{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:27:57Z","timestamp":1772162877528,"version":"3.50.1"},"reference-count":26,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"DHAC | National Health and Medical Research Council","award":["1196068"],"award-info":[{"award-number":["1196068"]}]},{"name":"DHAC | National Health and Medical Research Council","award":["2016396"],"award-info":[{"award-number":["2016396"]}]},{"DOI":"10.13039\/100020687","name":"Australian Centre of Research Excellence in Malaria Elimination","doi-asserted-by":"crossref","award":["2024622"],"award-info":[{"award-number":["2024622"]}],"id":[{"id":"10.13039\/100020687","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DHAC | National Health and Medical Research Council","award":["2018654"],"award-info":[{"award-number":["2018654"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,9,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>The rise of multidrug-resistant malaria requires accelerated development of novel antimalarial drugs. Pharmacokinetic\u2013pharmacodynamic (PK-PD) models relate blood antimalarial drug concentrations with the parasite\u2013time profile to inform dosing regimens. We performed a simulation study to assess the utility of a Bayesian hierarchical mechanistic PK-PD model for predicting parasite\u2013time profiles for a Phase 2 study of a new antimalarial drug, cipargamin. We simulated cipargamin concentration- and malaria parasite-profiles based on a Phase 2 study of eight volunteers who received cipargamin 7 days after inoculation with malaria parasites. The cipargamin profiles were generated from a two-compartment PK model and parasite profiles from a previously published biologically informed PD model. One thousand PK-PD data sets of eight patients were simulated, following the sampling intervals of the Phase 2 study. The mechanistic PK-PD model was incorporated in a Bayesian hierarchical framework, and the parameters were estimated. Population PK model parameters describing absorption, distribution, and clearance were estimated with minimal bias (mean relative bias ranged from 1.7% to 8.4%). The PD model was fitted to the parasitaemia profiles in each simulated data set using the estimated PK parameters. Posterior predictive checks demonstrate that our PK-PD model adequately captures the simulated PD profiles. The bias of the estimated population average PD parameters was low\u2013moderate in magnitude. This simulation study demonstrates the viability of our PK-PD model to predict parasitological outcomes in Phase 2 volunteer infection studies. This work will inform the dose\u2013effect relationship of cipargamin, guiding decisions on dosing regimens to be evaluated in Phase 3 trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00863-24","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T09:02:24Z","timestamp":1723539744000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of a Bayesian hierarchical pharmacokinetic\u2013pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5560-4345","authenticated-orcid":true,"given":"Meg K.","family":"Tully","sequence":"first","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4613-3672","authenticated-orcid":true,"given":"Saber","family":"Dini","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8809-726X","authenticated-orcid":false,"given":"Jennifer A.","family":"Flegg","sequence":"additional","affiliation":[{"name":"School of Mathematics and Statistics, The University of Melbourne, Melbourne, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-9718","authenticated-orcid":true,"given":"James S.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The University of Melbourne, at the Peter Doherty Institute for Infection &amp; Immunity, Melbourne, Australia"},{"name":"Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia"},{"name":"Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0076-3123","authenticated-orcid":false,"given":"David J.","family":"Price","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia"},{"name":"Department of Infectious Diseases, The University of Melbourne, at the Peter Doherty Institute for Infection &amp; Immunity, Melbourne, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2660-2013","authenticated-orcid":false,"given":"Julie A.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia"},{"name":"Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1314981"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2101746"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1005-2"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51015"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009133"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.16-0234"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2786"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01659-21"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2020.101765"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab716"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-021-04009-1"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1315860"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01423-20"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00479-17"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-014-9647-y"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab181"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02346-20"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.85"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-11-143"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-411"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-statistics-040522-015915"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1006113108"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-11-303"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz557"},{"key":"e_1_3_3_27_2","unstructured":"Stan Development Team. 2021. Stan modeling language users guide and reference manual. Version 2.21.0. https:\/\/mc-stan.org."},{"key":"e_1_3_3_28_2","unstructured":"R Core Team. 2021. R: a language and environment for statistical computing. Version 4.1.1. 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