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Plasma and Intracellular Pharmacokinetics of Darunavir/Ritonavir Once Daily and Raltegravir Once and Twice Daily in HIV-Infected Individuals

Jackson, Akil MBBS*; Watson, Victoria MSc†,‡; Back, David PhD; Khoo, Saye PhD; Liptrott, Neill PhD†,‡; Egan, Deidre BSc†,‡; Gedela, Keerti MBBS*; Higgs, Chris BSc*; Abbas, Riaz MSc§; Gazzard, Brian MD*; Boffito, Marta PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: 15 December 2011 - Volume 58 - Issue 5 - p 450–457
doi: 10.1097/QAI.0b013e3182364c67
Clinical Science

Objectives: To investigate the pharmacokinetics of darunavir/ritonavir and raltegravir, in HIV-infected subjects, in both plasma and at the intracellular (IC) site of action.

Methods: HIV-infected patients on antiretroviral therapy received raltegravir 400 mg twice daily for 21 days (period 1); darunavir/ritonavir 800/100 mg once daily was added for 14 days (period 2), and patients were randomized to continue raltegravir twice daily (group 1) or to switch to 800 mg once daily (group 2), then they all stopped raltegravir intake and continued darunavir/ritonavir once daily for 14 days (period 3). Drug concentrations in plasma and cells (peripheral blood mononuclear cell) were measured, and differences in geometric mean ratios (GMR) and 90% confidence intervals (CI) between period 2 versus period 3 and period 2 versus period 1 were assessed.

Results: Twenty-four patients completed the study. Group 1 GMR (90% CI) of darunavir area under the curve (AUC) with and without raltegravir was 1.24 (1.13 to 1.45) for plasma and 1.24 (1.07 to 1.73) for cells and for group 2 was 1.14 (1.07 to 1.24) and 1.03 (0.94 to 1.16). GMR (90% CI) of raltegravir AUC without and with darunavir/ritonavir (plasma and cells) for group 1 was 0.90 (0.73 to 1.44) and 1.02 (0.81 to 1.67) and for group 2 was 1.21 (1.03 to 1.77) and 1.27 (1.07 to 1.94). Geometric mean IC to plasma AUC ratios were 5.3 and 4.9 for darunavir in groups 1 and 2 when darunavir/ritonavir was given alone and 4.9 and 5.6 for raltegravir when given alone. These ratios were not altered by the coadministered drug.

Conclusions: No remarkable interactions between darunavir/ritonavir and raltegravir in plasma or cells were seen. Raltegravir IC concentrations are higher than previously reported; the difference being due to modified cell isolation procedures that reduced drug loss caused by washing.

*St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom

Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom

NIHR Biomedical Research Centre, Royal Liverpool Hospital Trust, Liverpool, United Kingdom

§Janssen-Cilag Ltd, High Wycombe, United Kingdom.

Supported by Janssen-Cilag Ltd, United Kingdom, and St. Stephen's AIDS Trust.

Some of the results of this study were presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27, to March 2, 2011; Boston, MA.

A. Jackson, D. Back, S. Khoo, B. Gazzard, and M. Boffito had received travel and research grants from and have been advisers for Tibotec, Roche, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Merck Sharp & Dohme, Abbott, and Boehringer Ingelheim. R. Abbas is full-time employee of Janssen-Cilag Ltd, United Kingdom.

A. Jackson and V. Watson should be considered joint first authors.

Correspondence to: Dr Marta Boffito, PhD, St. Stephen's Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom (e-mail: marta.boffito@chelwest.nhs.uk).

Received May 10, 2011

Accepted September 6, 2011

© 2011 Lippincott Williams & Wilkins, Inc.