One-Month Transplacental Pharmacokinetics of Raltegravir in a Premature Newborn after Short-Course Treatment of the HIV-1-Infected Mother

Clavel-Osorio, C.; Cazassus, François; Stegmann, Stephani; Huc-Anaïs, Patricia; Lecam, D.; Peytavin, Gilles

doi:10.1128/aac.01349-13

Cited by 10 publications

(5 citation statements)

References 5 publications

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“…RAL levels in infants within three hours after delivery were seven to nine times higher than maternal paired drug levels [58]. These data were in line with another case report analyzing PK of RAL in a premature newborn [59]. This study reported 29 ng/mL of RAL in plasma of the infant one month after transplacental exposure, and the calculated half-life of drug in this premature infant was approximately 168 h. Furthermore, RAL elimination in infants was found to be highly variable and prolonged.…”

Section: Raltegravir (Ral)supporting

confidence: 88%

HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment

2022

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Children born to mothers, with or at risk, of human immunodeficiency virus type-1 (HIV-1) infection are on the rise due to affordable access of antiretroviral therapy (ART) to pregnant women or those of childbearing age. Each year, up to 1.3 million HIV-1-infected women on ART have given birth with recorded mother-to-child HIV-1 transmission rates of less than 1%. Despite this benefit, the outcomes of children exposed to antiretroviral drugs during pregnancy, especially pre- and post- natal neurodevelopment remain incompletely understood. This is due, in part, to the fact that pregnant women are underrepresented in clinical trials. This is underscored by any potential risks of neural tube defects (NTDs) linked, in measure, to periconceptional usage of dolutegravir (DTG). A potential association between DTG and NTDs was first described in Botswana in 2018. Incidence studies of neurodevelopmental outcomes associated with DTG, and other integrase strand transfer inhibitors (INSTIs) are limited as widespread use of INSTIs has begun only recently in pregnant women. Therefore, any associations between INSTI use during pregnancy, and neurodevelopmental abnormalities remain to be explored. Herein, United States Food and Drug Administration approved ARVs and their use during pregnancy are discussed. We provide updates on INSTI pharmacokinetics and adverse events during pregnancy together with underlying mechanisms which could affect fetal neurodevelopment. Overall, this review seeks to educate both clinical and basic scientists on potential consequences of INSTIs on fetal outcomes as a foundation for future scientific investigations.

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Section: Raltegravir (Ral)supporting

confidence: 88%

HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment

2022

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“…A recent study documented that cART, which includes an INSTI backbone, induces a more rapid reduction in HIV-1 RNA viral load than other regimens during pregnancy, which may be important if HIV-1-infected pregnant women present late to prenatal care or have failed to initiate an appropriately selected ARV regimen (29). Given our findings and previous data (7,29,30), consideration should be given to the use of the newer-generation INSTIs as part of a first-line preferred regimen during pregnancy.…”

Section: Discussionsupporting

confidence: 48%

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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“…[9–11] While these reports suggest that raltegravir readily crosses the placenta, they provide limited data describing the postnatal elimination of transplacentally-acquired raltegravir in the infant. One preterm infant has been described who had raltegravir concentrations present one month after delivery, suggesting very prolonged elimination.…”

Section: Discussionmentioning

confidence: 99%

“…One preterm infant has been described who had raltegravir concentrations present one month after delivery, suggesting very prolonged elimination. [11]…”

Section: Discussionmentioning

confidence: 99%

Raltegravir Pharmacokinetics in Neonates Following Maternal Dosing

Clarke

Acosta

Rizk

et al. 2014

JAIDS Journal of Acquired Immune Deficiency Syndromes

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IMPAACT P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data was available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with median cord blood/maternal delivery plasma raltegravir concentration ratio 1.48 (range, 0.32–4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t½ 26.6 hours (range 9.3–184 hours)]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate, since raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Sub-therapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must be avoided as well. Two ongoing IMPAACT studies are investigating further the pharmacology of raltegravir in neonates.

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One-Month Transplacental Pharmacokinetics of Raltegravir in a Premature Newborn after Short-Course Treatment of the HIV-1-Infected Mother

Cited by 10 publications

References 5 publications

HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment

HIV-1 Integrase Strand Transfer Inhibitors and Neurodevelopment

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

Raltegravir Pharmacokinetics in Neonates Following Maternal Dosing

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