ORCID
0009-0009-9641-1325 (Doncel)
Document Type
Article
Publication Date
2025
DOI
10.1007/s40262-025-01589-y
Publication Title
Clinical Pharmacokinetics
Volume
Advance online publication
Pages
16 pp.
Abstract
Background and Objective
Tenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofovir-diphosphate concentrations during pregnancy among participants taking tenofovir disoproxil fumarate (TDF). Currently, there are no mechanism-based models describing the pharmacokinetics of tenofovir diphosphate (the active anabolite) in peripheral blood mononuclear cells (PBMCs) of pregnant individuals receiving TDF or tenofovir alafenamide (TAF), and the mechanisms behind observed differences between dried blood spots and PBMCs remain unclear.
Methods
To address this gap, we developed a semi-mechanistic model to simultaneously describe the pharmacokinetics of all clinically relevant TDF and TAF-derived moieties and conducted clinical trial simulations to compare TDF and TAF pharmacokinetics during pregnancy and postpartum.
Results
The pharmacokinetics of plasma TAF and TFV were best described by one-compartment and two-compartment models, respectively, with first-order absorption. A transit compartment was included to reflect the slower elimination rate of plasma TFV after receiving TAF. Cellular matrix PBMC and dried blood spots were included using a biophase model. For TDF, plasma TFV apparent clearance increased by 24.9% and 13.1% during the second and third trimesters of pregnancy, respectively, compared with non-pregnant populations. In the postpartum period, plasma TFV apparent clearance in pregnant women was 9.3% lower than in non-pregnant women. The bioavailability for TAF decreased by 17.3% and 5.1% during the second and third trimesters, respectively, and increased by 18% during the postpartum period relative to non-pregnant women. In pregnant women, simulations showed that TAF maintains approximately five times higher tenofovir diphosphate concentrations in PBMCs compared with TDF during the second and third trimesters, despite a decrease in PBMC tenofovir diphosphate concentrations for both drugs. This finding is consistent with the higher PBMC loading effect of TAF observed in non-pregnant populations.
Conclusions
Our semi-mechanistic model provides a framework for understanding pregnancy-associated pharmacokinetic changes and supports future research to refine dosing strategies for HIV treatment and prevention in pregnancy.
Rights
© 2025 The Authors.
This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original authors and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Data Availability
Article states: "The data cannot be made publicly available because of the ethical restrictions in the study’s informed consent documents and in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network’s approved human subjects protection plan; public availability may compromise participant confidentiality. However, data are available to all interested researchers upon request to the IMPAACT Statistical and Data Management Center’s data access committee (e-mail: sdac.data@fstrf.org) with the agreement of the IMPAACT Network."
Original Publication Citation
Yu, Y., Brooks, K. M., Doncel, G. F., Best, B. M., Marzinke, M. A., Mirochnick, M., Anderson, P., Myer, L., Celum, C., Heffron, R., Coleman, J., Davey, D. J., Hendrix, C. W., Momper, J. D., Bies, R., & Scott, R. K. (2025). Development of a semi-mechanistic population pharmacokinetic model for predicting tenofovir disoproxil fumarate and tenofovir alafenamide exposure in plasma and cellular matrices during pregnancy and postpartum. Clinical Pharmacokinetics. Advance online publication. https://doi.org/10.1007/s40262-025-01589-y
Repository Citation
Yu, Y., Brooks, K. M., Doncel, G. F., Best, B. M., Marzinke, M. A., Mirochnick, M., Anderson, P., Myer, L., Celum, C., Heffron, R., Coleman, J., Davey, D. J., Hendrix, C. W., Momper, J. D., Bies, R., & Scott, R. K. (2025). Development of a semi-mechanistic population pharmacokinetic model for predicting tenofovir disoproxil fumarate and tenofovir alafenamide exposure in plasma and cellular matrices during pregnancy and postpartum. Clinical Pharmacokinetics. Advance online publication. https://doi.org/10.1007/s40262-025-01589-y
Supplementary Information
Included in
Immune System Diseases Commons, Maternal and Child Health Commons, Obstetrics and Gynecology Commons, Women's Health Commons