{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:56:43Z","timestamp":1790672203209,"version":"4.1.0"},"reference-count":15,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-060170"],"award-info":[{"award-number":["INV-060170"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,2,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The development of new regimens to treat tuberculosis (TB), the disease caused by\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      , is critical to improving patient outcomes and decreasing global infectious disease mortality. Early evaluation of candidate regimens in non-clinical models of TB, such as the relapsing mouse model (RMM), remains an important step in prioritizing the most efficacious regimens for further clinical evaluation. Although RMM studies may be informative, they are also animal-, labor-, and time-intensive to complete and represent a significant investment in time and resources during non-clinical development. Given the strong pipeline of regimens in development, identification of \u201cleaner\u201d RMM studies may have a significant impact on resource utilization, and hence we compared alternative study designs to identify study attributes that can be modified to improve resource use, particularly animal use. By simulating relapse outcomes from \u201cvirtual\u201d studies (i.e., groups of mice treated for selected durations with control and hypothetical anti-TB regimens) followed by model-based analysis of the simulated data, we were able to compare the \u201ctrue\u201d (input) values with model estimates of time to 95% cure probability (T\n                      <jats:sub>95<\/jats:sub>\n                      ) and assess bias and precision of competing designs. Using this approach, we demonstrated that 28% fewer mice could be used in RMM studies while maintaining low bias and a precision for T\n                      <jats:sub>95<\/jats:sub>\n                      estimation within \u00b11\u20132 weeks for most regimens. Therefore, it is expected that RMM studies based upon the alternative designs evaluated herein may be employed to promote improved animal stewardship while generating informative data for decision-making.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01103-25","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T13:01:01Z","timestamp":1767013261000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["A stochastic simulation-based approach to inform the relapsing mouse model study design for non-clinical assessment of tuberculosis"],"prefix":"10.1128","volume":"70","author":[{"given":"James","family":"Clary","sequence":"first","affiliation":[{"name":"Simulations Plus, Inc.","place":["Lancaster, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc.","place":["Lancaster, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Hanna","sequence":"additional","affiliation":[{"name":"Gates Foundation","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Tagliavini","sequence":"additional","affiliation":[{"name":"Pharmacometrics, Aptuit (an Evotec Company)","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0507-6792","authenticated-orcid":true,"given":"Sylvie","family":"Sordello","sequence":"additional","affiliation":[{"name":"Translational Biology, Infection Diseases, Evotec France","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Upton","sequence":"additional","affiliation":[{"name":"Evotec USA Inc.","place":["Princeton, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hermann","sequence":"additional","affiliation":[{"name":"Gates Foundation","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7781-0755","authenticated-orcid":true,"given":"Alexander","family":"Berg","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc.","place":["Lancaster, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"World Health Organization. 2024. Global tuberculosis report 2024"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7108a1"},{"key":"e_1_3_4_4_2","unstructured":"World Health Organization. 2023. Target regimen profiles for tuberculosis treatment 2023 update. Geneva World Health Organization. https:\/\/www.who.int\/publications\/i\/item\/9789240081512."},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2012.07.003"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01793-21"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2004.03.002"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01691-15"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","unstructured":"Sordello S Brock L Tagliavini A Federico D Boulenc X Pergher M Claustre EH Metcalf D Walter ND Robertson GT Clary J Berg A Mdluli K Hermann D Flood D Upton AM. 2025. A modeling-based framework to evaluate forgiveness of TB drug combinations in a BALB\/c relapsing mouse model. bioRxiv. doi:10.1101\/2025.08.07.668704","DOI":"10.1101\/2025.08.07.668704"},{"key":"e_1_3_4_10_2","volume-title":"The principles of humane experimental technique","author":"Russell WMS","year":"1959","unstructured":"Russell WMS, Burch RL, Hume CW. 1959. The principles of humane experimental technique. Vol. 238. Methuen London."},{"key":"e_1_3_4_11_2","volume-title":"Management of animal care and use programs in research, education, and testing","author":"Weichbrod RH","year":"2018","unstructured":"Weichbrod RH, Thompson GA, Norton JN, eds. 2018. Management of animal care and use programs in research, education, and testing. 2nd ed. CRC Press\/Taylor & Francis, Boca Raton (FL).","edition":"2"},{"key":"e_1_3_4_12_2","unstructured":"2024. TB-platform for the aggregation of preclinical experiments data (TB-APEX). Available from: https:\/\/c-path.org\/tools-platforms\/tb-apex\/"},{"key":"e_1_3_4_13_2","unstructured":"RStudio Team. 2020. RStudio: integrated development for R. RStudio. PBC Boston MA"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-21706-2"},{"key":"e_1_3_4_15_2","unstructured":"Stan Development Team. 2023. RStan: the R interface to Stan. R package version 2.32.3"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","unstructured":"Wickham H. 2016. ggplot2: elegant graphics for data analysis. Springer-Verlag New York.","DOI":"10.1007\/978-3-319-24277-4_9"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01103-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01103-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T14:01:38Z","timestamp":1770213698000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01103-25"}},"subtitle":[],"editor":[{"given":"Sean","family":"Wasserman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,2,4]]},"references-count":15,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2,4]]}},"alternative-id":["10.1128\/aac.01103-25"],"URL":"https:\/\/doi.org\/10.1128\/aac.01103-25","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,4]]},"assertion":[{"value":"2025-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01103-25"}}