{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:21:17Z","timestamp":1790220077900,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T00:00:00Z","timestamp":1704153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1160955"],"award-info":[{"award-number":["OPP1160955"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1172544"],"award-info":[{"award-number":["OPP1172544"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea\u2010associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)\u2013infected adults with\/without cryptosporidiosis and diarrhea to examine diarrhea\u2010associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV\u2010infected adults with\/without <jats:italic>Cryptosporidium<\/jats:italic> infection using nonlinear mixed\u2010effects modeling. Covariates describing cryptosporidiosis\u2010associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two\u2010compartment model with lag time and first\u2010order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71\u2009L\/h, 18.2\u2009L\/h (interindividual variability [IIV] 45.0%), 473\u2009L (IIV 3.46%), and 3434\u2009L, respectively. The absorption rate constant was 0.625\u2009h<jats:sup>\u22121<\/jats:sup> (IIV 149%) and absorption lag time was 1.83\u2009h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.<\/jats:p>","DOI":"10.1002\/psp4.13092","type":"journal-article","created":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T08:25:45Z","timestamp":1704183945000},"page":"410-423","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Clofazimine pharmacokinetics in <scp>HIV\u2010infected<\/scp> adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0243-7842","authenticated-orcid":false,"given":"Cindy X.","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Conrad","sequence":"additional","affiliation":[{"name":"Emmes  Rockville Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hermann","sequence":"additional","affiliation":[{"name":"Bill &amp; Melinda Gates Foundation  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melita A.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group Malawi\u2010Liverpool Wellcome Trust Clinical Research Programme  Blantyre Malawi"},{"name":"Institute of Infection and Global Health University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Houpt","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3682-8892","authenticated-orcid":false,"given":"Pui\u2010Ying","family":"Iroh\u00a0Tam","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group Malawi\u2010Liverpool Wellcome Trust Clinical Research Programme  Blantyre Malawi"},{"name":"Liverpool School of Tropical Medicine  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khuzwayo C.","family":"Jere","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group Malawi\u2010Liverpool Wellcome Trust Clinical Research Programme  Blantyre Malawi"},{"name":"Institute of Infection and Global Health University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8742-8680","authenticated-orcid":false,"given":"Wilfred","family":"Nedi","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group Malawi\u2010Liverpool Wellcome Trust Clinical Research Programme  Blantyre Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darwin J.","family":"Operario","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Phulusa","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group Malawi\u2010Liverpool Wellcome Trust Clinical Research Programme  Blantyre Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Gerald V.","family":"Quinnan","sequence":"additional","affiliation":[{"name":"Emmes  Rockville Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh A.","family":"Sawyer","sequence":"additional","affiliation":[{"name":"Emmes  Rockville Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn K.","family":"Barrett","sequence":"additional","affiliation":[{"name":"Center for Emerging and Re\u2010emerging Infectious Diseases University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Thole","sequence":"additional","affiliation":[{"name":"Paediatrics and Child Health Research Group Malawi\u2010Liverpool Wellcome Trust Clinical Research Programme  Blantyre Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9047-217X","authenticated-orcid":false,"given":"Neema","family":"Toto","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley C.","family":"Van\u00a0Voorhis","sequence":"additional","affiliation":[{"name":"Center for Emerging and Re\u2010emerging Infectious Diseases University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8290-2347","authenticated-orcid":false,"given":"Samuel L. 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