Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Maternal Plasma and Breast Milk & Infant Cord Blood and Plasma: A Model‐Based Analysis of Mother–Infant Pairs for Tuberculosis Prevention

IMPAACT 2001 (NCT02651259) evaluated the safety and pharmacokinetics (PK) of once-weekly isoniazid and rifapentine in pregnant and postpartum women for tuberculosis prevention. Rifapentine (RPT) and desacetyl rifapentine (desRPT) PK data were collected in maternal plasma, breast milk, infant cord blood, and infant plasma. Longitudinal maternal plasma and breast milk RPT and desRPT concentrations were characterized using a multicompartment PK model with biophase effect compartments (NONMEM v7.4). Rate parameters describing drug entry into breast milk from plasma and breast milk-to-plasma ratio parameters were estimated. For mother-infant pairs, maternal plasma PK was simulated for the last RPT dose pre-delivery (with HIV and partum status covariates), and concentration ratios (observed infant cord blood or plasma relative to simulated maternal plasma) were calculated at the infant PK sample collection time. For RPT and desRPT, derived equilibration half-lives were 0.568 hr and 0.439 hr, and estimated concentration ratios of breast milk to maternal plasma were 0.0236 and 0.0411, respectively, indicating rapid equilibration between maternal plasma and breast milk and a minimal extent of drug excretion into breast milk. Maximum relative infant dose was estimated at <1%. Within 72 hours of maternal dosing, median concentration ratios of observed infant cord blood and plasma to predicted maternal plasma were approximately 0.280 and 0.612 for RPT and 0.493 and 1.83 for desRPT, respectively. RPT crosses the placenta and is measurable in infant plasma at concentrations unlikely to be clinically significant. Breast milk concentrations are very low, supporting safe use of RPT in breastfeeding women.

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Journal
Clinical Pharmacology & Therapeutics
Published
2026-10-15
DOI
https://doi.org/10.1002/cpt.70479
Primary Topic
Pharmaceutical studies and practices
Type
article
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article

Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Maternal Plasma and Breast Milk & Infant Cord Blood and Plasma: A Model‐Based Analysis of Mother–Infant Pairs for Tuberculosis Prevention

Tsungai Chipato, Radojka M. Savić, Amita Jain Gupta, Kelly E. Dooley et al.
Clinical Pharmacology & Therapeutics
Pharmaceutical studies and practices
article

Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Maternal Plasma and Breast Milk & Infant Cord Blood and Plasma: A Model‐Based Analysis of Mother–Infant Pairs for Tuberculosis Prevention

Tsungai Chipato, Radojka M. Savić, Amita Jain Gupta, Kelly E. Dooley, Priya Jayachandran, Stephanie Popson, Jyoti S. Mathad, Deborah Langat, Jennifer M. Norman, Vanessa Rouzier, Sandesh Patil, Lubbe Wiesner, Sarah Bradford, Amphan Chalermchockcharoenkit, Grace Montepiedra, Nan Zhang, Paula Britto, Ellen Townley, the IMPAACT 2001 Study Team
article en

Abstract

IMPAACT 2001 (NCT02651259) evaluated the safety and pharmacokinetics (PK) of once-weekly isoniazid and rifapentine in pregnant and postpartum women for tuberculosis prevention. Rifapentine (RPT) and desacetyl rifapentine (desRPT) PK data were collected in maternal plasma, breast milk, infant cord blood, and infant plasma. Longitudinal maternal plasma and breast milk RPT and desRPT concentrations were characterized using a multicompartment PK model with biophase effect compartments (NONMEM v7.4). Rate parameters describing drug entry into breast milk from plasma and breast milk-to-plasma ratio parameters were estimated. For mother-infant pairs, maternal plasma PK was simulated for the last RPT dose pre-delivery (with HIV and partum status covariates), and concentration ratios (observed infant cord blood or plasma relative to simulated maternal plasma) were calculated at the infant PK sample collection time. For RPT and desRPT, derived equilibration half-lives were 0.568 hr and 0.439 hr, and estimated concentration ratios of breast milk to maternal plasma were 0.0236 and 0.0411, respectively, indicating rapid equilibration between maternal plasma and breast milk and a minimal extent of drug excretion into breast milk. Maximum relative infant dose was estimated at <1%. Within 72 hours of maternal dosing, median concentration ratios of observed infant cord blood and plasma to predicted maternal plasma were approximately 0.280 and 0.612 for RPT and 0.493 and 1.83 for desRPT, respectively. RPT crosses the placenta and is measurable in infant plasma at concentrations unlikely to be clinically significant. Breast milk concentrations are very low, supporting safe use of RPT in breastfeeding women.

Clinical Pharmacology & Therapeutics
Family Health International 360 (US), National Institutes of Health (US), Siriraj Hospital (TH), Harvard University (US), Johns Hopkins University (US), University of Zimbabwe (ZW), University of Cape Town (ZA), University of California, San Francisco (US), B. J. Medical College & Sassoon Hospital (IN), Cornell University (US), Mahidol University (TH), United States Army Medical Research Directorate - Africa (KE), Reed Medical (United Kingdom) (GB), Center for Global Health (US), National Institute of Allergy and Infectious Diseases (US), Gheskio Centers (HT), Frontier Science & Technology Research Foundation, Inc. (US), Vanderbilt University Medical Center (US)
International Maternal Pediatric Adolescent AIDS Clinical Trials Network, National Institutes of Health, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Good health and well-being
Openalex Percentile: Top 8%
Pharmaceutical studies and practices
DOIOpen Access PDFOpenAlex
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