Using mechanistic physiologically-based pharmacokinetic models to assess prenatal drug exposure: Thalidomide versus efavirenz as case studies

Atoyebi, Shakir; Rajoli, Rajith K. R.; Adejuyigbe, Ebunoluwa A.; Owen, Andrew; Bolaji, Oluseye O.; Siccardi, Marco; Olagunju, Adeniyi

doi:10.1016/j.ejps.2019.105068

Cited by 22 publications

(24 citation statements)

References 37 publications

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“…The present model is an extension of a previously described materno-fetal PBPK model composed of integrated whole-body maternal model and multi-compartmental fetal model ( Supplementary Figure 1 ) ( 28 ). The model was implemented in Simbiology® (v. 9.5, MATLAB® 2018b, Mathworks Inc., Natick, Massachusetts, USA) and extended to include the lymphatic circulation ( Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…In some cases where necessary parameter values were not reported, published graph-plots of changes in the parameters: the placental thickness ( 18 ), rates of blood flow through the foramen ovale and ductus arteriosus ( 42 ), over the course of pregnancy were digitized (Plotdigitizer® version 2.6.6, Free Software Foundation, Boston, MA, USA). The data points obtained were used to generate equations of best-fit which were subsequently inputted into the model as previously described ( 28 ). Sensitivity analyses was conducted to observe the extent in which uncertainty in placental diffusion constant propagated into the fetal plasma predictions in the model ( Supplementary Figure 2 ).…”

Section: Methodsmentioning

confidence: 99%

“…In the current work, we describe the extension of our previous m-f PBPK model ( 28 ) to describe the penetration of efavirenz, dolutegravir and rilpivirine into the lymph and fetal plasma during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Pregnancy-induced changes in plasma pharmacokinetics of many antiretrovirals (ARV) are well-established. Current knowledge about the extent of ARV exposure in lymphoid tissues of pregnant women and within the fetal compartment is limited due to their inaccessibility. Subtherapeutic ARV concentrations in HIV reservoirs like lymphoid tissues during pregnancy may constitute a barrier to adequate virological suppression and increase the risk of mother-to-child transmission (MTCT). The present study describes the pharmacokinetics of three ARVs (efavirenz, dolutegravir, and rilpivirine) in lymphoid tissues and fetal plasma during pregnancy using materno-fetal physiologically-based pharmacokinetic models (m-f-PBPK). Lymphatic and fetal compartments were integrated into our previously validated adult PBPK model. Physiological and drug disposition processes were described using ordinary differential equations. For each drug, virtual pregnant women (n = 50 per simulation) received the standard dose during the third trimester. Essential pharmacokinetic parameters, including Cmax, Cmin, and AUC (0–24), were computed from the concentration-time data at steady state for lymph and fetal plasma. Models were qualified by comparison of predictions with published clinical data, the acceptance threshold being an absolute average fold-error (AAFE) within 2.0. AAFE for all model predictions was within 1.08–1.99 for all three drugs. Maternal lymph concentration 24 h after dose exceeded the reported minimum effective concentration (MEC) for efavirenz (11,514 vs. 800 ng/ml) and rilpivirine (118.8 vs. 50 ng/ml), but was substantially lower for dolutegravir (16.96 vs. 300 ng/ml). In addition, predicted maternal lymph-to-plasma AUC ratios vary considerably (6.431—efavirenz, 0.016—dolutegravir, 1.717—rilpivirine). Furthermore, fetal plasma-to-maternal plasma AUC ratios were 0.59 for efavirenz, 0.78 for dolutegravir, and 0.57 for rilpivirine. Compared with rilpivirine (0 h), longer dose forgiveness was observed for dolutegravir in fetal plasma (42 h), and for efavirenz in maternal lymph (12 h). The predicted low lymphoid tissue penetration of dolutegravir appears to be significantly offset by its extended dose forgiveness and adequate fetal compartment exposure. Hence, it is unlikely to be a predictor of maternal virological failure or MTCT risks. Predictions from our m-f-PBPK models align with recommendations of no dose adjustment despite moderate changes in exposure during pregnancy for these drugs. This is an important new application of PBPK modeling to evaluate the adequacy of drug exposure in otherwise inaccessible compartments.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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“…103 Furthermore, pharmacometric modeling tools such as PBPK modeling could be used to simulate fetal exposures and predict relevant doses for pregnant and lactating women when designing clinical trials. 104,88 Challenges and Opportunities for Future Research Historically, both pregnant women and children have been considered as "therapeutic orphans" because they encompass biologic complexity in Expert Reviews ajog.org terms of dynamic physiology and challenges regarding ethical, legal, logistical, and practical concerns in drug development and drug research. However, the implementation of the Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA) led to a paradigm shift in pediatric therapeutic research.…”

Section: Coronavirus Disease 2019 Treatment and Vaccine Trials In Pregnant And Lactating Womenmentioning

confidence: 99%

Drug development research in pregnant and lactating women

Ren

Bremer

Pawlyk

2021

American Journal of Obstetrics and Gynecology

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Pregnant and lactating women are considered "therapeutic orphans" because they generally have been excluded from clinical drug research and the drug development process owing to legal, ethical, and safety concerns. Most medications prescribed for pregnant and lactating women are used "off-label" because most of the clinical approved medications do not have appropriate drug labeling information for pregnant and lactating women. Medications that lack human safety data on use during pregnancy and lactation may pose potential risks for adverse effects in pregnant and lactating women as well as risks of teratogenic effects to their unborn and newborn babies. Federal policy requiring the inclusion of women in clinical research and trials led to considerable changes in research design and practice. Despite more women being included in clinical research and trials, the inclusion of pregnant and lactating women in drug research and clinical trials remains limited. A recent revision to the "Common Rule" that removed pregnant women from the classification as a "vulnerable" population may change the culture of drug research and drug development in pregnant and lactating women. This review article provides an overview of medications studied by the Obstetric-Fetal Pharmacology Research Units Network and Centers and describes the challenges in current obstetrical pharmacology research and alternative strategies for future research in precision therapeutics in pregnant and lactating women. Implementation of the recommendations of the Task Force on Research Specific to Pregnant Women and Lactating Women can provide legislative requirements and opportunities for research focused on pregnant and lactating women.

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“…PBPK models have proved invaluable for predicting the PK of several ARVs [ 69 ], including drug–drug interactions [ 70 , 71 ] and food–drug interactions [ 72 ]. For example, Atoyebi et al applied a similar PBPK model as a case study to predict fetal exposure to EFV and found significantly lower prenatal exposure when compared with known teratogens such as thalidomide [ 73 ]. In silico generation of data on the extent of fetal exposure to drugs may give us more insight into fetal exposure–safety relationships without exposing pregnant women and their fetuses to these teratogenic drugs.…”

Section: Innovative Approachesmentioning

confidence: 99%

Innovative Approaches for Pharmacology Studies in Pregnant and Lactating Women: A Viewpoint and Lessons from HIV

et al. 2020

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Medication use during pregnancy in the absence of pharmacokinetic and safety data is common, particularly for antiretrovirals, as pregnant women are not usually included in clinical trials leading to drug licensure. To date, data are typically generated through opportunistic pregnancy studies performed in the postmarketing setting, leading to a substantial time-lag between initial regulatory approval of a drug and availability of essential pregnancy-specific pharmacokinetic and safety data. During this period, health care providers lack key information on human placental transfer, fetal exposure, optimal maternal dosing in pregnancy, and maternal and fetal drug toxicity, including teratogenicity risk. We discuss new approaches that could facilitate the acquisition of these critical data earlier in the drug development process, aiding clinicians and patients in making informed decisions on drug selection and dosing during pregnancy. An integrated approach utilizing multiple novel methodologies (in vitro, ex vivo, in silico and in vivo) is needed to accelerate the availability of pharmacology data in pregnancy and lactation.

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Using mechanistic physiologically-based pharmacokinetic models to assess prenatal drug exposure: Thalidomide versus efavirenz as case studies

Cited by 22 publications

References 37 publications

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

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

Drug development research in pregnant and lactating women

Innovative Approaches for Pharmacology Studies in Pregnant and Lactating Women: A Viewpoint and Lessons from HIV

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