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Dolutegravir Persists Longer Than Elvitegravir After Dosing Stops
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16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
Dolutegravir persisted in plasma 72 hours after the last dose in all 17 HIV-negative participants in a 10-day study and remained above the protein binding-adjusted 90% inhibitory concentration (IC90) in 16 of 17 [1]. Elvitegravir, as part of Stribild, persisted in all 17 participants 36 hours after the last dose and above the IC90 in 11 of 17, but elvitegravir could not be detected 72 hours after the last dose in 8 of 17 participants. The findings of this UK study have implications for persistence of these integrase inhibitors after missed doses and for their use as preexposure prophylaxis (PrEP).
Until this two-phase open-label trial involving HIV-negative volunteers, there were no in vivo data on concentration decay of dolutegravir or elvitegravir, two licensed integrase inhibitors, after dosing stops. To fill that gap, researchers from Chelsea and Westminster Hospital, the University of Liverpool, and Imperial College London conducted this study in 17 healthy volunteers.
Study participants took the standard dolutegravir dose of 50 mg once daily for 10 days. After taking no drug for 9 days, they took 150 mg of elvitegravir coformulated with cobicistat and TDF/FTC as Stribild. Researchers collected serial samples before the final dose on day 10 of each dosing period then regularly for up to 216 hours after the last dose.
Twelve of 17 study participants were women, median age was 39 (range 26 to 52), and median body mass index 26 kg/m(2) (range 19 to 34). Nine participants were white and 8 were black.
In the 17 people who completed the study, dolutegravir plasma half-life within the 24-hour dosing interval was shorter than its terminal elimination half-life to the last measurable concentration within 216 hours (14.3 versus 23.1 hours). In contrast, elvitegravir plasma half-life within the dosing interval was longer than its terminal elimination half-life to the last measurable concentration (10.8 versus 5.2 hours).
During dosing geometric mean 24-hour area under the concentration-time curve (and 90% confidence interval) were 55505 ng*h/mL (51368 to 59642) for dolutegravir and 22965 ng*h/mL (21483 to 25592) for elvitegravir. Respective maximum concentrations were 3908 ng/mL (3571 to 4245) and 1675 ng/mL (1557 to 1884). Respective 24-hour concentrations were 1324 ng/mL (1178 to 1470) and 419 ng/mL (387 to 501). And respective 48-hour concentrations stood at 427 ng/mL (362 to 499) and 8 ng/mL (8 to 15).
Thirty-six hours after the last dose, dolutegravir remained detectable above the protein binding-adjusted IC90 (64 ng/mL) in all 17 participants, ranging from 230 to 1182 ng/mL. Elvitegravir remained detectable in all participants 36 hours after the last dose and lay above the protein-binding adjusted IC90 (45 ng/mL) in 11 of 17 people. Elvitegravir levels at that point ranged from 11 to 296 ng/mL.
Forty-eight hours after the last dose, dolutegravir concentrations continued to remain detectable and above the protein binding-adjusted IC90 in all 17 study participants, ranging from 109 to 791 ng/mL. After 48 hours elvitegravir could be detected in 16 of 17 participants but always below the protein binding-adjusted IC90.
Sixty hours after the last dose, dolutegravir remained detectable in all 17 participants and above the protein binding-adjusted IC90 in 16 of them (range 49 to 532 ng/mL). After 60 hours elvitegravir could be detected in 13 of 17 study participants, always below the protein binding-adjusted IC90.
Seventy-two hours after the last dose, dolutegravir remained detectable in all participants and above the protein binding-adjusted IC90 in 16 of 17. At 96 hours after the last dose, dolutegravir remained detectable in all participants and above the IC90 in 4 of 17. At 72 hours elvitegravir remained detectable in 9 of 17 participants, all below the IC90.
Reference
1. Elliot E, Amara A, Jackson A, et al. Pharmacokinetics of once-daily dolutegravir and elvitegravir/cobicistat following drug cessation. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 13.
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