{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:41:11Z","timestamp":1781264471055,"version":"3.54.1"},"reference-count":50,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:p>Atovaquone\u2010proguanil (ATV\u2010PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine\u2010pyrimethamine plus AQ for seasonal malaria chemoprevention in African children. This randomized, double\u2010blind, placebo\u2010controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PKs) of ATV\u2010PG plus AQ in healthy adult males and females of Black sub\u2010Saharan African origin. Participants were randomized to four treatment groups: ATV\u2010PG\/AQ (<jats:italic>n<\/jats:italic>\u00a0=\u00a08), ATV\u2010PG\/placebo (<jats:italic>n<\/jats:italic>\u00a0=\u00a012), AQ\/placebo (<jats:italic>n<\/jats:italic>\u00a0=\u00a012), and placebo\/placebo (<jats:italic>n<\/jats:italic>\u00a0=\u00a012). Treatments were administered orally once daily for 3\u00a0days (days 1\u20133) at daily doses of ATV\u2010PQ 1000\/400\u00a0mg and AQ 612\u00a0mg. Co\u2010administration of ATV\u2010PG\/AQ had no clinically relevant effect on PK parameters for ATV, PG, the PG metabolite cycloguanil, AQ, or the AQ metabolite N\u2010desethyl\u2010amodiaquine. Adverse events occurred in 8 of 8 (100%) of participants receiving ATV\u2010PG\/AQ, 11 of 12 (91.7%) receiving ATV\u2010PG, 11 of 12 (91.7%) receiving AQ, and 3 of 12 (25%) receiving placebo. The safety and tolerability profiles of ATV\u2010PG and AQ were consistent with previous reports. In the ATV\u2010PG\/AQ group, 2 of 8 participants experienced extrapyramidal adverse effects (EPAEs) on day 3, both psychiatric and physical, which appeared unrelated to drug plasma PKs or cytochrome P450 2C8 phenotype. Although rare cases are reported with AQ administration, the high incidence of EPAE was unexpected in this small study. Owing to the unanticipated increased frequency of EPAE observed, the combination of ATV\u2010PQ plus AQ is not recommended for further evaluation in prophylaxis of malaria in African children.<\/jats:p>","DOI":"10.1002\/cpt.2404","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T08:44:38Z","timestamp":1630140278000},"page":"867-877","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unanticipated CNS Safety Signal in a Placebo\u2010Controlled, Randomized Trial of Co\u2010Administered Atovaquone\u2010Proguanil and Amodiaquine"],"prefix":"10.1111","volume":"111","author":[{"given":"Stephan","family":"Chalon","sequence":"first","affiliation":[{"name":"Medicines for Malaria Venture Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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