{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T12:25:21Z","timestamp":1774268721789,"version":"3.50.1"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["19\u2010BMGF\u2010006"],"award-info":[{"award-number":["19\u2010BMGF\u2010006"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A novel oral combination of the long\u2010acting antimalarials pyronaridine (PYR) and piperaquine (PQP) has potential for malaria chemoprevention. This single\u2010center randomized, double\u2010blind, placebo\u2010controlled study assessed the effects of PYR and PQP alone and when co\u2010administered on Fridericia\u2010corrected QT interval (QTcF). Between February 14, 2022, and May 31, 2022, thirty\u2010seven healthy black adults of African sub\u2010Saharan origin were enrolled and randomized to PYR\u2009+\u2009PQP (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200915), PYR\u2009+\u2009placebo (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098), PQP\u2009+\u2009placebo (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098) or double placebo (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20096) administered once daily (fasted) for 3\u2009days at doses approved for malaria treatment. Triplicate digitalized electrocardiogram (ECG) recordings and pharmacokinetic samples were taken at matched timepoints. Concentration\u2013response analysis was performed for QTcF changes from baseline (\u0394QTcF), and the impact of PYR, PQP, and PYR\u2009+\u2009PQP administration on placebo\u2010corrected \u0394QTcF (\u0394\u0394QTcF) was assessed. The final qualified and validated concentration\u2013QTc model included a linear component for PYR and an\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    component for PQP. The maximum predicted effect on \u0394\u0394QTcF on day 3 was +4.94\u2009msec (90% CI 0.338, 9.54) with PYR\u2009+\u2009placebo, +19.2\u2009msec (14.6, 23.8) with PQP\u2009+\u2009placebo, and\u2009+\u200923.1\u2009msec (18.5, 27.6) with PYR\u2009+\u2009PQP. As expected, PQP increased \u0394\u0394QTcF above the regulatory threshold of concern (+10\u2009msec), whereas PYR did not. The small additional increase in \u0394\u0394QTcF with PYR\u2009+\u2009PQP coadministration was explained mainly by an increase in PQP\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    (1.4\u2010fold) versus monotherapy. In healthy adults, PYR\u2009+\u2009PQP coadministration does not appear to increase significantly the effect of PQP on \u0394\u0394QTcF versus PQP administered alone. However, further studies are needed in malaria patients to confirm these findings in the target population.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    identifier: NCT05160363; EudraCT number: 2021\u2010005698\u201021\n                  <\/jats:p>","DOI":"10.1111\/cts.70305","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T12:39:03Z","timestamp":1753101543000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Concentration\u2013Response Analysis of the Combination of Pyronaridine and Piperaquine on Corrected\n                    <scp>QT<\/scp>\n                    Interval From a Randomized, Double\u2010Blind, Placebo\u2010Controlled Study in Healthy Adults of African Sub\u2010Saharan Origin"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7903-8188","authenticated-orcid":false,"given":"Mathieu","family":"Felices","sequence":"first","affiliation":[{"name":"PhinC Development  Massy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2184-562X","authenticated-orcid":false,"given":"Isabelle","family":"Borghini\u2010Fuhrer","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5912-744X","authenticated-orcid":false,"given":"Nada","family":"Abla","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9306-1851","authenticated-orcid":false,"given":"Stephan","family":"Chalon","sequence":"additional","affiliation":[{"name":"MMV Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2471\/B09146"},{"key":"e_1_2_10_3_1","volume-title":"World Malaria Report","author":"World Health Organization","year":"2024"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(23)00211-2"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-024-05128-1"},{"key":"e_1_2_10_6_1","volume-title":"Eurartesim: EPAR \u2010 Product Information","author":"Europeans Medicines 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Non\u2010Antiarrhythmic Drugs \u201d(2015) Questions & Answers (R3) International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use https:\/\/database.ich.org\/sites\/default\/files\/E14_Q%26As_R3_Q%26As.pdf."},{"key":"e_1_2_10_21_1","first-page":"335","article-title":"Die Systolendauer Im Elektrokardiogramm bei Normalen Menchen und bei Herzkranken","volume":"15","author":"Fridericia L.","year":"1920","journal-title":"Acta Medica Scandinavica"},{"key":"e_1_2_10_22_1","first-page":"353","article-title":"An Analysis of the Time\u2010Relations of Electrocardiogram","volume":"7","author":"Bazett H.","year":"1920","journal-title":"Heart"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_10_24_1","unstructured":"ICH E14\/S7B Implementation Working Group \u201cClinical and Nonclinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential \u201d(2022) Questions and Answers International 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