavir (LPV)-ritonavir (RTV), or LPV/r, is used during pregnancy,...