Informing the risk assessment related to lactation and drug exposure: A physiologically based pharmacokinetic lactation model for pregabalin.

Breastfeeding is important in childhood development, and medications are often necessary for lactating individuals, yet information on the potential risk of infant drug exposure through human milk is limited. Establishing a lactation modeling framework can advance our understanding of this topic and potentiate clinical decision making. We expanded the modeling framework previously developed for sotalol using pregabalin as a second prototypical probe compound with similar absorption, distribution, metabolism, and elimination (ADME) properties. Adult oral models were developed in PK-Sim® and used to build a lactation model in MoBi® to simulate drug transfer into human milk. The adult model was applied to breastfeeding pediatrics (ages 1 to 23 months) and subsequently integrated with the lactation model to simulate infant drug exposure according to age, size, and breastfeeding frequency. Physiologically based pharmacokinetic (PBPK) model simulations captured the data used for verification both in adults and pediatrics. Lactation simulations captured observed milk and plasma data corresponding to doses of 150 mg administered twice daily to lactating individuals, and estimated a relative infant dose (RID) of approximately 7% of the maternal dose. The infant drug exposure simulations showed peak plasma concentrations of 0.44 µg/mL occurring within the first 2 weeks of life, followed by gradual decline with age after week four. The modeling framework performs well for this second prototypical drug and warrants expansion to other drugs for further validation. PBPK modeling and simulation approaches together with clinical lactation data could ultimately help inform infant drug exposure risk assessments to guide clinical decision making.

Food-Drug Effects and Pediatric Drug Development Studies Submitted to the US Food and Drug Administration, 2012-2022.

Food effect (FE) studies characterize food-drug interactions that may alter the efficacy or safety of a drug, but these studies are not conducted in pediatric patients. Pediatric patients have substantial physiologic, anatomic, and dietary differences from adults, which may result in differences in their FE considerations. Therefore, the objective of this study was to identify oral drug products approved for use in pediatric patients aged <6 years with an FE observed in adults. Additional objectives were to summarize the therapeutic areas, pharmacokinetic effects, and labeling instructions that resulted from these studies. Publicly available data were searched for products studied in pediatric patients and approved for use by the United States Food and Drug Administration (FDA) from 2012 to 2022. Of the 102 oral drug products approved for use in patients aged <6 years, 43 recommended the consideration of food intake in the drug labeling. These included drug products recommended to be taken with food (n = 21, 49%) or without food (n = 14, 33%). Each of the 14 drug products recommended to be taken without food are approved for use in pediatric patients aged <2 years. The products approved for use in pediatric patients aged <2 years comprised the highest proportion with area under the plasma concentration-time curve extrapolated to infinity (AUCinf, n = 35, 75%) and maximum serum concentration (Cmax, n = 45, 80%) affected by food. Close monitoring is warranted during the postapproval period for products identified as having a significant FE in adults and that are approved for use in pediatric patients aged <6 years. Promising tools for predicting pediatric FE may include physiologically based pharmacokinetic absorption modeling.

Healthcare providers' use of a concise summary to prescribe for lactating patients.

BACKGROUND: Most breastfeeding individuals take at least one prescription drug, yet limited data from lactation studies are available to inform the safety of these drugs during breastfeeding. As a result, healthcare providers (HCPs) rely on available information about safety of drugs used during pregnancy or on personal experiences to inform prescribing/counseling decisions for breastfeeding individuals. To improve risk communication regarding drugs used during lactation, the U.S. Food and Drug Administration published the Pregnancy and Lactation Labeling Rule (PLLR) in 2015, which added a narrative summary of available risk information to the lactation section of Prescribing Information (PI). Prior studies on labeling in PLLR format revealed that although HCPs found these details valuable, they regarded the narrative as too long to support decision-making during patient encounters. OBJECTIVE: This qualitative study's objective was to assess the utility of adding a concise summary to the Lactation subsection of PI to complement the narrative and succinctly communicate to busy HCPs a drug's risks when used during lactation. The concise summary consisted of a bolded headline, bulleted descriptions of available study findings and potential adverse reactions, and recommendations for risk mitigation. METHODS: Twenty-five online focus groups were conducted with five segments of HCPs to obtain their feedback on the concise summary and discuss their prescribing/counseling decisions for four fictitious prescription drugs including one vaccine. RESULTS: HCPs utilized the concise summary to make initial prescribing/counseling decisions. Many also used the labeling narrative for a comprehensive benefit-risk assessment. CONCLUSION: The findings indicate a need to continue to improve communication about safety of drugs used during lactation, and that the concise summary may help facilitate this communication. The study also highlights the need to educate HCPs about PI limitations when clinical data are lacking and the need to encourage clinical studies to be conducted to support actionable recommendations about use of prescription drugs during lactation.

Obesity Considerations in Pediatric Drug Development, 2016-2021.

Pediatric obesity is a global public health concern. Obesity-related physiological changes may affect the pharmacokinetics of drugs and lead to therapeutic failure or toxicities. An earlier review of pediatric drug development programs from 2007 to 2016 found that, of 89 programs listing obesity-related terms, only 4 (4%) products described pharmacokinetic changes associated with obesity. This review examined obesity considerations for 185 drug products for which pediatric drug development programs were submitted to the US Food and Drug Administration (FDA) between 2016 and 2021. The FDA-authored review documents and drug product labeling were queried for obesity-related terms and the review found 97/185 (52%) drug products had obesity-related terms in these sources. Of the 97 drug products, 55/97 (57%) had obesity-related terms in the FDA-authored reviews only, 13/97 (13%) had obesity-related terms in the drug product labeling only, and 29/97 (30%) had obesity-related terms in both FDA-authored reviews and drug product labeling. Most of the obesity-related information in the drug product labeling originated from data collected from adults. Only 13/185 (7%) drug product labeling contained obesity-related terms in reference to drug pharmacokinetics. Specific dosage recommendations for the use of the drug products in pediatric patients who are obese remain lacking. The dearth of available information to guide drug dosages in the obese pediatric population suggests that further research, innovative approaches, and evidence-based guidelines are needed to inform the optimal therapeutic use of drugs in this population.

Need for Representation of Pediatric Patients with Obesity in Clinical Trials.

Clinical trials are an integral aspect of drug development. Tremendous progress has been made in ensuring drug products are effective and safe for use in the intended pediatric population, but there remains a paucity of information to guide drug dosages in pediatric patients with obesity. This is concerning because obesity may influence the disposition of drug products. When pediatric patients with obesity are not enrolled in clinical trials, dosing options for use in this subpopulation may be suboptimal. Reliance on physiological-based dosing strategies that are not informed by evaluation of the pharmacokinetics of the drug product could lead to under- or over-dosing with ensuing therapeutic failure or toxicity consequences. Thus, representation of pediatric patients with obesity in clinical trials is crucial to understand the benefit-risk profile of drug products in this subpopulation. It is important to acknowledge that this is a challenging endeavor, but not one that is insurmountable. Collective efforts from multiple stakeholders including drug developers and regulators to enhance diversity in clinical trials can help fill critical gaps in knowledge related to the influence of obesity on drug disposition.

Informing a Comprehensive Risk Assessment of Infant Drug Exposure From Human Milk: Application of a Physiologically Based Pharmacokinetic Lactation Model for Sotalol.

Characterization of infant drug exposure through human milk is important and underexplored. Because infant plasma concentrations are not frequently collected in clinical lactation studies, modeling and simulation approaches can integrate physiology, available milk concentrations, and pediatric data to inform exposure in breastfeeding infants. A physiologically based pharmacokinetic model was built for sotalol, a renally eliminated drug, to simulate infant drug exposure from human milk. Intravenous and oral adult models were built, optimized, and scaled to an oral pediatric model for a breastfeeding-relevant age group (<2 years). Model simulations captured the data that were put aside for verification. The resulting pediatric model was applied to predict the impacts of sex, infant body size, breastfeeding frequency, age, and maternal dose (240 and 433 mg) on drug exposure during breastfeeding. Simulations suggest a minimal effect of sex or frequency on total sotalol exposure. Infants in the 90th percentile in height and weight have predicted exposures ≈20% higher than infants of the same age in the 10th percentile due to increased milk intake. The simulated infant exposures increase throughout the first 2 weeks of life and are maintained at the highest concentrations in weeks 2-4, with a consistent decrease observed as infants age. Simulations suggest that breastfeeding infants will have plasma concentrations in the lower range observed in infants administered sotalol. With further validation on additional drugs, physiologically based pharmacokinetic modeling approaches could use lactation data to a greater extent and provide comprehensive information to support decisions regarding medication use during breastfeeding.

Pediatric Efficacy Extrapolation in Drug Development Submitted to the US Food and Drug Administration 2015-2020.

Pediatric extrapolation plays a key role in the availability of reliable pediatric use information in approved drug labeling. This review examined the use of pediatric extrapolation in studies submitted to the US Food and Drug Administration and assessed changes in extrapolation approaches over time. Pediatric studies of 125 drugs submitted to the US Food and Drug Administration that led to subsequent pediatric information in drug labeling between 2015 and 2020 were reviewed. The use of pediatric extrapolation for each drug was identified and categorized as "complete," "partial," or "no" extrapolation. Approaches to pediatric extrapolation of efficacy changed over time. Complete extrapolation of efficacy was the predominantly used approach. "Complete," "partial," or "no" extrapolation was used for 51%, 23%, and 26% of the drugs, respectively. This represents a shift in extrapolation approaches when compared to a previous study that evaluated pediatrics drug applications between 2009 and 2014, which found complete, partial, or no extrapolation was used for 34%, 29%, and 37% of the drugs, respectively. Pediatric extrapolation approaches may continue to shift as emerging science fills gap in knowledge of the fundamental assumptions underlying this scientific tool. The international community continues to collaborate on discussions of pediatric extrapolation of efficacy from adults and other pediatric subpopulations to optimize its use for pediatric drug development.