Placental profiling of UGT1A enzyme expression and activity and interactions with preeclampsia at term

Collier, Abby C.; Thévenon, A; Goh, William; Hiraoka, Mark; Kendal-Wright, Claire E.

doi:10.1007/s13318-014-0243-4

Cited by 10 publications

(2 citation statements)

References 49 publications

(82 reference statements)

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“…DTG is mainly metabolized by UGT1A1, an enzyme known to be expressed in third trimester placental tissue as well and hypothesized to contribute to decreased fetal exposure to xenobiotics like bisphenol-A. 30,31 However, the interindividual variability of its activity is high and the contribution of placental metabolism to total metabolic DTG clearance could not be quantified. 32 Therefore, placental metabolism was not considered in this model and the organ was considered to be a barrier rather than a compartmental structure.…”

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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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: 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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“…In the model, the amount of CYP3A4, UGT1A1 and UGT1A9 in the fetal part of the placenta and the fetal body was informed based on reported data from previous studies that quantified the mRNA level of CYP3A4 [43] as well as protein levels and the activity of UGT1A1 [44,45] in various human tissues, including the adult liver, placenta and fetal liver. Further information can be found in the supplement.…”

Section: Parameterization Of Placental Metabolismmentioning

confidence: 99%

Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling

et al. 2020

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Background-Predicting drug pharmacokinetics (PK) in pregnant women including placental drug transfer remains challenging. This study aimed to develop and evaluate maternal-fetal physiologically-based PK (PBPK) models for two antiretroviral drugs (ARVs), dolutegravir (DTG) and raltegravir (RAL).Methods-PBPK models were built with the Open Systems Pharmacology software suite (PK-Sim/MoBi). Different approaches to inform placental drug transfer were applied and compared. Model performance was evaluated using in vivo DTG and RAL maternal plasma concentrations during the 2 nd and 3 rd trimesters and umbilical vein concentrations at delivery. All clinical in vivo data were obtained from the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s study.

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Predicting Human Fetal Drug Exposure Through Maternal‐Fetal PBPK Modeling and In Vitro or Ex Vivo Studies

Balhara

Kumar

Unadkat

2022

The Journal of Clinical Pharma

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Medication (drug) use in human pregnancy is prevalent. Determining fetal safety and efficacy of drugs is logistically challenging. However, predicting (not measuring) fetal drug exposure (systemic and tissue) throughout pregnancy is possible through maternal‐fetal physiologically based pharmacokinetic (PBPK) modeling and simulation. Such prediction can inform fetal drug safety and efficacy. Fetal drug exposure can be quantified in 2 complementary ways. First, the ratio of the steady‐state unbound plasma concentration in the fetal plasma (or area under the plasma concentration–time curve) to the corresponding maternal plasma concentration (ie, Kp,uu). Second, the maximum unbound peak (Cu,max,ss,f) and trough (Cu,min,ss,f) fetal steady‐state plasma concentrations. We (and others) have developed a maternal‐fetal PBPK model that can successfully predict maternal drug exposure. To predict fetal drug exposure, the model needs to be populated with drug specific parameters, of which transplacental clearances (active and/or passive) and placental/fetal metabolism of the drug are critical. Herein, we describe in vitro studies in cells/tissue fractions or the perfused human placenta that can be used to determine these drug‐specific parameters. In addition, we provide examples whereby this approach has successfully predicted systemic fetal exposure to drugs that passively or actively cross the placenta. Apart from maternal‐fetal PBPK models, animal studies also have the potential to estimate fetal drug exposure by allometric scaling. Whether such scaling will be successful is yet to be determined. Here, we review the above approaches to predict fetal drug exposure, outline gaps in our knowledge to make such predictions and map out future research directions that could fill these gaps.

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Placental profiling of UGT1A enzyme expression and activity and interactions with preeclampsia at term

Cited by 10 publications

References 49 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

Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling

Predicting Human Fetal Drug Exposure Through Maternal‐Fetal PBPK Modeling and In Vitro or Ex Vivo Studies

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