Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics and placental transfer

Ripamonti, Diego; Cattaneo, Dario; Maggiolo, Franco; Airoldi, Monica; Frigerio, Luigi; Bertuletti, Pierangelo; Ruggeri, Maurizio; Suter, Fredy

doi:10.1097/qad.0b013e32825a69d1

Cited by 93 publications

(66 citation statements)

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“…For atazanavir, the ratios were 0.13 (27) to 0.21 (10), and for lopinavir, the ratio was 0.20 (28). Similar ratios were also observed for nelfinavir and amprenavir (29), whereas cord blood concentrations were nearly undetectable for ritonavir, indinavir, and saquinavir (29,30).…”

supporting

confidence: 60%

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

Mandelbrot

Duro

Belissa

et al. 2014

Antimicrob Agents Chemother

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cPlacental transfer of the HIV protease inhibitor darunavir was investigated in 5 term human cotyledons perfused with darunavir (1,000 ng/ml) in the maternal to fetal direction. The mean (؎ the standard deviation [SD]) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 15.0% ؎ 2.1%, and the mean (؎SD) clearance index (darunavir FTR/ antipyrine FTR) was 40.3% ؎ 5.8%. This shows that darunavir crosses the placenta at a relatively low rate, resulting in fetal exposure.T he use of antiretroviral drugs has allowed for a spectacular reduction in mother-to-child transmission (MTCT) of HIV in the industrialized countries, with a current rate of Յ0.5% in France (1, 2). Darunavir is an HIV protease inhibitor (PI) that is increasingly used in combination with other drugs to treat HIV infection. It is now considered a first-line option in pregnant women (3, 4), although few data are available to date on its effects during pregnancy. It is classified by the FDA in pregnancy category C (4), meaning that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in pregnant women. Most of the adverse events described are related to nucleoside reverse transcriptase inhibitors, particularly mitochondrial disease (6) and hematologic or cardiac function toxicities (7), whereas few antiretroviral drugs have shown any relation to the risk of malformations (8). The HIV protease inhibitors are largely well tolerated in utero (9), although there are reports of elevated neonatal bilirubin levels following atazanavir exposure (10) and transient adrenal dysfunction following perinatal lopinavir-ritonavir treatment (11). Determining fetal exposure to a specific drug is important in estimating its potential for preexposure prophylaxis (12), as well as its risk for toxicities in the fetus. Since data from animal studies are difficult to extrapolate to humans due to the differences in placental physiology, human studies are required. There are some data on cord blood concentrations of darunavir at delivery, but these data reflect only a single time point, and larger series are required for population pharmacokinetic modeling (13,14). The ex vivo human cotyledon is an accepted model in which to study and interpret placental transfer (15).The purpose of this study was to investigate the placental transfer of darunavir in the ex vivo human perfused cotyledon.Placentas were collected after uneventful pregnancies and term deliveries (Ն37 weeks gestational age) in a single center (a university hospital maternity department in Colombes, France) and were rapidly perfused on site. Written informed consent was obtained from each woman who donated a placenta, according to French bioethics guidelines (article L1211-2 of the Public Health Code).The darunavir base was provided by the manufacturer (Janssen, Issy-les-Moulineaux, France) as antipyrine-phosphate-buffered saline (PBS). Bradford reagent was purchased from SigmaAldrich (Saint Quentin Fallav...

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confidence: 60%

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

Mandelbrot

Duro

Belissa

et al. 2014

Antimicrob Agents Chemother

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“…Previous studies have demonstrated placental transfer, with drug concentrations approaching 1 g/ml in maternal and cord blood ratios for certain nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) (15)(16)(17)32) with slightly lower ratios reported for non-NRTIs (18)(19)(20) and even lower ratios for the protease inhibitors (16,21). Studies analyzing placental transfer of TFV have reported variable results, with maternal and cord blood concentration ratios ranging from 0.82 to 6.0 (16,18).…”

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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Section: Table 2 (Continued)mentioning

confidence: 99%

“…In one study of lopinavir/RTV, compensation for the lower exposures required a dose increase to 533/133 mg twice daily (bid) from 400/100 mg bid in the third trimester to produce exposures similar to those in nonpregnant historical controls [7]. Conversely, Ripamonti et al [18] reported that the standard dose of ATV/r (300/100 mg) resulted in ATV exposures in women in the third trimester that were similar to their postpartum exposures. The most frequently observed adverse event with ATV is elevations of indirect bilirubin as a result of uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibition, and this gives rise to the theoretical concern that using ATV in pregnant women may exacerbate physiological hyperbilirubinaemia in the neonates [1].…”

mentioning

confidence: 99%

“…ATV concentrations appear to normalize by week 7 postpartum [18]. The ratio of maternal to cord blood ATV indicates that, as with other protease inhibitors [25], ATV does not freely cross the placenta; however, in this study, plasma protein binding in cord blood was lower than in maternal blood, indicating that free drug concentrations in the fetus were approximately twice as high as in the mothers at a similar total (bound and unbound or 'free') ATV plasma concentration [26], suggesting that the levels achieved in the cord blood may provide some antiviral protection to the fetus [18].A theoretical concern with ATV use during pregnancy is an increase in bilirubin in newborns [1]. This could occur either by passive back-diffusion of infant bilirubin across the placenta, as a result of saturation of protein binding of bilirubin in mothers with elevated maternal bilirubin, or theoretically through the effect of UGT1A1 inhibition in the fetus as a result of ATV crossing the placenta.…”

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confidence: 99%

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Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women

et al. 2011

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ObjectiveThere are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)-boosted atazanavir in HIV-1-infected pregnant women. MethodsIn this nonrandomized, open-label study, HIV-infected pregnant women were dosed with either 300/ 100 mg (n 5 20) or 400/100 mg (n 5 21) atazanavir/RTV once-daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C max ), trough observed plasma concentration 24 hour post dose (C min ) and area under concentration-time curve in one dosing interval (AUC t )] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV-infected nonpregnant adults (n 5 23). ResultsAt or before delivery, all mothers achieved HIV RNA o50 HIV-1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC t for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C min values were comparable. The C min value for atazanavir/RTV 400/100 mg was 39% higher than the C min for atazanavir/RTV 300/100 mg in historical controls, but the AUC t values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (42.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events. ConclusionsIn this study, use of atazanavir/RTV 300/100 mg qd produced C min comparable to historical data in nonpregnant HIV-infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother-to-child transmission of HIV-1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV.Keywords: atazanavir, HIV, pregnancy, prevention of mother-to-child transmission, protease inhibitor IntroductionTreatment guidelines for HIV-1 infection in pregnant women recommend highly active antiretroviral (ARV) therapy (HAART) with two nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine) plus the nonnucleoside reverse transcriptase inhibitor nevirapine [1][2][3]. Some guidelines also recommend the ritonavir (RTV)-boosted protease inhibitor lopinavir as an optional third agent [1], although others recommend several boosted protease inhibitors as optional agents [2]. All other ARV DOI: 10.1111/j.1468-1293.2011.00927.x HIV Medicine (2011 r 2011 British HIV Association 570 drugs are alternative agents or for use in special circumstances [1,4]. However, there are questions and concerns regarding the two most frequently recommended third agents: treatment initiation with nevirapine is associated with an increased risk of symptomatic liver toxicity, often accompanied by a rash, which is potentially fatal [1,5]. Concerns with RTV-boosted lopinavir inclu...

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Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics and placental transfer

Cited by 93 publications

References 20 publications

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

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

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

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women

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