Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

McCormack, Shelley A.; Best, Brookie M.

doi:10.1007/s40262-014-0185-7

Cited by 59 publications

(34 citation statements)

References 108 publications

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“…Fetal exposure to RAL was evaluated in nine paired cord and maternal blood samples at delivery (median 10 hours post-last RAL dose). The ratio of RAL in cord/maternal blood was 1.21 (IQR 1.02-2.17), similar to prior reports [58]. …”

Section: Pharmacokinetics In Special Populationssupporting

confidence: 90%

“…In addition to maternal influences on ARV PK, fetal exposure to ARVs during the antepartum period is also important for the prevention of HIV transmission. McCormack and Best recently published a comprehensive review of ARV placental transfer [58]; therefore, only in vivo information published since this recent review is described herein.…”

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

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Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors

Podany

Scarsi

Fletcher³

2016

Clin Pharmacokinet

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Dolutegravir (DTG), elvitegravir (EVG) and raltegravir (RAL), are members of latest class of antiretrovirals (ARV) available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors (INSTI). INSTIs are potent inhibitors of the HIV integrase enzyme with IC90/95 values in the low nanogram per milliliter range and they retain antiviral activity against strains of HIV with acquired resistance to other classes of ARVs. Each of the INSTIs have unique pharmacokinetic / pharmacodynamic properties, influencing their role in clinical use in specific subsets of patients. RAL and DTG have minimal drug-drug interaction profiles, as their metabolism has minimal cytochrome P450 (CYP) involvement. Conversely, EVG metabolism occurs primarily via CYP3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once daily dosing. EVG and DTG have the added benefit of the availability of fixed dose combination tablets, allowing for convenient and simplified ARV regimens. RAL is the only INSTI to be listed as a preferred agent on the current United States perinatal guidelines. All three of the INSTI agents are recommended regimens for treatment-naïve individuals on the United States Adult and Adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the INSTI agents, and describes specific pharmacokinetic considerations for special patient conditions: hepatic impairment, renal dysfunction, pregnancy and co-infections.

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Section: Pharmacokinetics In Special Populationssupporting

confidence: 90%

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors

Podany

Scarsi

Fletcher³

2016

Clin Pharmacokinet

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“…Low concentration ratios for EVG and DTG were noted between cord plasma and placenta, cord plasma and maternal plasma, and cord PBMCs and maternal PBMCs. There are limited PK data on placental transfer of EVG (4)(5)(6)(7)(8). Distributions of all five drug concentrations for all the matrices were analyzed and are plotted in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cobicistat is an important inhibitor of CYP3A, allowing ARV agents, such as EVG, to bypass first-pass metabolism in the liver and other tissues (9). A few studies have measured the PK of INSTIs during pregnancy (6). RTG has been shown to cross the placenta well, with drug concentrations detected in cord blood plasma from mothers receiving this ARV during pregnancy (11,14).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy

Rimawi

Johnson

Rajakumar

et al. 2017

Antimicrob Agents Chemother

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The integrase inhibitors elvitegravir (EVG) and dolutegravir (DTG) rapidly decrease the plasma HIV-1 viral load, a key factor in the prevention of maternal-tofetal transmission of HIV-1. No data have been reported on the concentrations of these drugs in cord blood, maternal peripheral blood mononuclear cells (PBMCs), or placental tissue in pregnant women. We present in vivo pharmacokinetic data on antiretrovirals (ARV) within maternal and cord blood and within placentae from HIV-1-infected pregnant women. Maternal blood and cord blood were obtained from women receiving EVG, cobicistat, tenofovir disoproxil fumarate, and emtricitabine as a single fixed-dose combination formulation or DTG as part of a combination regimen. Plasma and PBMCs from maternal and cord blood were obtained along with villous placental samples. Drug concentrations were simultaneously determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Utilizing medians and ranges to interpret our data, we compared the drug concentration ratios between different matrices (maternal and cord blood plasma, PBMCs, and placenta). All five agents transferred from maternal into fetal circulation via the placenta. Concentration ratios for EVG, cobicistat, tenofovir, and emtricitabine (n ϭ 10) and DTG (n ϭ 3) were determined between cord plasma and placenta, cord and maternal plasma, and cord PBMCs and maternal PBMCs. TFV moves from maternal plasma through the placenta to the cord blood and then into cord PBMCs, where it is phosphorylated into its active forms (TFV diphosphate). These five ARVs were detected in each of the compartments, highlighting transfer of these agents from the maternal into the fetal circulation.

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“…Next to the DTG-driven reduction in maternal viral load, fetal plasma DTG levels above the concentration that results in 90% of viral inhibition (0.324 µg/mL) may contribute to a reduced chance of MTCT. 16,17 The delicate balance between possible fetal toxicity and potential beneficial effects of fetal exposure in terms of fetal pre-exposure prophylaxis highlights that it is relevant to adequately describe fetal PK following maternal dosing. Although the umbilical cord blood-to-maternal blood (C:M) concentration ratio is used in clinical practice as an indicator of fetal exposure, its use has some drawbacks.…”

Section: Assessment Of Maternal and Fetal Dolutegravir Exposure By Inmentioning

confidence: 99%

Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically‐Based Pharmacokinetic Modeling

Freriksen

Schalkwijk²,

Colbers³

et al. 2020

Clin Pharma and Therapeutics

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Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologicallybased pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG). First, a PBPK model for DTG exposure in healthy volunteers was established based on physiological and DTG PK data. Next, the model was extended with a fetoplacental unit using transplacental kinetics obtained by performing ex vivo dual-side human cotyledon perfusion experiments. Simulations of fetal exposure after maternal dosing in the third trimester were in accordance with clinically observed DTG cord blood data. Furthermore, the predicted fetal trough plasma concentration (C trough ) following 50 mg q.d. dosing remained above the concentration that results in 90% of viral inhibition. Our integrated approach enables simulation of maternal and fetal DTG exposure, illustrating this to be a promising way to assess DTG PK during pregnancy.Dolutegravir (DTG) is being adopted as the preferred first-line treatment for HIV infection. 1,2 DTG-containing regimens have a favorable efficacy and tolerability benefit risk ratio, compared with a triple regimen consisting of either efavirenz or boosted protease inhibitors. Additionally, the low chance of resistance development and low costs make DTG superior to other antiretroviral therapy (ART) regimens. DTG is administered once daily either with emtricitabine and tenofovir disoproxil fumarate or as a fixed-dose combination tablet with abacavir and lamivudine. 3 As women of reproductive age represent a large proportion of all HIV-positive patients, knowledge about the safety of DTG during pregnancy is required. In 2016, there were 17.8 million women living with HIV worldwide. 4 They must be treated during pregnancy, not only to ensure their own health, but also because this reduces the risk of mother-to-child transmission (MTCT) of the virus from 20-45% to <1%. 5 A systematic review reported that DTG use in pregnancy did not result in increased rates of stillbirth, preterm birth, small for gestational age, or congenital anomalies. 6 This is in line with results from a large observational study that compared birth outcomes among women initiating either DTGbased ART or efavirenz-based ART (World Health Organization (WHO) first-line recommended regimen until 2016) and found

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Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

Cited by 59 publications

References 108 publications

Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors

Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors

Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy

Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically‐Based Pharmacokinetic Modeling

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