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  <front>
    <journal-meta>
      <journal-id journal-id-type="iso-abbrev">Pharmacophore</journal-id>
      <journal-id journal-id-type="publisher-id">pharmacophorejournal.com</journal-id>
      <journal-id journal-id-type="publisher-id">Pharmacophore</journal-id>
      <journal-title-group>
        <journal-title>Pharmacophore</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2229-5402</issn>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">pharmacophorejournal.com-6938</article-id>
      <article-id pub-id-type="doi">10.51847/XWR5pHgaUT</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Counterfactual Dosing with Causal Digital Twins under Patient Heterogeneity, Disease Evolution, and Time-Varying Treatment Response</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Collins</surname>
                <given-names>Grace</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Evans</surname>
                <given-names>Oliver</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Williams</surname>
                <given-names>Noah</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Brooks</surname>
                <given-names>Ethan</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Counterfactual Dosing and Causal Digital Twins, Faculty of Pharmacy, University of Sydney, Sydney, Australia.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Patient Heterogeneity and Disease Evolution, Faculty of Pharmacy, University of Queensland, Brisbane, Australia.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Time-Varying Treatment Response Modeling, Faculty of Pharmacy, University of Melbourne, Melbourne, Australia.
          </aff>
                          <author-notes>
            <corresp id="cor1">
              <bold>Address for correspondence:</bold> Prof. Wael Abu Dayyih, Department of
              Pharmaceutical Chemistry, Faculty of Pharmacy, Mutah University, Al-Karak 61710, Jordan.
                              E-mail: <email xlink:href="grace.collins@sydney.edu.au">grace.collins@sydney.edu.au</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>08</month>
        <year>2026</year>
      </pub-date>
      <volume>17</volume>
      <issue>4</issue>
      <fpage>83</fpage>
      <lpage>92</lpage>
      <permissions>
        <copyright-statement>
          Copyright: &#x000a9; 2026 Pharmacophore
        </copyright-statement>
        <copyright-year>2026</copyright-year>
        <license>
          <ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/"
            specific-use="textmining" content-type="ccbyncsalicense">
            https://creativecommons.org/licenses/by-nc-sa/4.0/</ali:license_ref>
          <license-p>This is an open access journal, and articles are distributed under the terms of
            the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
            others to remix, tweak, and build upon the work non-commercially, as long as appropriate
            credit is given and the new creations are licensed under the identical terms.</license-p>
        </license>
      </permissions>
      <abstract>
        <title>A<sc>BSTRACT</sc></title>
        <p>Individualized dosing is commonly framed as the selection of a dose that best predicts exposure, biomarker response, efficacy, or toxicity for a particular patient. That framing is incomplete when treatment decisions alter subsequent physiology, disease state, adherence, monitoring, and future treatment allocation. In such settings, the clinically relevant question is not merely what outcome is likely under the observed dose, but how the same patient might evolve under alternative feasible dose histories. This article proposes a causal dose twin: a conceptual treatment-simulation model that combines longitudinal causal structure, treatment-history representation, mechanistic pharmacokinetic–pharmacodynamic and disease models, sequential patient-state updating, and safety-constrained counterfactual comparison. The proposed architecture distinguishes prediction from causal estimation, observed response from treatment effect, prescribed dose from realized exposure, and model confidence from decision-relevant uncertainty. It treats patient heterogeneity as dynamic rather than fixed and represents disease progression, adherence, organ-function change, co-interventions, and monitoring as components that can alter both future response and future treatment. Counterfactual dose strategies are therefore evaluated as trajectories rather than isolated actions. The article further argues that validation must be matched to context of use and must include causal identification, state reconstruction, pharmacological adequacy, uncertainty calibration, transportability, safety behavior, and governance. The causal dose twin is presented as an original methodological synthesis, not as an empirically validated dosing system. Its usefulness is conditional on defensible causal assumptions, adequate longitudinal data, drug- and disease-specific mechanistic knowledge, clinically meaningful constraints, and accountable human authorization. The framework provides a research structure for moving individualized dosing beyond descriptive personalization toward bounded comparison of alternative treatment histories.</p>
      </abstract>
      <kwd-group>
                <kwd>Causal digital twin</kwd>
                <kwd>Individualized dosing</kwd>
                <kwd>Counterfactual treatment</kwd>
                <kwd>Time-varying confounding</kwd>
                <kwd>Pharmacometrics</kwd>
                <kwd>Disease evolution</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>