{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:09:24Z","timestamp":1789042164640,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,7]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Praziquantel (PZQ) is the only widely available chemotherapy that is effective against all species of schistosomes. Environmental enteric dysfunction (EED) is an acquired intestinal disorder of altered gut function whose effect on drug pharmacokinetics has not been directly explored.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Preschool-age children infected with\n                    <jats:italic>S. mansoni<\/jats:italic>\n                    were randomized to receive 40mg\/kg or 80mg\/kg of crushed PZQ tablets. Plasma PZQ concentrations were quantified using ultra-high performance liquid chromatography mass spectrometry. Maximum concentration (C\n                    <jats:sub>max<\/jats:sub>\n                    ), time to C\n                    <jats:sub>max<\/jats:sub>\n                    (T\n                    <jats:sub>max<\/jats:sub>\n                    ) and area under the curve (AUC) of PZQ were calculated. Biomarkers of intestinal inflammation (stool calprotectin), epithelial damage (plasma Intestinal Fatty Acid Binding Protein (IFABP)), permeability (urine lactulose:mannitol (LM) ratio and alpha-1 antitrypsin (AAT)), microbial translocation (plasma Endotoxin core antibodies (EndoCAb), systemic inflammation (plasma C-reactive protein (CRP)), and presence of faecal occult blood (FOB) were measured. Using linear regression, we assessed association of AUC, C\n                    <jats:sub>max<\/jats:sub>\n                    , T\n                    <jats:sub>max<\/jats:sub>\n                    and R- to S-PZQ exposure with each biomarker, adjusting for dose, age, and sex.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Of the 184 participants included in the final analysis, 91 received 40mg\/kg and 93 received 80mg\/kg of PZQ. The T\n                    <jats:sub>max<\/jats:sub>\n                    was associated with LM ratio (\u03b2=0.06, 95% CI 0.02 \u2013 0.11, p=0.003) and calprotectin (\u03b2=0.001, 0.0002 \u2013 0.002, p=0.013). CRP was associated with AUC (\u03b2=0.13, 95% CI 0.06 \u2013 0.21, p=0.001) and C\n                    <jats:sub>max<\/jats:sub>\n                    (\u03b2=0.12, 95% CI 0.05 \u2013 0.21, p=0.002). Calprotectin (\u03b2=0.12, 95% CI 0.04 - 0.20, p=0.003) and AAT (\u03b2=0.09, 95% CI 0.02 \u2013 0.15, p=0.008) were associated with a higher R-PZQ\/S-PZQ AUC ratio, while CRP was not (p=0.38).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    Elevated intestinal inflammatory markers were associated with increased T\n                    <jats:sub>max<\/jats:sub>\n                    , indicating reduced rate of absorption and relative increase in exposure to the active R-enantiomer. Systemic inflammation was associated with higher C\n                    <jats:sub>max<\/jats:sub>\n                    and AUC, implying increased exposure to PZQ. This is the first report linking alterations in praziquantel pharmacokinetics to EED markers and systemic inflammation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Author summary<\/jats:title>\n                  <jats:p>Schistosomiasis, also known as bilharzia, affects approximately 240 million people in 79 countries with children in Africa bearing almost 50% of the burden. Praziquantel (PZQ), an oral drug, is the only widely available treatment for the disease. However, some studies have reported differences in pharmacokinetics and efficacy of PZQ across geographical locations suggesting environmental factors to affect drug response. We hypothesized that environmental enteric dysfunction, a disorder of altered intestinal function, may affect absorption and metabolism of PZQ because of the damage it inflicts on the intestinal mucosa, and subsequent systemic inflammation due to leakage of intestinal contents, a process referred to as \u201cmicrobial translocation\u201d. Our findings indicate that markers of intestinal inflammation were associated with reduced rate of absorption while systemic inflammation was associated with increased plasma concentrations and overall exposure to PZQ. The reduced rate of absorption may result from destruction of the intestinal absorptive surface while increased plasma concentration and exposure may be due to reduced activity of PZQ-metabolizing enzymes in the liver. These observations could inform approaches for optimizing the effectiveness of PZQ by accounting for inflammation. This has implications for the use of PZQ as an effective control strategy and subsequent elimination of schistosomiasis by 2030, in line with World Health Organization targets.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.02.26362031","type":"posted-content","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:23:39Z","timestamp":1788841419000},"source":"Crossref","is-referenced-by-count":0,"title":["Markers of environmental enteric dysfunction are associated with changes in pharmacokinetics of praziquantel in preschool age children with\n                  <i>Schistosoma mansoni<\/i>\n                  infection in Albertine region of Uganda"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6884-0167","authenticated-orcid":false,"given":"Andrew","family":"Edielu","sequence":"first","affiliation":[{"name":"Vaccines Theme, MRC\/UVRI & LSHTM Uganda Research Unit, Entebbe, Uganda"},{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonniface","family":"Obura","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice A.","family":"Mawa","sequence":"additional","affiliation":[{"name":"Vaccines Theme, MRC\/UVRI & LSHTM Uganda Research Unit, Entebbe, Uganda"},{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom"},{"name":"Uganda Virus Research Institute, Entebbe, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5828-6318","authenticated-orcid":false,"given":"Martin J.","family":"Holland","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily L.","family":"Webb","sequence":"additional","affiliation":[{"name":"Vaccines Theme, MRC\/UVRI & LSHTM Uganda Research Unit, Entebbe, Uganda"},{"name":"MRC International Statistics and Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M.","family":"Elliott","sequence":"additional","affiliation":[{"name":"Vaccines Theme, MRC\/UVRI & LSHTM Uganda Research Unit, Entebbe, Uganda"},{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria Kakoba","family":"Ayebazibwe","sequence":"additional","affiliation":[{"name":"Vaccines Theme, MRC\/UVRI & LSHTM Uganda Research Unit, Entebbe, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1152-542X","authenticated-orcid":false,"given":"Hannah Wei","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for International Health Research, Rhode Island Hospital, Providence, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Mancini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian C.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, United States"},{"name":"Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1935-4197","authenticated-orcid":false,"given":"Susannah","family":"Colt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Alpert Medical School of Brown University, Providence, Rhode Island, United States"},{"name":"Center for International Health Research, Rhode Island Hospital, Providence, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meagan A.","family":"Barry","sequence":"additional","affiliation":[{"name":"Center for International Health Research, Rhode Island Hospital, Providence, United States"},{"name":"Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hope","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular & Integrative Biology, University of Liverpool"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona","family":"Waitt","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, University of Liverpool, Liverpool, United Kingdom"},{"name":"Infectious Diseases Institute, Makerere University, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer F.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Alpert Medical School of Brown University, Providence, Rhode Island, United States"},{"name":"Center for International Health Research, Rhode Island Hospital, Providence, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6131-4159","authenticated-orcid":false,"given":"Amaya L.","family":"Bustinduy","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"8","key":"2026091004200530000_2026.09.02.26362031v1.1","first-page":"21","article-title":"The prevalence of schistosomiasis in Uganda: A nationally representative population estimate to inform control programs and water and sanitation interventions","volume":"13","year":"2019","journal-title":"PLOS Neglected Tropical Diseases"},{"key":"2026091004200530000_2026.09.02.26362031v1.2","doi-asserted-by":"crossref","unstructured":"Faust, C.L , et al, Schistosomiasis Control: Leave No Age Group Behind. Trends in Parasitology, 2020. 36(7).","DOI":"10.1016\/j.pt.2020.04.012"},{"key":"2026091004200530000_2026.09.02.26362031v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt491"},{"issue":"4","key":"2026091004200530000_2026.09.02.26362031v1.4","doi-asserted-by":"crossref","first-page":"e00618","DOI":"10.1002\/prp2.618","article-title":"In vitro and in vivo human metabolism and pharmacokinetics of S- and R-praziquantel","volume":"8","year":"2020","journal-title":"Pharmacol Res Perspect"},{"key":"2026091004200530000_2026.09.02.26362031v1.5","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e328318978f"},{"issue":"9","key":"2026091004200530000_2026.09.02.26362031v1.6","first-page":"1","article-title":"Pharmacological and immunological effects of praziquantel against Schistosoma japonicum: a scoping review of experimental studies","volume":"7","year":"2018","journal-title":"BMC Infectious Diseases of Poverty"},{"issue":"2024","key":"2026091004200530000_2026.09.02.26362031v1.7","first-page":"1","article-title":"Praziquantel resistance in schistosomes: a brief report","volume":"3","year":"2024","journal-title":"Frontiers in Parasitology"},{"issue":"2020","key":"2026091004200530000_2026.09.02.26362031v1.8","first-page":"183","article-title":"Evaluation of the therapeutic efficacy of praziquantel against schistosomes in seven countries with ongoing large-scale deworming programs","volume":"14","year":"2020","journal-title":"International Journal for Parasitology: Drugs and Drug Resistance"},{"key":"2026091004200530000_2026.09.02.26362031v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4922(01)02209-7"},{"issue":"1","key":"2026091004200530000_2026.09.02.26362031v1.10","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1038\/s41598-024-84621-8","article-title":"Efficacy of single dose praziquantel against Schistosoma mansoni in East Africa: a systematic review and meta-analysis","volume":"15","year":"2025","journal-title":"Scientific Reports"},{"key":"2026091004200530000_2026.09.02.26362031v1.11","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.10.2903-2904.2000"},{"issue":"9","key":"2026091004200530000_2026.09.02.26362031v1.12","first-page":"1","article-title":"Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models","volume":"14","year":"2020","journal-title":"PLOS Neglected Tropical Diseases"},{"issue":"2022","key":"2026091004200530000_2026.09.02.26362031v1.13","first-page":"293","article-title":"-praziquantel integrated population pharmacokinetics in preschool- and school-aged African children infected with Schistosoma mansoni and S. haematobium and Lao adults infected with Opisthorchis viverrini","volume":"49","year":"2022","journal-title":"Journal of Pharmacokinetics and Pharmacodynamics"},{"key":"2026091004200530000_2026.09.02.26362031v1.14","doi-asserted-by":"publisher","DOI":"10.3391\/mbi.2016.7.1.01"},{"issue":"7","key":"2026091004200530000_2026.09.02.26362031v1.15","first-page":"1","article-title":"Protein undernutrition reduces the efficacy of praziquantel in a murine model of Schistosoma mansoni infection","volume":"16","year":"2022","journal-title":"PLOS Neglected Tropical Diseases"},{"key":"2026091004200530000_2026.09.02.26362031v1.16","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-197702010-00004"},{"issue":"9","key":"2026091004200530000_2026.09.02.26362031v1.17","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.2217\/fmb-2018-0016","article-title":"Exploring the Relationship Between Environmental Enteric Dysfunction and Oral Vaccine Responses","volume":"13","year":"2018","journal-title":"Future Microbiology"},{"issue":"5","key":"2026091004200530000_2026.09.02.26362031v1.18","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1038\/s41385-018-0036-1","article-title":"Pathophysiology of environmental enteric dysfunction and its impact on oral vaccine efficacy","volume":"11","year":"2018","journal-title":"Mucosal Immunol"},{"issue":"181","key":"2026091004200530000_2026.09.02.26362031v1.19","first-page":"1","article-title":"Environmental enteric dysfunction: a review of potential mechanisms, consequences and management strategies","volume":"17","year":"2019","journal-title":"BMC Medicine"},{"key":"2026091004200530000_2026.09.02.26362031v1.20","doi-asserted-by":"crossref","first-page":"733935","DOI":"10.3389\/fphar.2021.733935","article-title":"Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature","volume":"12","year":"2021","journal-title":"Front Pharmacol"},{"key":"2026091004200530000_2026.09.02.26362031v1.21","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1043836"},{"key":"2026091004200530000_2026.09.02.26362031v1.22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105017"},{"key":"2026091004200530000_2026.09.02.26362031v1.23","doi-asserted-by":"crossref","unstructured":"Denno, D.M , P.I. Tarr , and J.P. Nataro , Environmental Enteric Dysfunction: A Case Definition for Intervention Trials. American Journal of Tropical Medicine & Hygiene, 2017. 97(6).","DOI":"10.4269\/ajtmh.17-0183"},{"key":"2026091004200530000_2026.09.02.26362031v1.24","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ848"},{"issue":"1","key":"2026091004200530000_2026.09.02.26362031v1.25","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1186\/s13063-021-05558-1","article-title":"The praziquantel in preschoolers (PIP) trial: study protocol for a phase II PK\/PD-driven randomised controlled trial of praziquantel in children under 4 years of age","volume":"22","year":"2021","journal-title":"Trials"},{"issue":"6","key":"2026091004200530000_2026.09.02.26362031v1.26","doi-asserted-by":"crossref","first-page":"e1091","DOI":"10.1016\/S2214-109X(25)00095-6","article-title":"Safety and efficacy of praziquantel 40 mg\/kg versus 80 mg\/kg in preschool-aged children with intestinal schistosomiasis in Uganda: a 2&#x2008;&#xd7;&#x2008;2 factorial, double-blind, placebo-controlled, phase 2 randomised trial","volume":"13","year":"2025","journal-title":"The Lancet Global Health"},{"issue":"9","key":"2026091004200530000_2026.09.02.26362031v1.27","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1111\/tmi.12152","article-title":"Practical dosing of praziquantel for schistosomiasis in preschool-aged children","volume":"18","year":"2013","journal-title":"Tropical Medicine and International Health"},{"key":"2026091004200530000_2026.09.02.26362031v1.28","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000000459"},{"key":"2026091004200530000_2026.09.02.26362031v1.29","doi-asserted-by":"publisher","DOI":"10.1086\/430929"},{"issue":"17","key":"2026091004200530000_2026.09.02.26362031v1.30","first-page":"1569","article-title":"Role of fecal calprotectin in gastrointestinal disorders","volume":"2013","year":"2013","journal-title":"European Review for Medical and Pharmacological Sciences"},{"issue":"4","key":"2026091004200530000_2026.09.02.26362031v1.31","doi-asserted-by":"crossref","first-page":"308","DOI":"10.5863\/1551-6776-21.4.308","article-title":"Calprotectin: Clinical Applications in Pediatrics","volume":"21","year":"2016","journal-title":"The Journal of Pediatric Pharmacology and Therapeutics"},{"issue":"11","key":"2026091004200530000_2026.09.02.26362031v1.32","first-page":"1","article-title":"Fecal Occult Blood and Fecal Calprotectin as Point-of-Care Markers of Intestinal Morbidity in Ugandan Children with Schistosoma mansoni Infection","volume":"7","year":"2013","journal-title":"PLOS Neglected Tropical Diseases"},{"issue":"2018","key":"2026091004200530000_2026.09.02.26362031v1.33","first-page":"677","article-title":"Interpretation of the lactulose:mannitol test in rural Malawian children at risk for perturbations in intestinal permeability","volume":"243","year":"2018","journal-title":"Experimental Biology and Medicine"},{"key":"2026091004200530000_2026.09.02.26362031v1.34","doi-asserted-by":"crossref","unstructured":"Zhang, C.X. and S.L.M. Arnold , Potential and challenges in application of physiologically based pharmacokinetic modeling in predicting diarrheal disease impact on oral drug pharmacokinetics. Drug Metabolism & Disposition, 2025. 53(1).","DOI":"10.1124\/dmd.122.000964"},{"key":"2026091004200530000_2026.09.02.26362031v1.35","doi-asserted-by":"crossref","unstructured":"Abdallah, Y.E.H , et al, Drug-disease interaction: Clinical consequences of inflammation on drugs action and disposition. Journal of Pharmacy & Pharmaceutical Sciences, 2023. Volume 26 - 2023.","DOI":"10.3389\/jpps.2023.11137"},{"key":"2026091004200530000_2026.09.02.26362031v1.36","doi-asserted-by":"crossref","unstructured":"Agrawal, A. and Y. Wu , Editorial: Biology of C-reactive protein. Frontiers in Immunology, 2024: p. 1\u20133.","DOI":"10.3389\/978-2-8325-5090-8"},{"key":"2026091004200530000_2026.09.02.26362031v1.37","unstructured":"Yao, Z , Y. Zhang , and H. Wu , Regulation of C-reactive protein conformation in infammation. Inflammation Research, 2019: p. 1\u20139."},{"issue":"61","key":"2026091004200530000_2026.09.02.26362031v1.38","first-page":"78","article-title":"Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn\u2019s disease","volume":"2012","year":"2012","journal-title":"Inflammatory bowel disease"},{"issue":"1455721","key":"2026091004200530000_2026.09.02.26362031v1.39","first-page":"1","article-title":"Influence of C-reactive protein on the pharmacokinetics of voriconazole in relation to the CYP2C19 genotype: a population pharmacokinetics analysis","volume":"15","year":"2024","journal-title":"Frontiers in Pharmacology"},{"key":"2026091004200530000_2026.09.02.26362031v1.40","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-023-04727-9"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.02.26362031","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:20:19Z","timestamp":1789039219000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.02.26362031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":40,"URL":"https:\/\/doi.org\/10.64898\/2026.09.02.26362031","relation":{},"subject":[],"published":{"date-parts":[[2026,9,7]]},"subtype":"preprint"}}