{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:28:03Z","timestamp":1787311683123,"version":"build-2736575974"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["RIA2016MC\u20101606\u2010VirTUAL"],"award-info":[{"award-number":["RIA2016MC\u20101606\u2010VirTUAL"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["222075_Z_20_Z"],"award-info":[{"award-number":["222075_Z_20_Z"]}],"id":[{"id":"10.13039\/100010269","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":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Ritonavir\u2010boosted atazanavir (ATV\/r) and rifampicin are mainstays of second\u2010line antiretroviral and multiple anti\u2010TB regimens, respectively. Rifampicin induces CYP3A4, a major enzyme involved in atazanavir metabolism, causing a drug\u2013drug interaction (DDI) which might be exaggerated in pregnancy. Having demonstrated that increasing the dose of ATV\/r from once daily (OD) to twice daily (BD) in non\u2010pregnant adults can safely overcome this DDI, we developed a pregnancy physiologically based pharmacokinetic (PBPK) model to explore the impact of pregnancy. Predicted pharmacokinetic parameters were validated with separate clinical datasets of ATV\/r alone (NCT03923231) and rifampicin alone in pregnant women. The pregnancy model was considered validated when the absolute average fold error (AAFE) for\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>trough<\/jats:sub>\n                    and AUC\n                    <jats:sub>0\u201024<\/jats:sub>\n                    of both drugs were &lt;2 when comparing predicted vs. observed data. Thereafter, predicted atazanavir\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>trough<\/jats:sub>\n                    was compared against its protein\u2010adjusted IC\n                    <jats:sub>90<\/jats:sub>\n                    (14\u2009ng\/mL) when simulating the co\u2010administration of ATV\/r 300\/100\u2009mg OD and rifampicin 600\u2009mg OD. Pregnancy was predicted to increase the rifampicin DDI effect on atazanavir. For the dosing regimens of ATV\/r 300\/100\u2009mg OD, ATV\/r 300\/200\u2009mg OD, and ATV\/r 300\/100\u2009mg BD (all with rifampicin 600\u2009mg OD), predicted atazanavir\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>trough<\/jats:sub>\n                    was above 14\u2009ng\/mL in 29%, 71%, and 100%; and 32%, 73% and 100% of the population in second and third trimesters, respectively. Thus, PBPK modeling suggests ATV\/r 300\/100\u2009mg BD could maintain antiviral efficacy when co\u2010administered with rifampicin 600\u2009mg OD in pregnancy. Clinical studies are warranted to confirm safety and efficacy in pregnancy.\n                  <\/jats:p>","DOI":"10.1002\/psp4.13268","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T00:19:11Z","timestamp":1731111551000},"page":"1967-1977","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Physiologically based pharmacokinetic modeling of drug\u2013drug interactions between ritonavir\u2010boosted atazanavir and rifampicin in pregnancy"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1393-3753","authenticated-orcid":false,"given":"Shakir","family":"Atoyebi","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiara Camotti","family":"Montanha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6626-0329","authenticated-orcid":false,"given":"Ritah","family":"Nakijoba","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute Makerere University College of Health Sciences  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1134-7475","authenticated-orcid":false,"given":"Catherine","family":"Orrell","sequence":"additional","affiliation":[{"name":"Desmond Tutu Health Foundation, Institute of Infectious Disease and Molecular Medicine University of Cape Town  Cape Town South Africa"},{"name":"Department of Medicine University of Cape Town  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Mugerwa","sequence":"additional","affiliation":[{"name":"Joint Clinical Research Centre  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Siccardi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":false,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Department of Medicine University of Cape Town  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona","family":"Waitt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics University of Liverpool  Liverpool UK"},{"name":"Infectious Diseases Institute Makerere University College of Health Sciences  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a Public Health Approach","author":"World Health Organization","year":"2021"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11908-020-00726-x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12196302"},{"key":"e_1_2_10_5_1","unstructured":"AbbVie Inc.KALETRA (lopinavir and ritonavir). US Prescribing Information.2016."},{"key":"e_1_2_10_6_1","unstructured":"Tibotec Inc.PREZISTA\u2122 (Darunavir).2008."},{"key":"e_1_2_10_7_1","unstructured":"Bristol\u2010Myers Squibb.REYATAZ\u00ae (atazanavir sulfate) Capsules. US Prescribing Information2020."},{"key":"e_1_2_10_8_1","unstructured":"AbbVie Inc.Norvir\u2122 (ritonavir). US Pprescribing Iinformation2019."},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciad700"},{"key":"e_1_2_10_10_1","unstructured":"Department of Health and Human Services.Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. 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