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In a recent dose escalation clinical trial, we showed that increasing atazanavir\/ritonavir to 300\/100\u2009mg b.i.d. compensates for reduced drug exposure in plasma due to rifampicin, but the intracellular effects remained unexplored. This sub\u2010study investigated the intracellular penetration of atazanavir\/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMC). Twenty\u2010six healthy volunteers living with HIV, virologically suppressed, and taking atazanavir\/ritonavir containing regimens were enrolled. The trial consisted of four sequential periods: PK1, participants were on atazanavir\/ritonavir 300\/100\u2009mg q.d.; at PK2, rifampicin 600\u2009mg q.d. and dolutegravir 50\u2009mg b.i.d. were added (2\u2009weeks); at PK3, atazanavir\/ritonavir dose was increased to 300\/100\u2009mg b.i.d. (1\u2009week); at PK4, rifampicin dose was doubled (1\u2009week). Atazanavir, ritonavir, and dolutegravir were quantified in plasma and PBMC using LC\u2013MS\/MS methods to evaluate steady\u2010state concentrations at the end of each period. Atazanavir\/ritonavir dose escalation successfully restored intracellular concentrations comparable to those observed without rifampicin, with a geometric mean ratio of 0.99 (CI<jats:sub>90<\/jats:sub> 0.72\u20131.41) for atazanavir at PK3 compared with PK1. The intracellular concentration of dolutegravir increased significantly with atazanavir\/ritonavir dose escalation, similar to plasma. Finally, further, increasing the rifampicin dose did not show an additional impact on atazanavir\/ritonavir concentrations in PBMC. The study confirms that increasing the ATV\/r dose can be an effective strategy for compensating rifampicin effects even at the intracellular level, supporting its use in clinical settings.<\/jats:p>","DOI":"10.1002\/cpt.3572","type":"journal-article","created":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T05:38:31Z","timestamp":1738388311000},"page":"1393-1402","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Intracellular Penetration of Atazanavir, Ritonavir and Dolutegravir With Concomitant Rifampicin: A Dose Escalation Study"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5973-9948","authenticated-orcid":false,"given":"Amedeo","family":"De Nicol\u00f2","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences University of Turin  Turin 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