Pharmacokinetics, Placental and Breastmilk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV.



Hodel, Eva Maria ORCID: 0000-0001-5821-1685, Marzolini, Catia, Waitt, Catriona ORCID: 0000-0003-0134-5855 and Rakhmanina, Natella
(2019) Pharmacokinetics, Placental and Breastmilk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV. Current Pharmaceutical Design, 25 (5). pp. 556-576.

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Abstract

<h4>Background</h4>Remarkable progress has been achieved in the identification of HIV infection in pregnant women and in the prevention of vertical HIV transmission through maternal antiretroviral treatment (ART) and neonatal antiretroviral drug (ARV) prophylaxis in the last two decades. Millions of women globally are receiving combination ART throughout pregnancy and breastfeeding, periods associated with significant biological and physiological changes affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of ARVs. The objective of this review was to summarize currently available knowledge on the PK of ARVs during pregnancy and transport of maternal ARVs through the placenta and into the breast milk. We also summarized main safety considerations for in utero and breast milk ARVs exposures in infants.<h4>Methods</h4>We conducted a review of the pharmacological profiles of ARVs in pregnancy and during breastfeeding obtained from published clinical studies. Selected maternal PK studies used a relatively rich sampling approach at each ante- and postnatal sampling time point. For placental and breast milk transport of ARVs, we selected the studies that provided ratios of maternal to the cord (M:C) plasma and breast milk to maternal plasma (M:P) concentrations, respectively.<h4>Results</h4>We provide an overview of the physiological changes during pregnancy and their effect on the PK parameters of ARVs by drug class in pregnancy, which were gathered from 45 published studies. The PK changes during pregnancy affect the dosing of several protease inhibitors during pregnancy and limit the use of several ARVs, including three single tablet regimens with integrase inhibitors or protease inhibitors co-formulated with cobicistat due to suboptimal exposures. We further analysed the currently available data on the mechanism of the transport of ARVs from maternal plasma across the placenta and into the breast milk and summarized the effect of pregnancy on placental and of breastfeeding on mammal gland drug transporters, as well as physicochemical properties, C:M and M:P ratios of individual ARVs by drug class. Finally, we discussed the major safety issues of fetal and infant exposure to maternal ARVs.<h4>Conclusions</h4>Available pharmacological data provide evidence that physiological changes during pregnancy affect maternal, and consequently, fetal ARV exposure. Limited available data suggest that the expression of drug transporters may vary throughout pregnancy and breastfeeding thereby possibly impacting the amount of ARV crossing the placenta and secreted into the breast milk. The drug transporter's role in the fetal/child exposure to maternal ARVs needs to be better understood. Our analysis underscores the need for more pharmacological studies with innovative study design, sparse PK sampling, improved study data reporting and PK modelling in pregnant and breastfeeding women living with HIV to optimize their treatment choices and maternal and child health outcomes.

Item Type: Article
Additional Information: Based on reviewers’ comments the published version of the paper has the following changes from the pre-print submitted version: * Section 4.2: We made significant changes to this part of the paper, removed extensive details, shortened it and focused more on links between exposure of the infants (plasma concentrations at and after birth) and possible safety aspects, but did not change the overall focus of this part. We are not aware of any concentration related toxicity in infants related to breatsmilk and in utero concentrations of ARVs and stated so. * Introduction: We added “In fact, most ARVs are used off-label during pregnancy, and although the WHO, USA and European guidelines identify certain ARVs are preferred during pregnancy, the product label of these drugs does not include information supporting this rating, making their use off-label.” * We added the following sentence to the abstract: “We also summarized main safety considerations for in utero and breastmilk ARVs exposures in infants”. This reflects what we actually did as we really do not focus much on infant exposure from the point of view of PK. * We changed “By 2015, this pattern…” to “By 2015, this pattern was reversed with 92.8% of pregnant women on ART receiving full treatment regimen ART and 6.9% other “effective regimens” for prevention of vertical transmission only [12, 13]”. * The paragraph describing the ARVs used in pregnancy was reworded to better focus on only preferred regimens. We removed the part regarding the use of alternative ARVs during conception and up to eight weeks for other ARVs as it was left there in error. The rewritten paragraph focuses only on preferred regimens. * Methods: We added statement that data from the referenced workshops were used. * Section 3.1. Now mentions also “Conversely, the activity of CYP1A2 and CYP2C19 is inhibited thus resulting in higher exposure of drugs metabolized by these enzymes.” In line with Table 1. * More details on the lack of boosting effect of COBI on TAF. * We have added a statement to indicate that the half-life of intracellular phosphorylated NRTIs is generally longer than that of the parent drug in the plasma. Hence, changes in plasma NRTIs exposure might not be appropriate surrogate markers for virologic suppression. * Reference Stein Schalkwijk et al. CPK 2017, supporting the use of 400mg EFV in pregnancy, has been added. * Results on testing DRV/r increased dose in pregnancy (800/100 DRV/r BID), see poster CROI 2016 by Best et al., have been added. * We have moved the final sentence of paragraph 3.1.3 to the beginning of the paragraph. * We have added “and have a higher C:M ratio” to “Low molecular weight drugs, and drugs that are lipophilic, predominantly unionized or unbound, such as most NRTIs, INSTIs or NVP are likely to cross passively the placental barrier” to indicate that antiretroviral drugs crossing passively the placental barrier will consequently have a good placental transfer.For TDF related toxicity we used papers from 2007, 2016 and 2018. We have modified our TDF related text and added seven new references to support them. * Paragraph 4.3.: Added “prevention of infection of the infant” and clarified what the effect of induction/inhibition of efflux and uptake transporters means * Table 1: “Increased free drug concentration” has been amended to “Increased free drug fraction” * We have added a justification for the lack of estimates of spread around our ratios and the reason to the methods section, i.e. “Measures of spread around the ratios could not be calculated due to the heterogeneity between the studies, the varied measures reported across studies, the lack of spreads reported within each study, and the limited sample sizes (typically less than 30, hence making it impossible to test the Normality assumption according to the Central Limit Theorem).” * Tables 2 and 3 now also cover (i) Schalkwijk et al AIDS 2016 (Abacavir), (ii) increased DRV dose: Best et al. CROI 2016, and (iii) DRV/cobi Crauwels et al Pediatric Workshop 2017
Uncontrolled Keywords: HIV, women, antiretroviral drugs, pharmacology, pregnancy, placental transfer, breastfeeding
Depositing User: Symplectic Admin
Date Deposited: 29 Apr 2019 14:24
Last Modified: 07 Feb 2024 21:30
DOI: 10.2174/1381612825666190320162507
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3038892

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