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Cobicistat Doubles to Triples Exposure of GS-7340 (a Tenofovir Prodrug) and Resulting Tenofovir
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Giving GS-7340, the investigational tenofovir prodrug, with the boosting agent cobicistat doubled to tripled exposure of this novel reverse transcriptase inhibitor and of tenofovir, according to results of three studies in healthy volunteers [1]. The findings suggest that a combination tablet of GS-7340, cobicistat, elvitegravir, and emtricitabine (FTC) could contain as little as 10 mg of GS-7340. The 4-in-1 QUAD tablet contains 300 mg of tenofovir disoproxil fumarate (TDF).
Prior research suggested that GS-7340 may have several advantages over TDF, including enhanced delivery of tenofovir to the lymphatic system, higher intracellular concentrations of tenofovir, greater viral load suppression at doses lower than TDF, and lower circulating tenofovir levels, which may improve safety and tolerability [2,3].
Gilead Sciences researchers are seeking an appropriate GS-7340 dose for a 4-in-1 pill also including the integrase inhibitor elvitegravir, the booster cobicistat, and the nucleoside FTC. At the HIV Pharmacology Workshop, they reported results of three studies in healthy volunteers:
-- Study 1 enrolled 20 volunteers in a 4 x 4 crossover design to take (1) EVG/COBI/FTC/GS-7340 at doses of 150/150/200/40 mg or 150/150/200/25 mg daily, (2) EVG/COBI/FTC/TDF at a dose of 150/150/200/300 mg daily, or (3) GS-7340 alone at 25 mg for 12 days per treatment.
-- Study 2 enrolled 12 volunteers who sequentially took GS-7340 at 8 mg daily for 12 days, then GS-7340 plus cobicistat at 8/150 mg daily for 10 days.
-- Study 3 enrolled 34 volunteers in 2 crossover cohorts to take (1) EVG/COBI/FTC/GS-7340 at doses of 150/150/200/10 mg daily or EVG/COBI at 150/150 mg daily, each for 12 days and (2) EVG/COBI/FTC/GS-7340 at doses of 150/150/200/10 mg daily or FTC/GS-7340 200/25 mg daily, each for 12 days.
Cohorts 1, 2, and 3 had 10, 4, and 10 women, respectively, and 3, 3, and 14 blacks. Age in the three cohorts averaged 80.2, 78.5, and 74.9 kg.
Nineteen of 20 healthy volunteers completed study 1, with 1 person dropping out because of grade 2 rhabdomyolysis while taking GS-7340. Everyone completed study 2, and 33 of 34 people completed study 3. No grade 3 or 4 adverse events occurred in any study.
In study 1 the 4-in-1 tablet containing 25 mg of GS-7340 resulted in GS-7340 and tenofovir exposures much higher than with GS-7340 alone at 25 mg. Geometric mean ratios (GMRs) (and 90% confidence intervals [CI]) comparing the two regimens were 222 (200-246) for GS-7340 area under the concentration-time curve (AUC), 223 (187-265) for GS-7340 maximum concentration (Cmax), 307 (290-324) for tenofovir AUC, and 368 (320-423) for tenofovir Cmax.
In study 2 GS-7340 and tenofovir AUC and Cmax were similarly higher with GS-7340 at 8 mg plus cobicistat than with GS-7340 at 8 mg alone (GMR 265, 90% CI 229-307 for GS-7340 AUC; GMR 283, 90% CI 220-365 for GS-7340 Cmax; GMR 331, 90% CI 310-353 for tenofovir AUC; GMR 334, 90% CI 302-370 for tenofovir Cmax; GMR 335, 90% CI 312-359 for tenofovir trough). Those results suggested that cobicistat accounted for the interaction seen in study 1.
In study 3 GS-7340 at 10 mg in the 4-in-1 tablet yielded similar GS-7340 exposure as GS-7340 at 25 mg with FTC. Tenofovir exposures were comparable with the 4-in-1 tablet and with GS-7340 at 25 mg with FTC, but 90% lower than tenofovir exposures in attained with the QUAD, the experimental pill containing elvitegravir, cobicistat, tenofovir, and FTC..
The Gilead researchers concluded that GS-7340 and tenofovir exposure increase 2- to 3-fold with cobicistat, probably because cobicistat inhibits intestinal P-glycoprotein-mediated secretion of GS-7340. When GS-7340 was dosed at 10 mg daily in the 4-in-1 pill it provided GS-7340 and tenofovir exposures similar to GS-7340 alone at 25 mg. Tenofovir exposure with GS-7340 at 10 mg in the 4-in-1 pill was about 90% lower than with standard-dose QUAD.
NOTE
This was reported in the initial version of the report:
The single case of grade 2 rhabdomyolysis in a person taking GS-7340 resolved but still raised concerns among workshop attendees because of the greater tenofovir cell penetration achieved with GS-7340. Subsequent to the meeting the study author told us: The AE initially categorized as Gr 2 rhabdomyolysis was in fact noted to be a Grade 3 CPK elevation and this occurred during a 3-day washout phase between two treatments (subject had completed 3 different treatments and about 40 doses earlier). So it was study discontinuation rather than study-drug, since the subject was not receiving study drug at the time the lab increase was noted. The subject was followed and the CPK returned to normal range.
References
1. Ramanathan S, Wei X, Custodio J, Wang H, Dave A, Cheng A, Kearney BP. Pharmacokinetics of a novel EVG/COBI/FTC/GS-7340 single tablet regimen. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_13.
2. Ruane P, DeJesus E, D Berger D, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir disoproxil fumarate 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 103. http://www.natap.org/2012/CROI/croi_29.htm.
3. Markowitz M, Zolopa A, Ruane P, et al. GS-7340 Demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 152LB.
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