Fawaz Mzayek, Haiyan Deng, Frances J Mather, Elizabeth C Wasilevich, Huayin Liu, Christiane M Hadi, David H Chansolme, Holly A Murphy, Bekir H Melek, Alan N Tenaglia, David M Mushatt, Albert W Dreisbach, Juan J L Lertora, Donald J Krogstad
{"title":"Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers.","authors":"Fawaz Mzayek, Haiyan Deng, Frances J Mather, Elizabeth C Wasilevich, Huayin Liu, Christiane M Hadi, David H Chansolme, Holly A Murphy, Bekir H Melek, Alan N Tenaglia, David M Mushatt, Albert W Dreisbach, Juan J L Lertora, Donald J Krogstad","doi":"10.1371/journal.pctr.0020006","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug-resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans.</p><p><strong>Design: </strong>Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose.</p><p><strong>Setting: </strong>Tulane-Louisiana State University-Charity Hospital General Clinical Research Center in New Orleans.</p><p><strong>Participants: </strong>126 healthy adults 21-45 years of age.</p><p><strong>Interventions: </strong>10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13.</p><p><strong>Outcome measures: </strong>Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation.</p><p><strong>Results: </strong>No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract-related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0-14.7 l/h versus 9.5-11.3 l/h; p < or = 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ.</p><p><strong>Conclusions: </strong>These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.</p>","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2007-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1764434/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS clinical trials","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1371/journal.pctr.0020006","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Objectives: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug-resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans.
Design: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose.
Setting: Tulane-Louisiana State University-Charity Hospital General Clinical Research Center in New Orleans.
Participants: 126 healthy adults 21-45 years of age.
Interventions: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13.
Outcome measures: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation.
Results: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract-related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0-14.7 l/h versus 9.5-11.3 l/h; p < or = 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ.
Conclusions: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.
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