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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-6993</article-id>
      <article-id pub-id-type="doi">10.51847/8YU49A2ne4</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>When Learned Dose Predictions Conflict with Pharmacological Knowledge: A Theoretical Framework for Reconciling Artificial Intelligence with Mechanistic Pharmacokinetics</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Novak</surname>
                <given-names>Peter</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Haddad</surname>
                <given-names>Leila</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Nilsson</surname>
                <given-names>Johan</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Bello</surname>
                <given-names>Aisha</given-names>
              </name>
                              <xref rid="aff4" ref-type="aff">4</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Clinical Pharmacology and AI-Based Dosing, Charles University, Prague, Czech Republic.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Pharmacokinetics and Therapeutic Drug Monitoring, American University of Beirut, Beirut, Lebanon.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Clinical Pharmacy and Pharmacodynamics, Uppsala University, Uppsala, Sweden.
          </aff>
                  <aff id="aff4">
            <label>4</label>Department of Pharmaceutical Care and Precision Dosing, University of Lagos, Lagos, Nigeria.
          </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="peter.novak@cuni.cz">peter.novak@cuni.cz</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>10</month>
        <year>2026</year>
      </pub-date>
      <volume>17</volume>
      <issue>5</issue>
      <fpage>103</fpage>
      <lpage>111</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>Artificial intelligence is increasingly capable of generating patient-specific predictions of drug exposure, response, or dose requirements, while pharmacokinetic and pharmacodynamic models provide mechanistically structured estimates derived from drug disposition, exposure–response relationships, prior population information, and patient covariates. These approaches need not converge. Their disagreement creates a clinically important problem because superior retrospective prediction does not necessarily identify the more credible dose for an individual patient, whereas mechanistic plausibility does not guarantee that a model remains applicable when physiology, treatment context, or population characteristics depart from its assumptions. This theoretical reconciliation article examines how such conflicts should be interpreted when learned predictions, mechanistic PK/PD expectations, and therapeutic drug monitoring provide partially overlapping but non-equivalent information. The central argument is that no modality should receive automatic priority. Disagreement should first be diagnosed according to its likely source, including covariate representation, training-support limitations, model-form uncertainty, population transportability, changing patient biology, target definition, or measurement quality. Reconciliation should then depend on the provenance, clinical relevance, temporal proximity, and validation status of the competing evidence. Therapeutic drug monitoring becomes particularly important when valid patient-linked observations can discriminate among previously plausible predictions, but its evidentiary weight depends on sampling informativeness, analytical validity, and the exposure or response target being estimated. The resulting framework treats concordant, discordant, and unresolved states as provisional clinical states subject to monitoring and revision. Dose selection therefore becomes an evidence-updating process rather than a contest between artificial intelligence and pharmacological mechanism.</p>
      </abstract>
      <kwd-group>
                <kwd>Machine learning</kwd>
                <kwd>Model-informed precision dosing</kwd>
                <kwd>Pharmacokinetics</kwd>
                <kwd>Pharmacodynamics</kwd>
                <kwd>Therapeutic drug monitoring</kwd>
                <kwd>Dose reconciliation</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>
