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

Abstract

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

Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester

“…Furthermore, the maternal dolutegravir PK parameters during pregnancy predicted by the model employed in this present study were similar to those predicted by Liu et al ( 72 ). Additionally, the predicted fetal exposure to dolutegravir in the present study was comparable to that reported by Freriksen et al ( 71 ). Although, fetal-to-maternal AUC plasma exposure ratio was predicted in our study, it was assumed to be similar to and within the range of the cord blood-to-maternal blood concentration ratios predicted in their study and observed clinical data.…”

“…Although, fetal-to-maternal AUC plasma exposure ratio was predicted in our study, it was assumed to be similar to and within the range of the cord blood-to-maternal blood concentration ratios predicted in their study and observed clinical data. Likewise, the C max and the C min of the maternal plasma concentration predicted by our model was lower and higher, respectively, in comparison to their reported values ( 71 ). Further studies are still suggested to establish this assumption of similarity.…”

Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

“…Maternal and umbilical cord PK prediction [119] Efavirenz (CYP2B6) Similar PK during 2 nd and 3 rd trimesters to those observed in non-pregnant women [120][121][122].…”

Model‐Informed Dose Optimization in Pregnancy

“…PBPK to Predict Fetal Exposure of Drugs PBPK has been used to predict fetal exposure of drugs, and examples are discussed below and in Table 4. Freriksen et al 63 developed a PBPK model to predict fetal exposure of dolutegravir by integrating transplacental kinetics obtained from ex vivo dual-side cotyledon perfusion experiments. The simulated fetal exposure after maternal dosing in third trimester was in accordance with the observed clinical cord blood data.…”