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There are either concerns about unacceptable adverse effects such as neuropsychiatric sequalae (mefloquine), risks of hemolysis in patients with G6PD deficiency (8\u2010aminoquinolines such as tafenoquine), or cost and daily dosing (atovaquone\u2013proguanil). Therefore, there is a need to develop new chemoprophylactic agents to provide more affordable therapies with better compliance through improving properties such as pharmacokinetics to allow weekly, preferably monthly, dosing. Here we present a pharmacokinetic\u2013pharmacodynamic (PKPD) model constructed using DSM265 (a dihydroorotate dehydrogenase inhibitor with activity against the liver schizonts of malaria, therefore, a prophylaxis candidate). The PKPD model mimics the parasite lifecycle by describing parasite dynamics and drug activity during the liver and blood stages. A major challenge is the estimation of model parameters, as only blood\u2010stage parasites can be observed once they have reached a threshold. By combining qualitative and quantitative knowledge about the parasite from various sources, it has been shown that it is possible to infer information about liver\u2010stage growth and its initial infection level. Furthermore, by integrating clinical data, the killing effect of the drug on liver\u2010 and blood\u2010stage parasites can be included in the PKPD model, and a clinical outcome can be predicted. Despite multiple challenges, the presented model has the potential to help translation from preclinical to late development for new chemoprophylactic candidates.<\/jats:p>","DOI":"10.1002\/psp4.12875","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T11:52:04Z","timestamp":1669117924000},"page":"50-61","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A pharmacokinetic\u2013pharmacodynamic model for chemoprotective agents against malaria"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9630-3863","authenticated-orcid":false,"given":"Mohammed H.","family":"Cherkaoui\u2010Rbati","sequence":"first","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Andenmatten","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Burgert","sequence":"additional","affiliation":[{"name":"University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5636-4642","authenticated-orcid":false,"given":"Oluwaseun F.","family":"Egbelowo","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine The University of Texas at Austin  Texas Austin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Fendel","sequence":"additional","affiliation":[{"name":"Institute for Tropical Medicine University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9334-8513","authenticated-orcid":false,"given":"Chiara","family":"Fornari","sequence":"additional","affiliation":[{"name":"AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gabel","sequence":"additional","affiliation":[{"name":"Center for Modelling and Simulation in the Biosciences, BioQuant\u2010Center University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Mathematical Sciences University of Loughborough  Loughborough UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg J.","family":"M\u00f6hrle","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Gobeau","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.30875\/f309483f-en"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(13)60024\u20100"},{"key":"e_1_2_10_4_1","unstructured":"UNITAID.Unitaid project evaluation: Achieving Catalytic Expansion of Seasonal Malaria Chemoprevention in the Sahel (ACCESS\u2013SMC) \u2013 Final Report.2017;63https:\/\/unitaid.eu\/assets\/ACCESS\u2010SMC\u2010Midterm\u2010evaluation\u2010report\u2010June2017.pdf"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.4274\/tpd.galenos.2021.54264"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-187"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-016-1675-x"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(90)90258-G"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92587"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30171-8"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30139-1"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix613"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30309-8"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005255"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa6645"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004670"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00524"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/26.4.404"}],"container-title":["CPT: Pharmacometrics &amp; 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