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Due to the prolonged exposure, it can be challenging to undertake \u2018traditional\u2019 pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug\u2013drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co\u2010medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.hiv-druginteractions.org\/checker\">https:\/\/www.hiv-druginteractions.org\/checker<\/jats:ext-link>). LAI cabotegravir and rilpivirine have half\u2010lives of 6\u201312 and 13\u201328\u2009weeks, respectively. Cabotegravir is primarily metabolized by UDP\u2010glucuronyltransferase (UGT)\u20101A1 and rilpivirine by cytochrome P450 (CYP)\u20103A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co\u2010medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co\u2010medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and\/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and\/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir\/rilpivirine appropriately to minimize risk.<\/jats:p>","DOI":"10.1111\/bcp.16154","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T06:03:46Z","timestamp":1719381826000},"page":"2079-2091","source":"Crossref","is-referenced-by-count":10,"title":["Clinical pharmacology considerations and drug\u2013drug interactions with long\u2010acting cabotegravir and rilpivirine relevant to sub\u2010Saharan Africa"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7656-1136","authenticated-orcid":false,"given":"Adrian","family":"Steulet","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Nyon Hospital (GHOL)  Nyon Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-1795","authenticated-orcid":false,"given":"Bonniface","family":"Obura","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics Group, Department of Pharmacology and Therapeutics University of Liverpool  Liverpool UK"},{"name":"Department of Pharmacology and Therapeutics Lira University  Lira Uganda"}],"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"}]},{"given":"Eva","family":"Laker","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute Makerere University College of Health Sciences  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie R.","family":"Nicol","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology University of Minnesota Twin Cities  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona V.","family":"Cresswell","sequence":"additional","affiliation":[{"name":"MRC\/UVRI\u2010LSHTM Uganda Research Unit  Entebbe Uganda"},{"name":"Centre for Global Health Research Brighton and Sussex Medical School  Brighton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,25]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"Global HIV & AIDS statistics\u2014fact sheet [Internet]","author":"UNAIDS","year":"2023"},{"key":"e_1_2_8_3_1","unstructured":"UNAIDS.South Africa [Internet].2023. 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