Pharmacokinetics of dolutegravir with and without darunavir/cobicistat in healthy volunteers.

Elliot, Emilie R, Cerrone, Maddalena, Else, Laura, Amara, Alieu ORCID: 0000-0002-1137-2948, Bisdomini, Elisa, Khoo, Saye ORCID: 0000-0002-2769-0967, Owen, Andrew ORCID: 0000-0002-9819-7651 and Boffito, Marta (2019) Pharmacokinetics of dolutegravir with and without darunavir/cobicistat in healthy volunteers. The Journal of antimicrobial chemotherapy, 74 (1). pp. 149-156.

Text 0 Manuscript 073 V0.2 SK.docx - Author Accepted Manuscript Download (695kB)

Abstract

Background:Dolutegravir combined with darunavir/cobicistat is a promising NRTI-sparing and/or salvage strategy for the treatment of HIV-1 infection. Methods:This Phase I, open-label, 57 day, crossover, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65 years, who were randomized to one of two groups. Group 1 received dolutegravir (50 mg) once daily for 14 days followed by a 7 day washout, then a 14 day dolutegravir/darunavir/cobicistat (DTG/DRV/COBI) once-daily co-administration period followed by a 7 day washout and finally a 14 day period of darunavir/cobicistat (800/150 mg) once daily. Group 2 followed the same sequence starting with darunavir/cobicistat and concluding with dolutegravir. Each group underwent intensive PK sampling over 24 h on day 14 of each drug period and DTG/DRV/COBI concentrations were measured using validated LC-MS/MS methods. Results:Twenty participants completed all PK phases. Thirteen were female and median age and BMI were 33.5 years and 27 kg/m2. Dolutegravir geometric mean ratios (GMR, DTG/DRV/COBI versus dolutegravir alone) and 90% CI for Cmax, AUC0-24 and C24 were 1.01 (0.92-1.11), 0.95 (0.87-1.04) and 0.9 (0.8-1.0), respectively. Darunavir GMR (DRV/COBI/DTG versus darunavir/cobicistat alone) and 90% CI for Cmax, AUC0-24 and C24 were 0.90 (0.83-0.98), 0.93 (0.86-1.00) and 0.93 (0.78-1.11), respectively. No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusions:Concentrations of dolutegravir and darunavir, when boosted with cobicistat, decreased by <10% during co-administration, suggesting this combination can be prescribed safely in the treatment of HIV-1, with no adjustment to current guideline-recommended dosages.

Item Type:	Article
Uncontrolled Keywords:	Humans, Oxazines, Piperazines, Pyridones, Heterocyclic Compounds, 3-Ring, Anti-HIV Agents, Cross-Over Studies, Adolescent, Adult, Aged, Middle Aged, Female, Male, Young Adult, Healthy Volunteers, Drug-Related Side Effects and Adverse Reactions, Darunavir, Cobicistat
Depositing User:	Symplectic Admin
Date Deposited:	07 Jan 2019 10:06
Last Modified:	07 Feb 2024 15:11
DOI:	10.1093/jac/dky384
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3030902