Work

Parent-metabolite PBPK model of methotrexate to inform pediatric extrapolation, transporter-mediated drug–drug interactions, and renal impairment

Year: 2026

Type: article

Abstract: Methotrexate (MTX) is widely used in treating chronic inflammatory diseases and in chemotherapy for both adult and pediatric patients. Its pharmacokinetics are complex, as MTX is a substrate of multiple transporters. Particularly during high-dose chemotherapeutic use, it is associated with severe toxicities including reversible kidney impairment and hematological toxicity. Physiologically based pharmacokinetic (PBPK) modeling offers a mechanistic approach to predict drug pharmacokinetics and guide dosing, especially in pediatric applications where clinical data is limited. A whole-body parent-metabolite PBPK model of MTX and 7-hydroxymethotrexate was developed in PK-Sim ® (version 12.1) for intravenous and oral administration in adults and children. Model development used 42 MTX and 16 metabolite plasma concentration-time profiles and showed strong predictive performance, with 53/58 area under the plasma concentration-time curve and 38/39 maximum plasma concentration values within a 2-fold range of observed data. Pediatric extrapolation incorporating transporter ontogeny yielded adequate predictions. Drug-drug interaction simulations for five perpetrator drugs met established acceptance criteria, and renal impairment simulations revealed markedly increased exposure in the high-dose setting. The model will be made publicly available to support dose optimization across clinical scenarios.

Source: Scientific Reports

DOI: 10.1038/s41598-026-77381-0