{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T08:43:11Z","timestamp":1794040991064,"version":"4.8.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"abstract":"<jats:title>Abstract\n<\/jats:title><jats:sec>\n                <jats:title>Background\n<\/jats:title>\n                <jats:p>The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with <jats:italic>Plasmodium falciparum<\/jats:italic>-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42\u2009\u00b1\u20092. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>For a dose of 800\u00a0mg artefenomel administered with 640\u00a0mg, 960\u00a0mg, or 1440\u00a0mg piperaquine, the simulated adequate parasitological response at day 28 (APR<jats:sub>28<\/jats:sub>), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR<jats:sub>28<\/jats:sub> in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>This study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12916-024-03787-0","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T11:06:29Z","timestamp":1732791989000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria"],"prefix":"10.1186","volume":"22","author":[{"given":"Azrin N.","family":"Abd-Rahman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kaschek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"K\u00fcmmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Webster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Potter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Odedra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Woolley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Llewellyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lachlan","family":"Webb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Marquart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Chalon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam El","family":"Gaaloul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg J.","family":"M\u00f6hrle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget E.","family":"Barber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,28]]},"reference":[{"issue":"5","key":"3787_CR1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.pt.2009.02.002","volume":"25","author":"MR Galinski","year":"2009","unstructured":"Galinski MR, Barnwell JW. 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