<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD with MathML3 v1.3 20210610//EN" "JATS-archivearticle1-3-mathml3.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"
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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-6962</article-id>
      <article-id pub-id-type="doi">10.51847/6EVLCmJXCz</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Release Profiles Do Not Equal Therapeutic Performance in Controlled, Responsive, and Long-Acting Drug-Delivery Systems</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Mertens</surname>
                <given-names>Johan</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Dubois</surname>
                <given-names>Sylvie</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>De Smet</surname>
                <given-names>Pieter</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Wouters</surname>
                <given-names>Lukas</given-names>
              </name>
                              <xref rid="aff4" ref-type="aff">4</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Drug Delivery and Therapeutic Performance, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Release Profiles and Controlled Delivery, Faculty of Pharmacy, University of Lille, Lille, France.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Responsive and Long-Acting Drug-Delivery Systems, Faculty of Pharmacy, Wageningen University, Wageningen, Netherlands.
          </aff>
                  <aff id="aff4">
            <label>4</label>Department of Beyond-Release Therapeutic Modeling, Faculty of Pharmacy, University of Antwerp, Antwerp, Belgium.
          </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="johan.mertens@ugent">johan.mertens@ugent</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>06</month>
        <year>2026</year>
      </pub-date>
      <volume>16</volume>
      <issue>3</issue>
      <fpage>75</fpage>
      <lpage>85</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>Controlled, responsive, and long-acting drug-delivery systems are commonly evaluated through cumulative release curves, release-rate constants, burst fractions, or apparent duration of liberation. These measurements are indispensable for formulation characterization, yet they do not independently establish local exposure, systemic pharmacokinetics, biological response, therapeutic durability, safety, or clinical usefulness. This article develops an original drug-release theory to address the unresolved tendency to treat release performance as a surrogate for therapeutic performance. The proposed Release-to-Performance Coupling Theory organizes delivery-system behavior into linked but non-equivalent domains: assay-conditioned drug liberation, evolving depot state, material transformation, tissue transport, local and systemic exposure, biological response, and context-specific therapeutic performance. It further identifies physiological context and uncertainty as cross-cutting modifiers of every transition. The theory distinguishes analytical validity from biological relevance, correlation from mechanism, simulated exposure from prospective usefulness, and sustained drug presence from sustained therapeutic benefit. It also explains why formulations with similar cumulative release profiles may produce different exposure and response trajectories, whereas formulations with dissimilar in-vitro profiles may occasionally converge in vivo through compensating transport or disposition processes. The proposed construct is intended to guide mechanistic evaluation, model development, evidence integration, and formulation design rather than to function as a validated predictive model or regulatory decision rule. Its applicability is conditional on delivery platform, administration site, drug properties, disease state, biological trigger, and intended decision. Reframing release as one component of a multiscale performance chain may improve the design of biorelevant tests, computational models, responsive systems, and translation strategies while reducing unsupported claims based on cumulative release curves alone.</p>
      </abstract>
      <kwd-group>
                <kwd>Controlled release</kwd>
                <kwd>Long-acting injectables</kwd>
                <kwd>Responsive drug delivery</kwd>
                <kwd>Depot evolution</kwd>
                <kwd>Local pharmacokinetics</kwd>
                <kwd>Systemic exposure</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>