Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

Ke, Alice Ban; Greupink, Rick; Abduljalil, Khaled

doi:10.1002/psp4.12274

Cited by 59 publications

(51 citation statements)

References 51 publications

(110 reference statements)

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“…This physiologically-based approach may provide additional insights for selecting an adequate dosing regimen for HIV-positive pregnant women. 14,15 It is equally important to predict fetal drug exposure following maternal dosing. Exposure of the developing unborn child could lead to adverse effects but it may also have beneficial effects from a perspective of fetal pre-exposure prophylaxis.…”

Section: Assessment Of Maternal and Fetal Dolutegravir Exposure By Inmentioning

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: Assessment Of Maternal and Fetal Dolutegravir Exposure By Inmentioning

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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“…Pregnancy may alter the expression of drug transporters in metabolising and eliminating organs, but there is little quantitative information on the influence of pregnancy on transporter activity in the basolateral and canalicular membrane of hepatocytes, and the resulting effect on DAA excretion. Due to this lack of knowledge, no pregnancy physiologically‐based pharmacokinetic (PBPK) models have been published which simulate the role of biliary drug excretion . Sofosbuvir is mainly renally eliminated as its pharmacologically inactive metabolite GS‐331007 (78%) and to a lesser extent as unchanged sofosbuvir (3.5%).…”

Section: Effect Of Pregnancy On Maternal Exposure To Direct‐acting Anmentioning

confidence: 99%

Review article: direct‐acting antivirals for the treatment of HCV during pregnancy and lactation ‐ implications for maternal dosing, foetal exposure, and safety for mother and child

Freriksen

Seyen²,

Judd

et al. 2019

Aliment Pharmacol Ther

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Summary Background With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct‐acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended. Aim To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation Methods A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation. Results Exposure to all DAAs studied is likely to be altered during pregnancy, mostly related to pregnancy‐induced effects on drug absorption and metabolism. Although animal studies show that most DAAs are reported to cross the placenta and transfer into breast milk, most DAA combinations show a favourable safety profile. Because of the rapid viral decline after treatment initiation, and to avoid the critical period of organogenesis, treatment may be started at the end of the second trimester or early third trimester. Conclusions Treatment of HCV infection during pregnancy is realistic, as DAAs are highly effective and treatment duration is relatively short. There is an urgent need to study DAAs during pregnancy and lactation to contribute to the goal of HCV elimination.

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“…PBPK models have been used to represent particular disease states or specific patient groups, such as pediatric patients or pregnant women [9] as well as to predict drug-drug interactions [10][11][12][13][14][15][16], food-drug interactions [17][18][19], drug formulation effects [20,21], crossspecies extrapolation [22][23][24], and constitute key components of multiscale models [25]*.…”

Section: Physiologically Based Pharmacokinetic Modelsmentioning

confidence: 99%

In silico models in drug development: where we are

Piñero

Furlong

Sanz

2018

Current Opinion in Pharmacology

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The use and utility of computational models in drug development has significantly grown in the last decades, fostered by the availability of high throughput datasets and new data analysis strategies. These in silico approaches are demonstrating their ability to generate reliable predictions as well as new knowledge on the mode of action of drugs and the mechanisms underlying their side effects, altogether helping to reduce the costs of drug development. The aim of this review is to provide a panorama of developments in the field in the last two years.

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Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

Cited by 59 publications

References 51 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

Review article: direct‐acting antivirals for the treatment of HCV during pregnancy and lactation ‐ implications for maternal dosing, foetal exposure, and safety for mother and child

In silico models in drug development: where we are

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