{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T20:08:02Z","timestamp":1779394082451,"version":"3.53.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0012078","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000}}],"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union Seventh Framework Programme Africoleish","award":["305178"],"award-info":[{"award-number":["305178"]}]},{"name":"WHO-Special Programme for Research and Training in Tropical Diseases"},{"DOI":"10.13039\/501100011061","name":"Agence Fran\u00e7aise de D\u00e9veloppement","doi-asserted-by":"publisher","award":["CZZ2062"],"award-info":[{"award-number":["CZZ2062"]}],"id":[{"id":"10.13039\/501100011061","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UK aid"},{"name":"Federal Ministry of Education and Research (BMBF) through KfW"},{"DOI":"10.13039\/100008196","name":"M\u00e9decins Sans Fronti\u00e8res","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009131","name":"Swiss Agency for Development and Cooperation","doi-asserted-by":"crossref","award":["81017718 and 642.33\/2010\/0779\/02 NID"],"award-info":[{"award-number":["81017718 and 642.33\/2010\/0779\/02 NID"]}],"id":[{"id":"10.13039\/100009131","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007729","name":"Dutch Ministry of Foreign Affairs","doi-asserted-by":"crossref","award":["PDP15CH21"],"award-info":[{"award-number":["PDP15CH21"]}],"id":[{"id":"10.13039\/501100007729","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004892","name":"Spanish Agency for International Development Cooperation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004892","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ZonMw\/Dutch Research Council (NWO) Veni grant","award":["project no. 91617140"],"award-info":[{"award-number":["project no. 91617140"]}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["VR 2022-01251"],"award-info":[{"award-number":["VR 2022-01251"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating<jats:italic>Leishmania<\/jats:italic>parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study.<jats:italic>Leishmania<\/jats:italic>kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>Parasite proliferation was best described by an exponential growth model, with an<jats:italic>in vivo<\/jats:italic>parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an E<jats:sub>max<\/jats:sub>model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusion<\/jats:title><jats:p>This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pntd.0012078","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T17:28:27Z","timestamp":1713547707000},"page":"e0012078","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokinetic-pharmacodynamic model"],"prefix":"10.1371","volume":"18","author":[{"given":"Luka","family":"Verrest","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9verine","family":"Monnerat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Musa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Mbui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eltahir A. G.","family":"Khalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Olobo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Wasunna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Yu","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin D. R.","family":"Huitema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk D. F. H.","family":"Schallig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-8435","authenticated-orcid":true,"given":"Thomas P. C.","family":"Dorlo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"pntd.0012078.ref001","first-page":"1","article-title":"Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.","author":"M Wasunna","year":"2016","journal-title":"PLoS Negl Trop Dis."},{"issue":"9","key":"pntd.0012078.ref002","doi-asserted-by":"crossref","DOI":"10.1093\/cid\/ciy747","article-title":"Pharmacokinetics, Safety, and Efficacy of an Allometric Miltefosine Regimen for the Treatment of Visceral Leishmaniasis in Eastern African Children: An Open-label, Phase II Clinical Trial","volume":"68","author":"J Mbui","year":"2019","journal-title":"Clinical Infectious Diseases"},{"key":"pntd.0012078.ref003","article-title":"Paromomycin and Miltefosine Combination as an Alternative to Treat Patients with Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial","author":"AM Musa","year":"2022","journal-title":"Clinical Infectious Diseases"},{"issue":"11","key":"pntd.0012078.ref004","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1093\/cid\/cit102","article-title":"Increasing failure of miltefosine in the treatment of kala-azar in nepal and the potential role of parasite drug resistance, reinfection, or noncompliance","volume":"56","author":"S Rijal","year":"2013","journal-title":"Clinical Infectious Diseases"},{"issue":"6","key":"pntd.0012078.ref005","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0000705","article-title":"Visceral leishmaniasis relapse in Southern Sudan (1999\u20132007): A retrospective study of risk factors and trends.","volume":"4","author":"S Gorski","year":"2010","journal-title":"PLoS Negl Trop Dis."},{"key":"pntd.0012078.ref006","first-page":"951","volume-title":"The Lancet","author":"S Burza","year":"2018"},{"key":"pntd.0012078.ref007","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1093\/infdis\/173.4.1041","article-title":"Models of Relapse of Experimental Visceral Leishmaniasis.","volume":"173","author":"HW Murray","year":"1996","journal-title":"The Journal oflnfectious Diseases"},{"issue":"9","key":"pntd.0012078.ref008","article-title":"Visceral Leishmaniasis in Ethiopia: An Evolving Disease.","volume":"8","author":"S Leta","year":"2014","journal-title":"PLoS One."},{"issue":"3","key":"pntd.0012078.ref009","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s12288-010-0027-1","article-title":"Hematologic changes in visceral Leishmaniasis\/Kala Azar","volume":"26","author":"N Varma","year":"2010","journal-title":"Indian Journal of Hematology and Blood Transfusion"},{"issue":"1","key":"pntd.0012078.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13071-016-1412-x","article-title":"Regulation of immunity during visceral Leishmania infection","volume":"9","author":"V Rodrigues","year":"2016","journal-title":"Parasit Vectors"},{"issue":"5","key":"pntd.0012078.ref011","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1093\/cid\/ciab124","article-title":"Blood Parasite Load as an Early Marker to Predict Treatment Response in Visceral Leishmaniasis in Eastern Africa","volume":"73","author":"L Verrest","year":"2021","journal-title":"Clinical Infectious Diseases"},{"issue":"4","key":"pntd.0012078.ref012","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1128\/JCM.42.4.1858.2004","article-title":"Erratum: Real-Time PCR Assay for Clinical Management of Human Immunodeficiency Virus-Infected Patients with Visceral Leishmaniasis","volume":"42","author":"S Bossolasco","year":"2004","journal-title":"J Clin Microbiol"},{"key":"pntd.0012078.ref013","first-page":"109","article-title":"Polymerase chain reaction in the diagnosis and prognosis of Mediterranean visceral leishmaniasis in immunocompetent children","author":"A Cascio","year":"2002","journal-title":"Pediatrics"},{"key":"pntd.0012078.ref014","doi-asserted-by":"crossref","first-page":"S185","DOI":"10.1016\/S0035-9203(02)90074-X","article-title":"A nested polymerase chain reaction (Ln-PCR) for diagnosing and monitoring Leishmania infantum infection in patients co-infected with human immunodeficiency virus.","volume":"96","author":"I Cruz","year":"2002","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"3","key":"pntd.0012078.ref015","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.actatropica.2004.08.002","article-title":"Rapid clearance of circulating Leishmania kinetoplast DNA after treatment of visceral leishmaniasis","volume":"92","author":"J Disch","year":"2004","journal-title":"Acta Trop"},{"key":"pntd.0012078.ref016","doi-asserted-by":"crossref","first-page":"S191","DOI":"10.1016\/S0035-9203(02)90075-1","article-title":"A nested polymerase chain reaction for diagnosis and follow-up of human visceral leishmaniasis patients using blood samples","volume":"96","author":"R Fisa","year":"2002","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"1","key":"pntd.0012078.ref017","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.04298-14","article-title":"Vries PJ De, Dorlo TPC. Systematic Review of Biomarkers To Monitor Therapeutic Response in","volume":"59","author":"AE Kip","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pntd.0012078.ref018","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1128\/JCM.38.1.236-240.2000","article-title":"Optimized PCR using patient blood samples for diagnosis and follow-up of visceral leishmaniasis, with special reference to AIDS patients","volume":"38","author":"L Lachaud","year":"2000","journal-title":"J Clin Microbiol"},{"issue":"5","key":"pntd.0012078.ref019","doi-asserted-by":"crossref","first-page":"858","DOI":"10.4269\/ajtmh.2006.75.858","article-title":"Reference values for Leishmania infantum parasitemia in different clinical presentations: Quantitative polymerase chain reaction for therapeutic monitoring and patient follow-up","volume":"75","author":"C Mary","year":"2006","journal-title":"American Journal of Tropical Medicine and Hygiene"},{"issue":"11","key":"pntd.0012078.ref020","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.1128\/JCM.42.11.5249-5255.2004","article-title":"Quantification of Leishmania infantum DNA by a real-time PCR assay with high sensitivity","volume":"42","author":"C Mary","year":"2004","journal-title":"J Clin Microbiol"},{"issue":"3","key":"pntd.0012078.ref021","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1093\/infdis\/171.3.751","article-title":"Diagnosis of symptomatic visceral leishmaniasis by use of the polymerase chain reaction on patient blood","volume":"171","author":"E Nuzum","year":"1995","journal-title":"Journal of Infectious Diseases"},{"issue":"1","key":"pntd.0012078.ref022","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1128\/JCM.39.1.357-361.2001","article-title":"Role of PCR in Diagnosis and Prognosis of Visceral Leishmaniasis in Patients Coinfected with Human Immunodeficiency Virus Type 1","volume":"39","author":"M Pizzuto","year":"2001","journal-title":"J Clin Microbiol"},{"issue":"8","key":"pntd.0012078.ref023","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1093\/jac\/dkr185","article-title":"Study of parasite kinetics with antileishmanial drugs using real-time quantitative PCR in Indian visceral leishmaniasis","volume":"66","author":"M Sudarshan","year":"2011","journal-title":"Journal of Antimicrobial Chemotherapy"},{"key":"pntd.0012078.ref024","article-title":"Exploring prognosis in chronic relapsing visceral leishmaniasis among HIV-infected patients: Circulating Leishmania DNA","volume":"172","author":"GF Cota","year":"2017","journal-title":"Acta Trop"},{"issue":"5","key":"pntd.0012078.ref025","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1002\/cpt.1893","article-title":"Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study","volume":"108","author":"AN Abd-Rahman","year":"2020","journal-title":"Clin Pharmacol Ther"},{"key":"pntd.0012078.ref026","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1111\/bcp.12962","article-title":"Pharmacokinetic\/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an induced blood stage malaria study in healthy subjects","author":"A Krause","year":"2016","journal-title":"Br J Clin Pharmacol"},{"issue":"4","key":"pntd.0012078.ref027","doi-asserted-by":"crossref","first-page":"e01583","DOI":"10.1128\/AAC.01583-20","article-title":"Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria","volume":"65","author":"T Wattanakul","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"issue":"8","key":"pntd.0012078.ref028","doi-asserted-by":"crossref","DOI":"10.1038\/psp.2014.29","article-title":"Population pharmacokinetics and antimalarial pharmacodynamics of piperaquine in patients with Plasmodium vivax Malaria in Thailand.","volume":"3","author":"J Tarning","year":"2014","journal-title":"CPT Pharmacometrics Syst Pharmacol."},{"key":"pntd.0012078.ref029","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1093\/jac\/dkaa314","article-title":"Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa","volume":"75","author":"S Palic","year":"2020","journal-title":"J Antimicrob Chemother"},{"issue":"1\u20132","key":"pntd.0012078.ref030","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jchromb.2008.02.005","article-title":"Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry","volume":"865","author":"TPC Dorlo","year":"2008","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"pntd.0012078.ref031","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s40262-014-0136-3","article-title":"Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies.","volume":"53","author":"A. Tarral","year":"2014","journal-title":"Clin Pharmacokinet"},{"issue":"3","key":"pntd.0012078.ref032","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1128\/AAC.46.3.834-840.2002","article-title":"Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate.","volume":"46","author":"I Bekersky","year":"2002","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pntd.0012078.ref033","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0035-9203(88)90267-2","article-title":"Pharmacokinetics of antimony during treatment of visceral leishmaniasis with sodium stibogluconate or meglumine antimoniate","volume":"82","author":"JD Chulay","year":"1988","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"4","key":"pntd.0012078.ref034","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1086\/510860","article-title":"Pharmacokinetics of antimony in children treated for leishmaniasis with meglumine antimoniate","volume":"195","author":"A Cruz","year":"2007","journal-title":"Journal of Infectious Diseases"},{"issue":"6","key":"pntd.0012078.ref035","doi-asserted-by":"crossref","first-page":"3524","DOI":"10.1128\/AAC.01781-15","article-title":"A Replicative In Vitro Assay for Drug Discovery against Leishmania donovani","volume":"60","author":"D Tegazzini","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"pntd.0012078.ref036","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/BF00928929","article-title":"Leishmania donovani: In vitro culture and [1H] NMR characterization of amastigote-like forms","volume":"142","author":"JJ Castilla","year":"1995","journal-title":"Mol Cell Biochem"},{"issue":"11","key":"pntd.0012078.ref037","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1093\/jac\/dkx283","article-title":"Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: A population pharmacokinetic\/pharmacodynamic study","volume":"72","author":"TPC Dorlo","year":"2017","journal-title":"Journal of Antimicrobial Chemotherapy"},{"issue":"11","key":"pntd.0012078.ref038","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1093\/cid\/cit102","article-title":"Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance","volume":"56","author":"S Rijal","year":"2013","journal-title":"Clin Infect Dis"},{"issue":"6","key":"pntd.0012078.ref039","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1084\/jem.167.6.1927","article-title":"The dynamics of granuloma formation in experimental visceral leishmaniasis","volume":"167","author":"MJ McElrath","year":"1988","journal-title":"Journal of Experimental Medicine"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0012078","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012078","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T17:31:39Z","timestamp":1731778299000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012078"}},"subtitle":[],"editor":[{"given":"Helen P.","family":"Price","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,4,19]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0012078","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0012078","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,19]]}}}