De Nicolo, Amedeo, Palermiti, Alice, Mugerwa, Henry, Nakabuye, Shamim, Namusanje, Josephine, Kobusingye, Josephine, Odoch, Denis, Lamorde, Mohammed, Kengo, Allan, Denti, Paolo et al (show 7 more authors)
(2025)
Intracellular Penetration of Atazanavir, Ritonavir and Dolutegravir With Concomitant Rifampicin: A Dose Escalation Study
CLINICAL PHARMACOLOGY & THERAPEUTICS, 117 (5).
pp. 1393-1402.
ISSN 0009-9236, 1532-6535
Abstract
Ritonavir-boosted atazanavir is a victim of drug–drug interaction with rifampicin, a key component of antitubercular treatment. In a recent dose escalation clinical trial, we showed that increasing atazanavir/ritonavir to 300/100 mg b.i.d. compensates for reduced drug exposure in plasma due to rifampicin, but the intracellular effects remained unexplored. This sub-study investigated the intracellular penetration of atazanavir/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMC). Twenty-six 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 mg q.d.; at PK2, rifampicin 600 mg q.d. and dolutegravir 50 mg b.i.d. were added (2 weeks); at PK3, atazanavir/ritonavir dose was increased to 300/100 mg b.i.d. (1 week); at PK4, rifampicin dose was doubled (1 week). Atazanavir, ritonavir, and dolutegravir were quantified in plasma and PBMC using LC–MS/MS methods to evaluate steady-state 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<inf>90</inf> 0.72–1.41) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Leukocytes, Mononuclear, Humans, HIV Infections, Oxazines, Piperazines, Pyridones, Ritonavir, Heterocyclic Compounds, 3-Ring, Rifampin, HIV Protease Inhibitors, Anti-HIV Agents, Drug Therapy, Combination, Dose-Response Relationship, Drug, Drug Interactions, Adult, Middle Aged, Female, Male, Young Adult, Healthy Volunteers, Atazanavir Sulfate, Dolutegravir |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 26 Mar 2025 10:41 |
| Last Modified: | 16 Jun 2026 20:03 |
| DOI: | 10.1002/cpt.3572 |
| Open Access URL: | https://doi.org/10.1002/cpt.3572 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3191037 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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