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Pharmacokinetics of Crushed Elvitegravir Combination Tablet Given With Drip Feed
Angela Colbers1; Mieke de Hoon1; Reinout van Crevel1; Martine Kruijssen1; Marjolijn Duisenberg-van Essenberg2; Evertine Abbink1; David M. Burger1
1Radboud Univ Med Cntr, Nijmegen, Netherlands;2Elisabeth-TweeSteden Ziekenhuis, Tilburg, Netherlands
If HIV-patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is often crushed and solved prior to administration. Currently, there is no information about crushing the fixed-dose combination of elvitegravir/cobicistat/emtricitabine/tenofovir (E/C/E/T). Crushing can influence pharmacokinetics (PK) leading to altered drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Therefore crushing of E/C/E/T is not recommended. A possible PK interaction between elvitegravir (EVG) and drip feed is expected, based on the interaction between EVG and antacids. No interaction occurs between other pH-increasing drugs (omeprazole) and EVG, therefore the interaction is most likely caused by complexation between EVG and cations.
An open-label, 3-period, randomized, cross-over, trial in 24 healthy volunteers was conducted. Subjects randomly received a single dose of STB with a 7-day washout period. Reference treatment A: E/C/E/T whole tablet with breakfast (350 kcal), intervention treatments B: crushed and suspended E/C/E/T with breakfast and C: crushed and suspended E/C/E/T with drip feed (350kcal). To show bioequivalence between reference A versus B and C a 32-h PK profile was measured for EVG, COBI (cobicistat), FTC (emtricitabine) and TDF (tenofovir). Geometric mean ratios (GMR) with 90% confidence interval (CI) for AUC and Cmax were calculated. Safety and tolerability were evaluated.
24 healthy volunteers (23 Caucasian and 1 mixed-race,12 female), 37(20-54) years and BMI of 24(19-29) (median (range)) were included in the trial.
The GMR (90% CI) of Cmax and AUC of EVG were 117% (106-129) and 109% (99-120) for B vs A, 104% (94-115) and 104% (94-114) for C vs A. GMR of Cmax and AUC for COBI were 83% (76-91) and 89% (82-97) for B vs A and 101% (92-110) and 102% (94-111) for C vs A.
For FTC the GMR of AUC and Cmax were 89% (83-97) and 99% (95-104) for B vs A and 96% (89-104) and 101% (97-106) for C vs A. For TDF the GMR of AUC and Cmax were 81% (71-92) and 100% (92-113) for B vs A and 94% (83-107) 105% (97-108) for C vs A.
No SAEs were reported during the trial.
AUCs fell within the bioequivalence ranges for all compounds. For Cmax the 90% CI were just outside the bioequivalence range, but this was considered not clinically relevant. E/C/E/T can be crushed and suspended and given with drip feed.