First pharmacokinetic data of bictegravir in pregnant women living with HIV

Bukkems, Vera E.; Hidalgo-Tenorio, Carmen; García, Coral; Hulzen, Astrid G W van; Richel, Olivier; Burger, David M.

doi:10.1097/qad.0000000000003032

Cited by 15 publications

(11 citation statements)

References 5 publications

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“…Clinical and pre-clinical studies showed high levels of transplacental transfer of INSTI drugs ( Schalkwijk et al, 2016 ; Mulligan et al, 2018 ; Mandelbrot et al, 2019 ; Waitt et al, 2019 ; Bollen et al, 2021 ; Bukkems et al, 2021 ). Studies of DTG have found high placental transfer of DTG from mother to fetus with median cord blood to maternal blood drug level ratios from 1.21 up to 1.29 ( Schalkwijk et al, 2016 ; Mulligan et al, 2018 ; Mandelbrot et al, 2019 ; Waitt et al, 2019 ; Bollen et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Further, DTG was also found to accumulate in the fetus with noted prolonged elimination of drug from infants after birth ( Mulligan et al, 2018 ; Waitt et al, 2019 ). Although few studies have addressed placental transfer of CAB and BIC, evidence does suggest that these INSTIs also cross the placental barrier ( Pencole et al, 2020 ; Bukkems et al, 2021 ; Le et al, 2022 ). Our previous work investigated pharmacokinetic (PK) and biodistribution (BD) of DTG during pregnancy in mice and confirmed that DTG levels are detectable in brain tissues of embryos following daily oral administration at supratherapeutic dosage ( Bade et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors

et al. 2023

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More than fifteen million women with the human immunodeficiency virus type-1 (HIV-1) infection are of childbearing age world-wide. Due to improved and affordable access to antiretroviral therapy (ART), the number of in utero antiretroviral drug (ARV)-exposed children has exceeded a million and continues to grow. While most recommended ART taken during pregnancy suppresses mother to child viral transmission, the knowledge of drug safety linked to fetal neurodevelopment remains an area of active investigation. For example, few studies have suggested that ARV use can be associated with neural tube defects (NTDs) and most notably with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). After risk benefit assessments, the World Health Organization (WHO) made recommendations for DTG usage as a first and second-line preferred treatment for infected populations including pregnant women and those of childbearing age. Nonetheless, long-term safety concerns remain for fetal health. This has led to a number of recent studies underscoring the need for biomarkers to elucidate potential mechanisms underlying long-term neurodevelopmental adverse events. With this goal in mind, we now report the inhibition of matrix metalloproteinases (MMPs) activities by INSTIs as an ARV class effect. Balanced MMPs activities play a crucial role in fetal neurodevelopment. Inhibition of MMPs activities by INSTIs during neurodevelopment could be a potential mechanism for adverse events. Thus, comprehensive molecular docking testing of the INSTIs, DTG, bictegravir (BIC), and cabotegravir (CAB), against twenty-three human MMPs showed broad-spectrum inhibition. With a metal chelating chemical property, each of the INSTI were shown to bind Zn++ at the MMP’s catalytic domain leading to MMP inhibition but to variable binding energies. These results were validated in myeloid cell culture experiments demonstrating MMP-2 and 9 inhibitions by DTG, BIC and CAB and even at higher degree than doxycycline (DOX). Altogether, these data provide a potential mechanism for how INSTIs could affect fetal neurodevelopment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors

et al. 2023

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Section: Discussionmentioning

confidence: 99%

“…In this case, no vertical transmission occurred, and the baby was born normally. 16 Another case report for pregnant women who continued BIC/TAF/FTC throughout the second trimester and were able to maintain viral suppression until delivery. 17 Rupture of the membranes near the end of a pregnancy can be caused by a variety of factors, including natural weakening of the membranes or contraction force, low socioeconomic conditions, previous preterm birth, and unexplained causes.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Bictegravir-Based Regimen in Pregnant Women Living with HIV: A Case Report

Alsulami

Alotaibi

Damfu

et al. 2022

J Int Assoc Provid AIDS Care

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Bictegravir (BIC) is included in international guidelines as the first line of therapy for patients living with Human Immunodeficiency Virus (HIV), either as initial therapy or as a replacement for patients with prior antiretroviral therapy (ART). Due to limited efficacy and safety data, BIC is currently not recommended during pregnancy. Data on the safety and efficacy of BIC during pregnancy were unavailable at the time of drug approval. In our case, BIC/TAF/FTC was effective in suppressing viral load (VL) in pregnancy, and there were no reported safety issues for the mother or the baby.

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“…However, in vivo data are still critical as discrepancies have been identified with some predictive and ex vivo models. To illustrate, for bictegravir, an ex vivo human cotyledon model predicted placental transfer of 0.07%, 37 whereas case reports with in vivo data have reported ratios of 0.68‐1.49 38,39 . Thus, further refinement of models and assessment of factors that may affect placental transfer are warranted.…”

Section: Placental and Breast Milk Transfermentioning

confidence: 99%

Translating Clinical Pharmacology Data in Pregnancy to Evidence‐Based Guideline Recommendations: Perspectives From the HIV Field

Brooks

Scott

Best

et al. 2023

The Journal of Clinical Pharma

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Pharmacokinetic (PK) studies in pregnant, postpartum, and breastfeeding people are critical to informing appropriate medication use and dosing. A key component of translating PK results in these complex populations into clinical practice involves the systematic review and interpretation of data by guideline panels, composed of clinicians, scientists, and community members, to leverage available data for informed decision making by clinicians and patients and offer clinical best practices. Interpretation of PK data in pregnancy involves evaluation of multiple factors such as the study design, target population, and type of sampling performed. Assessments of fetal and infant drug exposure while in utero or during breastfeeding, respectively, are also critical for informing whether medications are safe to use during pregnancy and throughout postpartum in lactating people. This review will provide an overview of this translational process, discussion of the various factors considered by guideline panels, and practical aspects of implementing certain recommendations, using the HIV field as an example.

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First pharmacokinetic data of bictegravir in pregnant women living with HIV

Cited by 15 publications

References 5 publications

Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors

Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors

Efficacy and Safety of Bictegravir-Based Regimen in Pregnant Women Living with HIV: A Case Report

Translating Clinical Pharmacology Data in Pregnancy to Evidence‐Based Guideline Recommendations: Perspectives From the HIV Field

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