Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk
Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologicall...
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| Vydáno v: | Clinical pharmacology and therapeutics Ročník 111; číslo 5; s. 1111 |
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| Hlavní autoři: | , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.05.2022
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| ISSN: | 1532-6535, 1532-6535 |
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| Abstract | Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologically-based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure. Drug-specific model inputs were parameterized using data from the literature. Population-specific inputs were derived from a previously conducted systematic literature review of anatomic and physiologic changes in postpartum women. Model predictions were evaluated using ondansetron plasma and breast milk concentration data collected prospectively from 78 women in the Commonly Used Drugs During Lactation and infant Exposure (CUDDLE) study. The final model predicted breast milk and plasma exposures following a single 4 mg dose of intravenous ondansetron in 1,000 simulated women who were 2 days postpartum. Model predictions showed good agreement with observed data. Breast milk median prediction error (MPE) was 18.4% and median absolute prediction error (MAPE) was 53.0%. Plasma MPE was 32.5% and MAPE was 43.2%. The model-predicted daily and relative infant doses were 0.005 mg/kg/day and 3.0%, respectively. This model adequately predicted ondansetron passage into breast milk. The calculated low relative infant dose indicates that mothers receiving ondansetron can safely breastfeed. The model building blocks and population database are open-source and can be adapted to other drugs. |
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| AbstractList | Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologically-based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure. Drug-specific model inputs were parameterized using data from the literature. Population-specific inputs were derived from a previously conducted systematic literature review of anatomic and physiologic changes in postpartum women. Model predictions were evaluated using ondansetron plasma and breast milk concentration data collected prospectively from 78 women in the Commonly Used Drugs During Lactation and infant Exposure (CUDDLE) study. The final model predicted breast milk and plasma exposures following a single 4 mg dose of intravenous ondansetron in 1,000 simulated women who were 2 days postpartum. Model predictions showed good agreement with observed data. Breast milk median prediction error (MPE) was 18.4% and median absolute prediction error (MAPE) was 53.0%. Plasma MPE was 32.5% and MAPE was 43.2%. The model-predicted daily and relative infant doses were 0.005 mg/kg/day and 3.0%, respectively. This model adequately predicted ondansetron passage into breast milk. The calculated low relative infant dose indicates that mothers receiving ondansetron can safely breastfeed. The model building blocks and population database are open-source and can be adapted to other drugs. Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologically-based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure. Drug-specific model inputs were parameterized using data from the literature. Population-specific inputs were derived from a previously conducted systematic literature review of anatomic and physiologic changes in postpartum women. Model predictions were evaluated using ondansetron plasma and breast milk concentration data collected prospectively from 78 women in the Commonly Used Drugs During Lactation and infant Exposure (CUDDLE) study. The final model predicted breast milk and plasma exposures following a single 4 mg dose of intravenous ondansetron in 1,000 simulated women who were 2 days postpartum. Model predictions showed good agreement with observed data. Breast milk median prediction error (MPE) was 18.4% and median absolute prediction error (MAPE) was 53.0%. Plasma MPE was 32.5% and MAPE was 43.2%. The model-predicted daily and relative infant doses were 0.005 mg/kg/day and 3.0%, respectively. This model adequately predicted ondansetron passage into breast milk. The calculated low relative infant dose indicates that mothers receiving ondansetron can safely breastfeed. The model building blocks and population database are open-source and can be adapted to other drugs.Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologically-based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure. Drug-specific model inputs were parameterized using data from the literature. Population-specific inputs were derived from a previously conducted systematic literature review of anatomic and physiologic changes in postpartum women. Model predictions were evaluated using ondansetron plasma and breast milk concentration data collected prospectively from 78 women in the Commonly Used Drugs During Lactation and infant Exposure (CUDDLE) study. The final model predicted breast milk and plasma exposures following a single 4 mg dose of intravenous ondansetron in 1,000 simulated women who were 2 days postpartum. Model predictions showed good agreement with observed data. Breast milk median prediction error (MPE) was 18.4% and median absolute prediction error (MAPE) was 53.0%. Plasma MPE was 32.5% and MAPE was 43.2%. The model-predicted daily and relative infant doses were 0.005 mg/kg/day and 3.0%, respectively. This model adequately predicted ondansetron passage into breast milk. The calculated low relative infant dose indicates that mothers receiving ondansetron can safely breastfeed. The model building blocks and population database are open-source and can be adapted to other drugs. |
| Author | Job, Kathleen M Balevic, Stephen Berens, Pamela Humphrey, Kelsey Zimmerman, Kanecia Saade, George Hughes, Brenna Dallmann, André Hornik, Christoph Parry, Samuel Watt, Kevin Haas, David M Chen, Jia-Yu Fu, Christina |
| Author_xml | – sequence: 1 givenname: Kathleen M surname: Job fullname: Job, Kathleen M organization: Division of Clinical Pharmacology, Department of Pediatrics, The University of Utah, Salt Lake City, Utah, USA – sequence: 2 givenname: André surname: Dallmann fullname: Dallmann, André organization: Pharmacometrics/Modeling & Simulation, Research & Development, Bayer AG, Leverkusen, Germany – sequence: 3 givenname: Samuel surname: Parry fullname: Parry, Samuel organization: Division of Maternal-Fetal Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 4 givenname: George surname: Saade fullname: Saade, George organization: University of Texas Medical Branch-Galveston, Galveston, Texas, USA – sequence: 5 givenname: David M surname: Haas fullname: Haas, David M organization: Indiana University School of Medicine, Indianapolis, Indiana, USA – sequence: 6 givenname: Brenna surname: Hughes fullname: Hughes, Brenna organization: Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina, USA – sequence: 7 givenname: Pamela surname: Berens fullname: Berens, Pamela organization: McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA – sequence: 8 givenname: Jia-Yu surname: Chen fullname: Chen, Jia-Yu organization: The Emmes Company, LLC, Rockville, Maryland, USA – sequence: 9 givenname: Christina surname: Fu fullname: Fu, Christina organization: The Emmes Company, LLC, Rockville, Maryland, USA – sequence: 10 givenname: Kelsey surname: Humphrey fullname: Humphrey, Kelsey organization: The Emmes Company, LLC, Rockville, Maryland, USA – sequence: 11 givenname: Christoph surname: Hornik fullname: Hornik, Christoph organization: Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA – sequence: 12 givenname: Stephen surname: Balevic fullname: Balevic, Stephen organization: Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA – sequence: 13 givenname: Kanecia surname: Zimmerman fullname: Zimmerman, Kanecia organization: Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA – sequence: 14 givenname: Kevin surname: Watt fullname: Watt, Kevin organization: Division of Clinical Pharmacology, Department of Pediatrics, The University of Utah, Salt Lake City, Utah, USA |
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| SubjectTerms | Breast Feeding Female Humans Infant Lactation Milk, Human Ondansetron - adverse effects Postpartum Period |
| Title | Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk |
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