{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:38:42Z","timestamp":1789695522954,"version":"4.0.1"},"reference-count":31,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Tau aggregation contributes to the pathology of Alzheimer's disease (AD). Tau aggregation inhibitors (TAI) are potential disease\u2010modifying drugs for AD and other tauopathies. Hydromethylthionine (HMT) is a potent orally administered TAI, which also has tau\u2010independent symptomatic activity. The purpose of this analysis was to characterize HMT pharmacokinetics (PK) in healthy volunteers and AD patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Data from five Phase I studies and the TRx\u2010237\u2010039 Phase 3 study (mild to moderate AD and mild cognitive impairment) were combined, including single doses of hydromethylthionine mesylate (HMTM) (4\u2013100\u2009mg), multiple dose regimens (8\u201380\u2009mg\/day) and long\u2010term data (16\u2009mg\/day) over a maximum of 104\u2009weeks. In TRx\u2010237\u2010039, methylthioninium chloride (MTC, 4\u2009mg twice weekly), which also delivers HMT, was intended to maintain blinding for urine discoloration without therapeutic activity based on linear PK modelling of earlier trial data. The PK model characterized active HMT, regardless of its source. Plasma HMT data from 710 participants with 7784 measurements were analysed using non\u2010linear mixed effects modelling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The model described inter\u2010individual variability, time\u2010varying (U\u2010shaped) clearance, and the impact of clinically relevant covariates on the PK. The U\u2010shaped clearance over 24\u2009months led to increasing plasma levels at 12\u2009months that were 3\u2009\u00d7\u2009(HMTM) and 5\u2009\u00d7\u2009(MTC) above linear model predictions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The exposure increase at 12\u2009months and the dual pharmacology of HMT explain the unexpected symptomatic activity of low dose MTC. The data suggest it is not possible to maintain comparable urinary discolouration without therapeutic activity in a standard placebo\u2010controlled trial design.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70539","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T03:30:25Z","timestamp":1775014225000},"page":"2645-2656","source":"Crossref","is-referenced-by-count":2,"title":["Atypical population pharmacokinetics of hydromethylthionine in patients with Alzheimer's disease explains unexpected phase 3 trial results"],"prefix":"10.1002","volume":"92","author":[{"given":"Eline","family":"van Maanen","sequence":"first","affiliation":[{"name":"Certara Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Certara Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Certara Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris","family":"Fauchet","sequence":"additional","affiliation":[{"name":"Certara Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinziana","family":"Cristea","sequence":"additional","affiliation":[{"name":"Certara Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Smith","sequence":"additional","affiliation":[{"name":"Certara Inc.  Radnor Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Baddeley","sequence":"additional","affiliation":[{"name":"TauRx Therapeutics Ltd  Aberdeen UK"},{"name":"University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Shiells","sequence":"additional","affiliation":[{"name":"TauRx Therapeutics Ltd  Aberdeen UK"},{"name":"University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Hewitt","sequence":"additional","affiliation":[{"name":"TauRx Therapeutics Ltd  Aberdeen UK"},{"name":"University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjoern O.","family":"Schelter","sequence":"additional","affiliation":[{"name":"TauRx Therapeutics Ltd  Aberdeen UK"},{"name":"University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude M.","family":"Wischik","sequence":"additional","affiliation":[{"name":"TauRx Therapeutics Ltd  Aberdeen UK"},{"name":"University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(12)70291\u20100"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa342"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041\u2010019\u20100448\u20101"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010018\u20100439\u2010y"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075091"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2022.10.006"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.5755"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000063311.58879.01"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2010.01.016"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(16)31275\u20102"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3233\/jad\u2010170560"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.3233\/jad\u2010190772"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.616029"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2018.08.010"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.20.11213"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3233\/jad\u2010142874"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15553"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213\u2010008\u20101394\u20102"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/fbp.0000000000000865"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.63"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.219352"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2026.100480"},{"key":"e_1_2_9_24_1","unstructured":"ICON plc Nonmem user guides. NONMEM|Nonlinear Mixed Effects Modelling."},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1109\/TAC.1974.1100705"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100241"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010011\u20109255\u2010z"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13882"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/25424823251379878"},{"key":"e_1_2_9_30_1","unstructured":"U.S. Food and Drug Administration Provayblue (methylene blue) injection USP: Prescribing information retrievedhttps:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/204630s000lbl.pdf"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2016.00437"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu268"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70539","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bcp.70539","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70539","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:27:16Z","timestamp":1785371236000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":31,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/bcp.70539"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70539","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]}}}