{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "Charlotte Maria Ursula Dette"
    },
    {
      "name": "Fatima Zahra Marok"
    },
    {
      "name": "Veronika Alberg"
    },
    {
      "name": "Christiane Dings"
    },
    {
      "name": "Dominik Selzer"
    },
    {
      "name": "Matthias Schwab"
    },
    {
      "name": "Barbara Faganel Kotnik"
    },
    {
      "name": "Vita Dolžan"
    },
    {
      "name": "Daniela Yildiz"
    },
    {
      "name": "Jörg Bittenbring"
    },
    {
      "name": "Marc Remke"
    },
    {
      "name": "Thorsten Lehr",
      "orcid": "0000-0002-8372-1465"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b0mvb7be46dgq.bib",
  "cited_by": 0,
  "doi": "10.1038/s41598-026-77381-0",
  "fulltext_url": null,
  "id": "b0mvb7be46dgq",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://www.nature.com/articles/s41598-026-77381-0",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2735|Pharmaceutical studies and practices"
    ]
  ],
  "openalex": "W7225416160",
  "pdf_url": "https://www.nature.com/articles/s41598-026-77381-0.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-07",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/b0mvb7be46dgq.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:20:25Z",
      "native_id": "10.1038/s41598-026-77381-0",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41598-026-77381-0"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2735|Pharmaceutical studies and practices",
      "subfield": "reproductive-child"
    }
  ],
  "title": "Parent-metabolite PBPK model of methotrexate to inform pediatric extrapolation, transporter-mediated drug–drug interactions, and renal impairment",
  "title_text": "Parent-metabolite PBPK model of methotrexate to inform pediatric extrapolation, transporter-mediated drug–drug interactions, and renal impairment",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T00:20:23Z",
  "url": "https://research.draconitic.com/paper/b0mvb7be46dgq",
  "venue": "Scientific Reports",
  "versions": []
}