Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 May;111(5):1111-1120.
doi: 10.1002/cpt.2530. Epub 2022 Mar 5.

Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk

Kathleen M Job  1 , André Dallmann  2 , Samuel Parry  3 , George Saade  4 , David M Haas  5 , Brenna Hughes  6 , Pamela Berens  7 , Jia-Yu Chen  8 , Christina Fu  8 , Kelsey Humphrey  8 , Christoph Hornik  9 , Stephen Balevic  9 , Kanecia Zimmerman  9 , Kevin Watt  1
Affiliations

Development of a Generic Physiologically-Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk

Kathleen M Job et al. Clin Pharmacol Ther. 2022 May.

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.

Trial registration: ClinicalTrials.gov NCT03511118.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: Dr. André Dallmann is an employee of Bayer AG and uses Open Systems Pharmacology software, tools, and models in his professional role. All other authors declared no competing interests for this work.

Figures

Figure 1:
Figure 1:
Overview of the process for building the lactation PBPK model. The process includes four major components: 1) creation of the PBPK structure in MoBi, 2) creation of a postpartum population, 3) model simulation, and 4) model evaluation.
Figure 2:
Figure 2:
Structure of the lactation physiologically based kinetic model. Panel A) shows the compartments and processes specific to the postpartum period are drawn with dashed lines and boxes. The lactation PBPK structure includes an additional three compartments compared to a non-pregnant woman, and four less compartments (e.g., maternal/fetal placenta, fetus, and amniotic fluid) compared to a pregnant woman model. Thick arrows represent drug transport via the blood flow and thin arrows drug transport via the gastrointestinal motility or via the biliary excretion pathway via the gallbladder. Panel B) shows the structure of the breast compartment in the lactation model. A sub-compartment for milk was added to the breast compartment. Drug transfer is assumed to occur by passive diffusion between the plasma and milk sub-compartments.
Figure 3:
Figure 3:
Population PBPK model predictions of breast milk and plasma exposure following a single 4 mg IV dose of ondansetron in 1000 lactating women who were two days postpartum. Data from 55 lactating women from the CUDDLE study who received a single 4mg IV dose of ondansetron are overlayed.
Figure 4:
Figure 4:
The predicted milk (panel A) and plasma (panel B) concentrations are plotted against the observed plasma concentrations. The residuals versus time after first dose are shown for milk and plasma in panels C and D, respectively.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acevedo M, Pretini J, Micelli M, Sequeira G, Kerzberg E. Breastfeeding initiation, duration, and reasons for weaning in patients with systemic lupus erythematosus. Rheumatol Int. Jul 2017;37(7):1183–1186. doi:10.1007/s00296-017-3750-1 - DOI - PubMed
    1. Ito S, Lieu M, Chan W, Koren G. Continuing drug therapy while breastfeeding. Part 1. Common misconceptions of patients. Can Fam Physician. Apr 1999;45:897–9. - PMC - PubMed
    1. Matheson I, Kristensen K, Lunde PK. Drug utilization in breast-feeding women. A survey in Oslo. Eur J Clin Pharmacol. 1990;38(5):453–9. - PubMed
    1. Saha MR, Ryan K, Amir LH. Postpartum women’s use of medicines and breastfeeding practices: a systematic review. Int Breastfeed J. 2015;10:28. doi:10.1186/s13006-015-0053-6 - DOI - PMC - PubMed
    1. Schirm E, Schwagermann MP, Tobi H, de Jong-van den Berg LT Drug use during breastfeeding. A survey from the Netherlands. Eur J Clin Nutr. Feb 2004;58(2):386–90. doi:10.1038/sj.ejcn.1601799 - DOI - PubMed

Publication types

Associated data