Julia Macente1, Nina Nauwelaerts1, Justine Marine Badée2, Rodolfo Hernandes Bonan3, Miao-Chan Huang1, Martje Van Neste1,4, Anne Smits4,5,6, Karel Allegaert1,4,5,7, Frederico Severino Martins8, Pieter Annaert1,3
1KU Leuven, 2Pharmacokinetic Sciences BioMedical Research, Novartis , 3BioNotus CommV, 4Clinical Pharmacology and Pharmacotherapy, Child & Youth Institute, KU Leuven , 5Department of Development and Regeneration, KU Leuven, 6Neonatal intensive care unit, University Hospitals, 7Department of Hospital Pharmacy, Erasmus University Medical Center, 8Faculty of Pharmaceutical Sciences, Universidade de São Paulo
Objectives: Breastfeeding women still face the challenge of balancing necessary medical treatment while breastfeeding, despite the lack of information regarding pediatric systemic exposure and potential safety risks [1].Lactation PBPK models can support risk assessment by providing information on maternal drug exposure during lactation, estimating the milk-to-plasma (M/P) ratio of maternal medication, and predicting the potential systemic exposure of infants to drugs through human milk [2–4]. This work is part of the Innovative Medicines Initiative (IMI) project ConcePTION, which aims to generate a non-clinical testing platform to determine drug transfer into human milk and subsequent infant exposure. While this platform relies on non-clinical and computational methodologies (i.e., in vivo animal studies, in vitro experiments, and in silico modeling), the predicted outcomes are clinically relevant (e.g., concentration-time profiles of drugs in maternal blood and human milk). Lactation PBPK models have been developed applying semi-mechanistic relying on drug physicochemical properties [5] (e.g., Koshimichi model [6]) to estimate the bidirectional clearances between plasma and milk. The aim of the present study was to evaluate the performance of lactation PBPK models, by integrating bidirectional in vitro permeability coefficients recently measured from in vitro blood milk barrier model. Methods: Five physico-chemically small molecules exhibiting different elimination pathways and with available clinical lactation data in literature (plasma and human milk) were selected to investigate drug transfer into human milk and assess potential exposure risk to breastfed infants: amoxicillin, caffeine, cetirizine, levetiracetam, and nevirapine. First, for each drug, a PBPK model for adult healthy volunteers (HV) was developed, adapted or re-built based on literature data using Simcyp V24 software. Second, the verified adult HV model was used to establish lactation PBPK model, reflecting the lactation physiology of postpartum women. To ensure a standardized approach and for feasibility reasons, lactation PBPK models were developed and evaluated for lactating women at three months postpartum. The permeability rate-limited model within the Simcyp built-in lactation module was adjusted to adequately map or describe the two-compartment breast model (plasma-milk). In vitro bidirectional permeability coefficients (Papp) across the human mammary epithelial cells previously determined [7] for each drug were used to parametrize the drug transfer from plasma into human milk. Intrinsic bidirectional (secretion and reuptake) clearances were calculated for each drug by multiplying the Papp value by the calculated in vivo total surface area of 1.20 m² for the mammary tissues [8]. Passive drug diffusion was assumed to be driven by the total unbound and unionized drug permeating through the blood-milk barrier. The fraction unbound in human whole milk (fumilk) was calculated using the multiple Emax algorithm [9]. Additionally, drug removal from the milk compartment was accounted for by the infant daily milk intake. For each simulation, the administration protocol was adapted to the clinical study design (e.g., dose, route and regimen) reported in literature. The performance of the lactation PBPK models was evaluated by visual inspection of the predicted plasma and human milk concentration over time profiles against clinical data available in the literature. Furthermore, the M/P ratio within 2-fold margin of the clinical observed values were evaluated. PBPK simulations at steady state were carried out to predict the M/P ratio of each drug and to estimate the daily infant dosage (DID, mg/kg/day) based on the predicted human milk average concentration at steady state. For safety risk assessment purposes, two scenarios were considered: i) a daily milk intake of 150 mL/kg/day and ii) an assumed daily milk intake of 200 mL/kg/day [10]. Subsequently, the DID was compared with the maternal dosage to evaluate the relative infant dose (RID, %). Additionally, to assess drug intake during the breastfeeding period, a comparison between the estimated daily infant dosage and the daily therapeutic dosage of the drug in infants when available, can be evaluated for risk assessment by calculating the relative therapeutic infant dose. Results: The PBPK models adequately captured the plasma concentration-time profiles as well as the primary PK parameters (i.e., Cmax and AUC) in healthy adult volunteers after single/multiple intravenous and oral administrations at different dose levels, within a 2-fold range of the observed clinical data used for model development and qualification purposes. This suggests that the PBPK model is qualified as a base model for establishing a lactation PBPK model for lactating women. To account for the difference between in vivo effective permeability and in vitro permeability, a scaling factor (SF) was applied for each compound (SF=25 for amoxicillin, cetirizine and levetiracetam and SF=5 for nevirapine and caffeine). The drug removal from the milk compartment was calculated to be 0.03 L/h for all drugs. The predicted M/P ratios were within a 2-fold margin to the reported values in the literature for all drugs, and most of the in vivo human milk concentration from observed clinical data were within the 90% confidence interval of the predictions. The estimated daily doses received by the breastfed infant were lower than the maternal doses (RID, <10%). When available, the estimated dose was compared to the recommended pediatric dose used for therapeutic reasons, the results revealed that the estimated DIDs represented less than 25% of the recommended infant dosing. Conclusion: The PBPK models presented herein adequately describe the plasma concentration profiles for five small molecules. The lactation PBPK models were able to capture human milk profiles and predict the M/P ratios, as compared to clinical reports, using an in vitro permeability model across the blood-milk barrier and applying a scaling factor enabling the estimation of DID and RID. The estimated RID remained below 10% for all drugs. Future work aims apply this workflow to 11 drugs selected in the context of the IMI ConcePTION project and to further integrate the maternal PBPK models with infant PBPK models to assess relative infant exposure. Acknowledgement: This work has received support from the EU/EFPIA (Innovative Medicines initiative). Joint Undertaking ConcePTION grant No. 821520. The research leading to these Results was conducted as part of the ConcePTION consortium. This abstract only reflects the personal views of the stated authors. Nina Nauwelaerts also received a PhD scholarship by Research-Foundation-Flanders (1S50721N). The research activities of Anne Smits are supported by a Senior Clinical Investigatorship of the Research Foundation – Flanders (FWO) (18E2H24N).
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Reference: PAGE 33 (2025) Abstr 11556 [www.page-meeting.org/?abstract=11556]
Poster: Drug/Disease Modelling - Other Topics