Clinical lactation studies and the role of pharmacokinetic modeling and simulation in predicting drug exposures in breas
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REVIEW PAPER
Clinical lactation studies and the role of pharmacokinetic modeling and simulation in predicting drug exposures in breastfed infants Philip O. Anderson1 • Jeremiah D. Momper1 Received: 3 December 2019 / Accepted: 27 January 2020 Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The relative lack of information on medication use during breastfeeding is an ongoing problem for health professionals and mothers alike. Most nursing mothers are prescribed some form of medication, yet some mothers either discontinue breastfeeding or avoid medications entirely. Although regulatory authorities have proposed a framework for clinical lactation studies, data on drug passage into breastmilk are often lacking. Model-based approaches can potentially be used to estimate the passage of drugs into milk, predict exposures in breastfed infants, and identify drugs that need clinical lactation studies. When a human study is called for, measurement of the drug concentration in milk are often adequate to characterize safety. Data from these studies can be leveraged to further refine pharmacokinetic models with subsequent Monte Carlo simulations to estimate the spread of exposure values. Both clinical lactation studies and model-based approaches have some limitations and pitfalls which are discussed. Keywords Breastfeeding Human milk Lactation Pharmacokinetic modeling
Introduction Benefits of breastfeeding for the infant are widely recognized and well documented (Table 1) [1, 2]. Less well recognized are the substantial benefits that accrue to the nursing mother (Table 2) [3–5]. A cost analysis found that if United States breastfeeding rates could be increased to 90% compliance with the recommendations of pediatric and obstetric guidelines would save $9.2 billion in total infant healthcare costs and 721 infant deaths annually, mostly from sudden infant death syndrome and necrotizing enterocolitis. Surprisingly, maternal cost benefits for breastfeeding for 4 or more months are even greater at $12 trillion annually. These saving include $7 trillion/year in premature deaths and $2.4 trillion/year in medical costs. Additionally, 3,340 excess maternal deaths/year could be avoided, mainly from decreases in myocardial infarction, breast cancer and
diabetes [6]. Similar calculations have found large savings internationally [7]. Regulatory authorities have proposed a framework for pre- and post-marketing clinical lactation studies, yet data on drug passage into breastmilk for individual drugs are often lacking and human studies are difficult to conduct for a variety of logistical and practical reasons. Modeling and simulation-based approaches may help bridge this knowledge gap by predicting drug exposures in breastfed infants. The objectives of this review are to (1) describe the landscape of medication use during breastfeeding and approaches to clinical lactation studies, and (2) outline the role for pharmacokinetic modeling and simulation in leveraging available data to predict systemic drug expos
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