{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T10:47:12Z","timestamp":1756810032850,"version":"3.41.2"},"reference-count":2,"publisher":"Wiley","issue":"4S3","license":[{"start":{"date-parts":[[2014,11,2]],"date-time":"2014-11-02T00:00:00Z","timestamp":1414886400000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of the International AIDS Society"],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Treatment of HIV\/TB co\u2010infection is challenging due to high drug\u2013drug interaction potential between antiretrovirals and rifamycins, such as rifampicin (RIF). The PK interaction between darunavir\/ritonavir (DRV\/RTV) and RIF has not been studied. Utilizing other protease inhibitor data, population PK modelling and simulation was applied to assess the impact of RIF on DRV\/RTV PK and generate alternative dosing strategies to aid future clinical trial design.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>A previously developed model describing DRV\/RTV PK including data from three studies in HIV patients was used [n=51, 7 female, DRV\/RTV 800\/100 mg (n=32) or 900\/100 mg once daily (<jats:italic>qd<\/jats:italic>; n=19) [<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#CIT0001\">1<\/jats:ext-link>]. The PK interaction between DRV\/RTV and RIF was assumed to mimic that observed in HIV\u2010infected, TB negative patients receiving lopinavir (LPV)\/RTV (n=21) [<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#CIT0002\">2<\/jats:ext-link>]. Simulations of DRV\/RTV 800\/100 mg <jats:italic>qd<\/jats:italic> (n=1000) were performed (\u2010RIF). The model was adapted to increase the typical value of apparent oral clearance (CL\/F) by 71% and 36% and decrease relative bioavailability (F) by 20% and 45% for DRV and RTV, respectively [<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#CIT0002\">2<\/jats:ext-link>]; 1000 simulations were generated (+RIF). Dose adjustments of DRV\/RTV 1200\/200 mg <jats:italic>qd<\/jats:italic>, 800\/100 mg and 1200\/150 mg twice daily (<jats:italic>bid<\/jats:italic>) were simulated to overcome the interaction. DRV trough (C<jats:sub>trough<\/jats:sub>) for each dosing scenario was compared to the reference (\u2010RIF) by GMR (90% CI).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DRV and RTV were described by a 1 and 2\u2010compartment model, respectively. A maximum effect model, with RTV inhibiting DRV CL\/F, best described the relationship between the drugs. Compared to the reference (\u2010RIF), simulated DRV C<jats:sub>trough<\/jats:sub> was 70%, 46% and 20% lower for 800\/100 mg <jats:italic>qd<\/jats:italic>, 1200\/200 mg <jats:italic>qd<\/jats:italic> and 800\/100 mg <jats:italic>bid<\/jats:italic> all +RIF, respectively. C<jats:sub>trough<\/jats:sub> was 38% higher with 1200\/150 mg <jats:italic>bid<\/jats:italic> +RIF (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#T0001_19586\">Table 1<\/jats:ext-link>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Modelling and simulation was used to investigate the theoretical impact of RIF on DRV\/RTV PK. Based on simulations, 800\/100 mg and 1200\/150 mg both <jats:italic>bid<\/jats:italic> could largely overcome the impact of the interaction. However, the risk of increased RTV\u2010related side effects and higher pill burden should be considered. <jats:italic>In vitro<\/jats:italic> work is ongoing to develop a physiologically based model characterizing the interaction and informing simulations.<\/jats:p><\/jats:sec>","DOI":"10.7448\/ias.17.4.19586","type":"journal-article","created":{"date-parts":[[2014,11,3]],"date-time":"2014-11-03T08:30:34Z","timestamp":1415003434000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Simulation of the impact of rifampicin on darunavir\/ritonavir PK and dose adjustment strategies in HIV\u2010infected patients: a population PK approach"],"prefix":"10.1002","volume":"17","author":[{"given":"Laura","family":"Dickinson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Winston","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Boffito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saye","family":"Khoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Back","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Siccardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,11,2]]},"reference":[{"unstructured":"DickinsonL JacksonA GarveyL WatsonV KhooS WinstonA et al.11th International Congress on Drug Therapy in HIV 11\u201315 November 2012.Glasgow UK.","key":"e_1_2_2_2_1"},{"doi-asserted-by":"publisher","key":"e_1_2_2_3_1","DOI":"10.1111\/j.1365-2125.2011.04154.x"}],"container-title":["Journal of the International AIDS Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.7448%2FIAS.17.4.19586","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.7448\/IAS.17.4.19586","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T17:12:41Z","timestamp":1695575561000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.7448\/IAS.17.4.19586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11]]},"references-count":2,"journal-issue":{"issue":"4S3","published-print":{"date-parts":[[2014,11]]}},"alternative-id":["10.7448\/IAS.17.4.19586"],"URL":"https:\/\/doi.org\/10.7448\/ias.17.4.19586","archive":["Portico"],"relation":{},"ISSN":["1758-2652","1758-2652"],"issn-type":[{"type":"print","value":"1758-2652"},{"type":"electronic","value":"1758-2652"}],"subject":[],"published":{"date-parts":[[2014,11]]},"assertion":[{"value":"2014-11-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"19586"}}