Pharmacokinetic and toxicological considerations affecting antiretroviral drug dosing in pregnant women

ABSTRACT

Introduction

To prevent mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV) during pregnancy, the appropriate dosing regimens of antiretroviral (ARV) drugs need to be determined. Reliable data about pharmacokinetic (PK) characteristics of ARVs from randomized clinical trials (RCTs) are lacking, and post-marketing observational studies may offer valuable, but sometimes insufficient data, especially in pregnant people living with HIV (PLWHIV). This review article is focused PK and toxicological considerations affecting ARV dosing in pregnant PLWHIV.

Areas covered

In our search, we included studies focused on PKs of ARVs in pregnancy available on PubMed, abstracts from recent global conferences and data from modeling studies. There are no significant changes in PKs of nucleoside/nucleotide reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors throughout pregnancy. In contrast, the PKs of PIs and INSTIs are more variable, especially in the second and third trimesters.

Expert opinion

Pregnant women are left out of RCTs. To the greatest extent possible, future research should include pregnant persons in RCTs, including PK studies, strictly considering maternal and fetal safety. Alternative innovative approaches/models need to be developed to obtain reliable data about rational pharmacotherapy of ARVs in the effective PMTCT of HIV, with maximum safety.

KEYWORDS:

• Antiretroviral drugs
• HIV
• pharmacokinetics
• pregnancy
• toxicology

Article highlights

• Treatment recommendations for antiretroviral drug usage in pregnant persons living with HIV are based on new and updated international guidelines in 2021–2024.

• There is a great impact of combined antiretroviral therapy (cART) in pregnant HIV-infected persons during the periconceptional period, pregnancy, and labor for prevention of mother-to-child transmission (PMTCT).

• Randomized clinical trials (RCTs) data in pregnant HIV-infected women are still lacking, which could be overcome by physiologically based pharmacokinetic modeling (PBPK) and extended use of pharmacogenetic and pharmacogenomic tests.

• The primary stain of cART during pregnancy is dual nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) backbone together with either integrase strand transfer inhibitors (INSTIs) or HIV protease inhibitors (PI/r).

• The drug of choice within cART during pregnancy depends not just on the HIV-RNA plasma viral load (pVL) and PK properties of each single drug, but also on drug availability, especially in low- and middle-income countries.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

All authors state that the submitted article is their work. All authors substantially contributed to the conception and design of the review article and interpreting the relevant literature and have been involved in writing the review article or revised it for intellectual content.

Additional information

Funding

This paper was not funded.