Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester
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 concentration...
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| Format: | Article |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2021.734122/full |
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| author | Babajide Shenkoya Shakir Atoyebi Shakir Atoyebi Ibrahim Eniayewu Ibrahim Eniayewu Abdulafeez Akinloye Adeniyi Olagunju Adeniyi Olagunju |
| author_facet | Babajide Shenkoya Shakir Atoyebi Shakir Atoyebi Ibrahim Eniayewu Ibrahim Eniayewu Abdulafeez Akinloye Adeniyi Olagunju Adeniyi Olagunju |
| author_sort | Babajide Shenkoya |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T06:54:53Z |
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| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-12-22T06:54:53Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pediatrics |
| spelling | doaj.art-fc48f1d596354111a4a5e070b4ce7a422022-12-21T18:35:01ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602021-09-01910.3389/fped.2021.734122734122Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third TrimesterBabajide Shenkoya0Shakir Atoyebi1Shakir Atoyebi2Ibrahim Eniayewu3Ibrahim Eniayewu4Abdulafeez Akinloye5Adeniyi Olagunju6Adeniyi Olagunju7Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, NigeriaDepartment of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, NigeriaDepartment of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United KingdomDepartment of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, NigeriaDepartment of Pharmaceutical and Medicinal Chemistry, University of Ilorin, Ilorin, NigeriaDepartment of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, NigeriaDepartment of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, NigeriaDepartment of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United KingdomPregnancy-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.https://www.frontiersin.org/articles/10.3389/fped.2021.734122/fullpregnancyantiretrovirallymphpharmacokineticsPBPKfetus |
| spellingShingle | Babajide Shenkoya Shakir Atoyebi Shakir Atoyebi Ibrahim Eniayewu Ibrahim Eniayewu Abdulafeez Akinloye Adeniyi Olagunju Adeniyi Olagunju Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester Frontiers in Pediatrics pregnancy antiretroviral lymph pharmacokinetics PBPK fetus |
| title | Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester |
| title_full | Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester |
| title_fullStr | Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester |
| title_full_unstemmed | Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester |
| title_short | Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester |
| title_sort | mechanistic modeling of maternal lymphoid and fetal plasma antiretroviral exposure during the third trimester |
| topic | pregnancy antiretroviral lymph pharmacokinetics PBPK fetus |
| url | https://www.frontiersin.org/articles/10.3389/fped.2021.734122/full |
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