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

Rimawi, Bassam H.; Johnson, Erica L.; Rajakumar, Augustine; Tao, Sijia; Jiang, Yong; Gillespie, Scott; Schinazi, Raymond F.; Mirochnick, Mark; Badell, Martina; Chakraborty, Rana

doi:10.1128/aac.02213-16

Cited by 36 publications

(22 citation statements)

References 30 publications

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“…As the placenta is incorporated as a barrier in this model, possible retention of DTG within the placenta could not be simulated. This could, however, be of relevance as placental retention is reported to occur in vivo 36 and we were also able to measure DTG in placental tissue samples upon perfusion. However, concentrations did remain relatively low, and no relevant placental accumulation was observed as found for several other drugs.…”

Section: Discussionmentioning

confidence: 95%

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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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Section: Discussionmentioning

confidence: 95%

“…33,34 In addition, simulated fetal exposure was compared to in vivo fetal exposure, as umbilical cord blood-to-maternal blood concentration ratios are reported. 34,36 To study the impact of modeling assumptions and uncertainty around some parameter values on simulated concentration-time profiles, sensitivity analyses were conducted.…”

Section: Articlementioning

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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“…Pharmacokinetic studies show a reduced trough concentration in pregnancy but good placental and breastmilk penetration, which can be beneficial for protecting infants from perinatal HIV [10,11]. However, there remains a knowledge gap regarding viral suppression, development of resistance and neonatal outcomes from infants with in-utero exposure to DTG.…”

Section: Introductionmentioning

confidence: 99%

Evaluating outcomes of mother–infant pairs using dolutegravir for HIV treatment during pregnancy

Grayhack

Sheth

Kirby

et al. 2018

Aids

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Objectives:Dolutegravir (DTG), a second-generation integrase inhibitor, is an effective treatment for HIV but its safety and efficacy are not well established in pregnancy. Here, we assess maternal and infant outcomes of mother–infant pairs using DTG-containing regimens during pregnancy.Methods:We performed a retrospective cohort analysis of pregnant women with HIV on DTG from two urban clinics in the United States, 2015–2018. Maternal outcomes included viral suppression (viral load of <20 copies/ml prior to delivery), development of resistance, and tolerability to DTG. Infant outcomes included preterm delivery (birth at <37 weeks), small for gestational age (SGA, weight <10th percentile), infant HIV status at birth, birth defect(s), and Appearance, Pulse, Grimace, Activity, Respiration (APGAR) scores. We performed a trend analysis to assess DTG use over time.Results:A total of 66 women used DTG during pregnancy and the proportion on DTG increased each year: in 2015, 8% (5/60) of women were on DTG, versus 22% (15/67) in 2016, 42% (30/71) in 2017, and 59% (16/27) in 2018 (P < 0.05). Among women who delivered (n = 57), 77.2% were undetectable at delivery. There were no drug resistance and no reported side effects during pregnancy. Infants had a mean APGAR score of 8 (SD 1.5) at 1 min and 9 (SD 0.8) at 5 min; 31.6% were born prematurely and 15.8% were SGA, and 2 infants had a birth defect. No cases of HIV transmission occurred.Conclusion:Our findings suggest that DTG can be an effective treatment during pregnancy. Infant outcomes (preterm deliveries and birth defects) need to be investigated in larger studies.

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“…Previously, EVG has been quantified in human biological matrixes such as plasma , seminal plasma , and peripheral blood mononuclear cells , as well as mouse plasma and tissue using LC–MS. A recent report has described the measurement of the integrase inhibitors raltegravir, dolutegravir, and EVG in human plasma and CSF .…”

Section: Introductionmentioning

confidence: 99%

“…Previously, EVG has been quantified in human biological matrixes such as plasma [4][5][6][7][8][9], seminal plasma [10,11], and peripheral blood mononuclear cells [12], as well as mouse plasma and tissue [13] using LC-MS. A recent report has described the measurement of the integrase inhibitors raltegravir, dolutegravir, and EVG in human plasma and CSF [14]. The assay had a calibration range of 5-1500 ng/mL in plasma and 1-200 ng/mL in CSF, which is not ideal considering the average trough concentrations of EVG in plasma at steady state is typically 409 ng/mL while the Cmax concentrations are 2500 ng/mL [15].…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a UHPLC–MS/MS assay for elvitegravir measurement in human plasma and cerebrospinal fluid

Ocque

Hagler

Lapham

et al. 2018

Separation Science Plus

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The quantification of the integrase inhibitor, elvitegravir, in cerebrospinal fluid will significantly help understand its effects in the central nervous system. An ultra high performance liquid chromatography with tandem mass spectrometry method was successfully validated to measure elvitegravir in human plasma and cerebrospinal fluid. The biological fluid was diluted with methanol and the clear supernatant was injected into the chromatography system. The calibration was linear from 10.0 to 5000 ng/mL in plasma and 1.00 to 25 ng/mL in cerebrospinal fluid. Inter‐day and intra‐day variability ranged from 1.46 to 8.34% and accuracy ranged from –8.36 to 7.50% for quality controls in either plasma or cerebrospinal fluid analysis. The method was then applied to the measurement of elvitegravir concentrations in plasma and cerebrospinal fluid samples from an HIV+ patient enrolled in a clinical study who switched medications of Stribild® to Genvoya®. The validated method is suitable for the quantification of elvitegravir in plasma and cerebrospinal fluid.

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

Cited by 36 publications

References 30 publications

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

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

Evaluating outcomes of mother–infant pairs using dolutegravir for HIV treatment during pregnancy

Development and validation of a UHPLC–MS/MS assay for elvitegravir measurement in human plasma and cerebrospinal fluid

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