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Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naive individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA)
Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.;Dept Internal Med, Rotterdam, Netherlands..
Radboud Univ Nijmegen, Dept Pharm, Med Ctr, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.;Radboud Inst Hlth Sci, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Dept Pharm, Med Ctr, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.;Radboud Inst Hlth Sci, POB 9101, 9101, Geert Grootepl Zuid 10,route 864, NL-6500 HB Nijmegen, Netherlands.ORCID iD: 0000-0002-0093-6445
Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.;Dept Internal Med, Rotterdam, Netherlands..
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2023 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 61, no 1, article id 106697Article in journal (Refereed) Published
Abstract [en]

To the authors' knowledge, there is currently no literature or guidance recommendation regard-ing whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and com-pared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretro-viral therapy within < 24 h of enrolment: DTG 50 mg BID, DRV/r 80 0/10 0 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs there-after (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration-time profile of 0-24 h (AUC0-24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90-2.55). Total exposure during DTG BID increased but did not double [AUC0-24h GMR 1.65 (90% CI 1.50-1.81) h.mg/L]. DTG glucuronidation MR increased by approxi-mately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads <= 40 copies/mL. The drug-drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Place, publisher, year, edition, pages
Elsevier, 2023. Vol. 61, no 1, article id 106697
Keywords [en]
Darunavir, ritonavir, Acute HIV infection, Dolutegravir, Population PK
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:uu:diva-495898DOI: 10.1016/j.ijantimicag.2022.106697ISI: 000910030500001PubMedID: 36470510OAI: oai:DiVA.org:uu-495898DiVA, id: diva2:1735031
Available from: 2023-02-07 Created: 2023-02-07 Last updated: 2023-02-07Bibliographically approved

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Svensson, Elin M.

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