Exploring the Knowledge Gaps in Infant Drug Exposure From Human Milk: A Clinical Pharmacology Perspective

Guinn, Daphne; Pressly, Michelle; Liu, Zhichao; Ceresa, C.; Samuels, Sherbet; Wang, Yow‐Ming; Madabushi, Rajanikanth; Schmidt, Stephan; Fletcher, Elimika Pfuma

doi:10.1002/jcph.2177

Cited by 5 publications

(2 citation statements)

References 9 publications

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“…RID is the percent of the weight‐adjusted maternal dosage consumed in breast milk over 24 hours and is calculated by dividing the infant dosage (mg/kg/day) by the maternal dosage (mg/kg/day), which is then multiplied by 100 9 . Although no consensus has been reached, a common paradigm in literature is that drugs with a RID of <10% are generally considered safe, whereas drugs with a RID of 10%‐25% should be used with caution, and those with a RID >25% are likely unsafe 34 . However, further consideration is needed to ensure the applicability of these risk categories, which were developed decades ago across various medications.…”

Section: Discussionmentioning

confidence: 99%

“…9 Although no consensus has been reached, a common paradigm in literature is that drugs with a RID of <10% are generally considered safe, whereas drugs with a RID of 10%-25% should be used with caution, and those with a RID >25% are likely unsafe. 34 However, further consideration is needed to ensure the applicability of these risk categories, which were developed decades ago across various medications. In certain situations, such as antineoplastic medications, there may be a concern for infant toxicity at exposures <10% RID.…”

Section: Study Design and Data Analysismentioning

confidence: 99%

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Clinical Lactation Studies of Neuropsychiatric Medications: Clinical Pharmacology and Labeling Considerations

Nallani,

Baisden,

Dinatale

et al. 2023

The Journal of Clinical Pharma

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The availability of clinical pharmacology and safety data regarding the use of prescription medications in pregnant and lactating individuals has been historically limited, despite significant efforts to improve the quantity and quality of the information in labeling. The Food and Drug Administration's (FDA) Pregnancy and Lactation Labeling Rule took effect on June 30, 2015, and updated information in labeling to more clearly describe available data to assist health care providers in counseling pregnant and lactating individuals. Additionally, the FDA published a revised draft guidance, “Clinical Lactation Studies: Considerations for Study Design,” to provide pharmaceutical companies and investigators with information about how and when to conduct lactation studies. Clinical pharmacology information derived from lactation studies is important in determining the presence of medications in breast milk and counseling lactating individuals regarding the potential of medication exposure in the breast milk and its attendant risks to the breastfed infant. Examples of Pregnancy and Lactation Labeling Rule labeling changes that resulted from dedicated clinical lactation studies for certain neuropsychiatric medications are described in this publication. These medications are discussed because neuropsychiatric conditions commonly affect women of reproductive potential, including lactating individuals. As the FDA guidance and these studies illustrate, bioanalytical method validation, study design, and data analysis considerations are essential for obtaining quality lactation data. Well‐designed clinical lactation studies play an important role in informing product labeling that ultimately is useful to health care providers in making prescribing decisions with lactating individuals.

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Section: Discussionmentioning

confidence: 99%

Section: Study Design and Data Analysismentioning

confidence: 99%

Clinical Lactation Studies of Neuropsychiatric Medications: Clinical Pharmacology and Labeling Considerations

Nallani,

Baisden,

Dinatale

et al. 2023

The Journal of Clinical Pharma

View full text Add to dashboard Cite

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Dose Optimization Informed by PBPK Modeling: State‐of‐the Art and Future

Rowland Yeo,

Gil Berglund,

Chen

2024

Clin Pharma and Therapeutics

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Model‐informed drug development (MIDD) is a powerful quantitative approach that plays an integral role in drug development and regulatory review. While applied throughout the life cycle of the development of new drugs, a key application of MIDD is to inform clinical trial design including dose selection and optimization. To date, physiologically‐based pharmacokinetic (PBPK) modeling, an established component of the MIDD toolkit, has mainly been used for assessment of drug–drug interactions (DDIs) and consequential dose adjustments in regulatory submissions. As a result of recent scientific advances and growing confidence in the utility of the approach, PBPK models are being increasingly applied to provide dose recommendations for subjects with differing ages, genetics, and disease states. In this review, we present our perspective on the current landscape of regulatory acceptance of PBPK applications supported by relevant case studies. We also discuss the recent progress and future challenges associated with expanding the utility of PBPK models into emerging areas for regulatory decision making, especially dose optimization in highly vulnerable and understudied populations and facilitating diversity in clinical trials.

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Transfer of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women

Kaufmann,

Muehlan,

Anliker‐Ort

et al. 2024

The Journal of Clinical Pharma

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The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post‐marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects.This single‐center, open‐label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre‐dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated.All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies.Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded.

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Exploring the Knowledge Gaps in Infant Drug Exposure From Human Milk: A Clinical Pharmacology Perspective

Cited by 5 publications

References 9 publications

Clinical Lactation Studies of Neuropsychiatric Medications: Clinical Pharmacology and Labeling Considerations

Clinical Lactation Studies of Neuropsychiatric Medications: Clinical Pharmacology and Labeling Considerations

Dose Optimization Informed by PBPK Modeling: State‐of‐the Art and Future

Transfer of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women

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