Physiologically-based Pharmacokinetics modelling to predict the systemic exposure of medicines in infants via breastmilk: a contribution from the ConcePTION Project.
Julia Macente (1), Nina Nauwelaerts (1), Justine Marine Badée (2), Miao- Chan Huang (1), Rodolfo Hernandes Bonan (3), Martje Van Neste (1), Karel Allegaert (1), Frederico Severino Martins (4), Pieter Annaert (1,3).
KU Leuven, Leuven Belgium1, Novartis Institutes for BioMedical Research, Basel, Switzerland 2, BioNotus3, State University of Maringa 4.
Objectives:
For ethical premises, the voluntary and unnecessary exposure of vulnerable patients, such as lactating women and their breastfed infants, is generally avoided. Physiologically-based Pharmacokinetic (PBPK) appears to be a very useful tool to predict the concentrations of medicines in human milk during the lactation phase, as well as to estimate the milk-to-plasma (M/P) ratio of maternal medication, and subsequently, the systemic exposure in infants[2]–[4]. This work is part of the Innovative medicines initiative (IMI) research consortium and project ConcePTION, with the main goal to reduce uncertainty about the use of medication during pregnancy and breastfeeding. The aim of this study was to develop and evaluate the performance of lactation and infant PBPK to determine the infant (28 days to 3 months old) systemic exposure to maternally administered amoxicillin (AMX) and levetiracetam (LEV) via human milk.
Methods:
First, a PBPK model for adult healthy volunteers (HV) was developed (or re-built from literature[5]) and evaluated for LEV and AMX using Simcyp v21 software. The verified adult HV model was scaled to infants using the Sim-paediatrics population, accounting for the physiological changes, ontogeny functions and values regarding the age dependency of anthropometrics (e.g., weight and height) within the SimCYP. Once the predictions for infants were verified ,the models were exploited to predict the systemic exposure of medicines via breastfeeding after the maternal use of the medication. The daily infant dose (DID) received via breastfeeding was calculated from the lactation PBPK models developed using both Simcyp and PK-Sim (deliverable submitted), assuming the maximally reported maternal dose regimen administered. The DID was calculated based on both the maximum (Cmax, milk) and average (Cave, milk) predicted concentration in human milk. The estimated milk volume intake was assumed to equal 150 mL/kg/day, An alternative volume (200 mL/kg/day) was also considered based on the higher milk intake in early infancy [6] was considered. Next, simulations at steady-state were carried out for a virtual infant population with the estimated dose per feed (DID/6 feedings per day). Infant over maternal plasma AUC ratio was used to evaluate the relative infant exposure (RIE).
Results:
The PBPK models established for AMX and LEV were qualified as a base model to extrapolate the PBPK model to infants. The infant PBPK model presented a good prediction compared with observed clinical data. GMFE values for AMX were 1.18 for AUC and 1.26 for Cmax. For LEV, the AUC and Cmax ratio were 1.42 and 0.95 , respectively . The predicted over observed AUC and Cmax ratio were within 2-fold for both medicines.
For AMX, the simulated infant concentration Cave,ss ranged from 0.12 to 0.27 mg/L. The AMX RIE was in the range of 1.27% to 3.86% for milk intake of 150-200 mL/kg/day.
For LEV, the simulated infant concentration Cave,ss ranged from 4.87 to 9.54 mg/L. The LEV RIE was in the range of 4.57% to 8.95% for milk intake of 150-200 mL/kg/day. The results obtained for LEV are in line with literature report (infant serum averaged 14% of the maternal serum levels).[7]
Systemic infant exposure of AMX and LEV were less than 10% compared to the maternal exposure (maximum relative infant exposure was 3.86% for AMX and 8.95% for LEV).
Conclusions:
The herein presented PBPK models adequately describe the plasma PK of AMX and LEV in adults, including milk concentrations in lactating women. The developed PBPK models for infants showed a good prediction of the PK parameters. Infant systemic plasma exposure simulations revealed a low (<10%) exposure compared to the maternal exposure. These results suggest a reasonable safety margin for the use of these medicines by mothers during breastfeeding. However, possible age-dependent differences in susceptibility to toxic effects need to be considered and case by case judgment is required . This workflow will be applied to 10 additional medicines selected in the context of the IMI ConcePTION project.
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.
References:
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