{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T08:26:34Z","timestamp":1773476794547,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,4,9]],"date-time":"2024-04-09T00:00:00Z","timestamp":1712620800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Drug resistance to sulfadoxine\u2010pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria. This randomized, double\u2010blind, placebo\u2010controlled (double\u2010dummy), parallel\u2010group, single site phase I study in healthy adult males or females of Black sub\u2010Saharan African ancestry investigated the safety, tolerability, and pharmacokinetics of PYR\u2009+\u2009PQP (<jats:italic>n<\/jats:italic>\u2009=\u200915), PYR\u2009+\u2009placebo (<jats:italic>n<\/jats:italic>\u2009=\u20098), PQP\u2009+\u2009placebo (<jats:italic>n<\/jats:italic>\u2009=\u20098), and double placebo (<jats:italic>n<\/jats:italic>\u2009=\u20096) administered orally once daily for 3\u2009days at the registered dose for the treatment of uncomplicated malaria. All participants completed the study. Forty\u2010five adverse events were reported in 26 participants, most (41\/45) were mild\/moderate in severity, with no serious adverse events, deaths, or study withdrawals. Adverse events were reported in 66.7% (10\/15) of participants administered PYR\u2009+\u2009PQP, 87.5% (7\/8) with PYR\u2009+\u2009placebo, 50.0% (4\/8) with PQP\u2009+\u2009placebo, and 83.3% (5\/6) with placebo. For PYR containing regimens, five of 23 participants had asymptomatic transient increases in alanine and\/or aspartate aminotransferase. With PQP containing regimens, four of 23 participants had mild Fridericia\u2010corrected QT interval prolongation. Liver enzyme elevations and prolonged QTc interval were consistent with observations for PYR\u2010artesunate and dihydroartemisinin\u2010PQP, respectively, administered to healthy adults and malaria patients. Increases in PYR and PQP exposures were observed following co\u2010administration versus placebo, with substantial interparticipant variability. The findings suggest that PYR\u2009+\u2009PQP may have potential in chemoprevention strategies. Further studies are needed in the target populations to assess chemoprotective efficacy and define the benefit\u2013risk profile, with special considerations regarding hepatic and cardiac safety.<\/jats:p>","DOI":"10.1111\/cts.13738","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T04:15:40Z","timestamp":1712722540000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Randomized, placebo\u2010controlled, double\u2010blind phase I trial of co\u2010administered pyronaridine and piperaquine in healthy adults of <scp>sub\u2010Saharan<\/scp> origin"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-2676","authenticated-orcid":false,"given":"Andrea","family":"Kuemmerle","sequence":"first","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2704-1560","authenticated-orcid":false,"given":"Denis","family":"Gossen","sequence":"additional","affiliation":[{"name":"Mangareva SRL  Kraainem Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7426-0304","authenticated-orcid":false,"given":"Annick","family":"Janin","sequence":"additional","affiliation":[{"name":"AKJ Consulting  Divonne France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3800-7403","authenticated-orcid":false,"given":"Andrew","family":"Stokes","sequence":"additional","affiliation":[{"name":"Richmond Pharmacology Ltd.  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