Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Fetal Compartment (Placenta and Amniotic Fluid)

Else, Laura; Taylor, Stephen; Back, David; Khoo, Saye

doi:10.3851/imp1918

Cited by 53 publications

(39 citation statements)

References 107 publications

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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%

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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Section: Resultsmentioning

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 CLI values reported using this ex vivo placental perfusion model were 40.3% for darunavir (18) and 73% for lopinavir at a 2% serum albumin concentration (19), whereas there was nearly no placental transfer for saquinavir (10). For the nucleoside reverse transcriptase inhibitors, the fetal concentrations were equal to or higher than the maternal concentrations (20), whereas the CLI of the CCR5 inhibitor maraviroc was 26%, and the fusion inhibitor enfuvirtide did not cross the placenta (21). This ex vivo model does have important limitations.…”

Section: Rilpivirine (4-[[4-[[4-[(e)-2-cyanoethenyl]-26-dimethylphenmentioning

confidence: 92%

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Mandelbrot

Duro

Belissa

et al. 2015

Antimicrob Agents Chemother

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e Placental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% ؎ 8% (mean ؎ standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% ؎ 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother.A ntiretroviral drugs are remarkably effective for preventing vertical transmission of HIV-1, resulting in a decline in the rate of transmission, which is now less than 0.5% in France (1, 2). Current guidelines recommend antiretroviral therapy for all HIVinfected pregnant women for their own health and to prevent transmission (3, 4)., a diarylpyrimidine analog, is a nonnucleoside reverse transcriptase inhibitor (NNRTI) which is increasingly used to treat HIV infection and in recent guidelines is considered a first-line treatment. It is available in a single-tablet formulation in combination with tenofovir and emtricitabine (Complera-Eviplera). Rilpivirine is classified as a pregnancy category B drug by the Food and Drug Administration (4), which means that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in HIV-1-infected pregnant women. To date, only one report has been published on two cases of rilpivirine use in pregnant women (5), in which the plasma concentrations of rilpivirine were lower than would be expected in nonpregnant women. Placental transfer was studied in one of these two cases. Currently, there are no data on the safety of rilpivirine use during pregnancy.Determining fetal exposure is important for all new medications in order to estimate the potential for preexposure prophylaxis and the risk for toxicities to the fetus. A number of adverse events have been reported following perinatal exposure to antiretroviral medications, including mitochondrial diseases (6). Since data from animal studies are difficult to extrapolate to humans due to differences in placental physiology, other preclinical approaches are required.The ex vivo human cotyledon is an accepted model used to study and interpret placental transfer (7,8). The purpose of this study was to investigate the placental transfer of rilpivirine in an ex vivo perfused human cotyledon.Placentas were collected after uncomplicated pregnancy with full-term delivery (Ն37 weeks gestational age) in mothers who were seronegative for HIV and hepatitis B and C viruses and had taken no medication, except for vitamin supplements and perimedullar analgesia. They were collected in a single center, the maternity ward of the Hôpitaux Universitaires Paris-Nord Val de Seine (Colombes, France), and were rapidly perfused on site. Written informed consent was obtained from each of the women who donated a placenta, acc...

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“…[32][33][34][35] Nevirapine attains nearly equivalent concentrations in maternal and umbilical cord blood, and concentrations in amniotic fluid are roughly 75.0% of those in maternal blood. 36,37 Limited data exist on efavirenz. Placental transfer of etravirine has been documented in rats, and animal studies have not demonstrated any harmful teratogenic effects.…”

Section: Etravirine In Pregnancymentioning

confidence: 99%

“…Placental transfer of etravirine has been documented in rats, and animal studies have not demonstrated any harmful teratogenic effects. 36 Furco et al described a 38-yearold woman with multidrug-resistant HIV and pregnant with a twin gestation who received etravirine 200 mg twice daily beginning at 25 weeks' gestation in combination with darunavir, ritonavir, and enfuviritide. 38 Her HIV RNA viral load improved from 4,660 copies/mL to ,50 copies/mL, while her CD4 count decreased from 471 cells/µL to 356 cells/µL.…”

Section: Etravirine In Pregnancymentioning

confidence: 99%

“…Paired maternal-cord blood specimens were not collected, but placental transfer was estimated to have ranged from 29.0% to 46.0%. 36,38 The infants were born via cesarean section at 34 weeks' gestation, and received 2 days of enfuviritide, one week of nevirapine, and 2 weeks of didanosine. 38 At 4 months of age, neither infant was infected with HIV.…”

Section: Etravirine In Pregnancymentioning

confidence: 99%

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Profile of etravirine in the treatment of HIV in pediatrics

Dehority¹,

Viani

2013

PHMT

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Etravirine is a non-nucleoside reverse transcriptase inhibitor now licensed for treatment of human immunodeficiency virus (HIV)-1 infection in both children over 6 years of age and adults. Etravirine demonstrates a high genetic barrier to the development of resistance, as multiple mutations are typically required prior to the onset of reduced susceptibility to the drug. It retains in vitro and clinical activity against many HIV-1 isolates, demonstrating resistance to other non-nucleoside reverse transcriptase inhibitors, such as efavirenz and nevirapine. Given the ability of HIV to develop resistance rapidly across the non-nucleoside reverse transcriptase inhibitor class of antiretrovirals, etravirine has a welcome place in the management of HIVinfected patients, particularly treatment-experienced individuals harboring non-nucleoside reverse transcriptase inhibitor mutations. Etravirine has been shown to improve CD4 counts and viral load significantly in HIV-infected adults on combination antiretroviral therapy when compared with placebo in a large, randomized controlled trial. Data on the utility of etravirine in children are still somewhat limited, although a recent pediatric trial has demonstrated adequate pharmacokinetics, safety, and efficacy of etravirine in a small number of HIV-infected children and adolescents. In both children and adults, rash appears to be the most common adverse effect described. Despite its high genetic barrier to resistance, evidence of mutations conferring etravirine resistance has been documented in both adult and pediatric patients. Such mutations have been best described in treatment-experienced populations, including those who have never been exposed to the drug. This review describes the existing literature on the use of etravirine in the pediatric population, and highlights future and ongoing directions of investigation.

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Pharmacokinetics of Antiretroviral Drugs in Anatomical Sanctuary Sites: The Fetal Compartment (Placenta and Amniotic Fluid)

Cited by 53 publications

References 107 publications

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

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

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Profile of etravirine in the treatment of HIV in pediatrics

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