GENVOYA(elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide)tablets(二十)
ed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was not significantly affected. ‡ t 1/2 values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs. § Dosing in mass balance studies: elvitegravir (single dose administration of [ 14C] elvitegravir coadministered with 100 mg ritonavir); cobicistat (single dose administration of [ 14C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [ 14C] TAF).
Absorption
Tmax (h) 4 3 3 1
Effect of light meal (relative to fasting): AUC Ratio* 1.34
(1.19, 1.51) 1.03
(0.90, 1.17) 0.95
(0.91, 1.00) 1.15
(1.07, 1.24)
Effect of high fat meal (relative to fasting): AUC Ratio* 1.87
(1.66, 2.10) 0.83
(0.73, 0.95) 0.96
(0.92, 1.00) 1.18
(1.09, 1.26)
Distribution
% Bound to human plasma proteins ~99 ~98 <4 ~80
Source of protein binding data Ex vivo In vitro In vitro Ex vivo
Blood-to-plasma ratio 0.73 0.5 0.6 1.0
Metabolism
Metabolism CYP3A (major)
UGT1A1/3 (minor) CYP3A (major)
CYP2D6 (minor) Not significantly metabolized Cathepsin A† (PBMCs)
CES1 (hepatocytes)
CYP3A (minimal)
Elimination
Major route of elimination Metabolism Metabolism Glomerular filtration and active tubular secretion Metabolism (>80% of oral dose)
t1/2 (h)‡ 12.9 3.5 10 0.51
% Of dose excreted in urine§ 6.7 8.2 70 <1%
% Of dose excreted in feces§ 94.8 86.2 13.7 31.7
Table 7 Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA with Food in HIV-Infected Adults
Parameter
Mean (CV%) Elvitegravir* Cobicistat* Emtricitabine* TAF† Tenofovir‡
CV = Coefficient of Variation; NA = Not Applicable
* From Intensive PK analysis in Study 102, N=19 † From Population PK analysis in Studies 104 and 111, N=539 ‡ From Population PK analysis in Studies 104 and 111, N=841
Cmax
(microgram per mL) 2.1 (33.7) 1.5 (28.4) 2.1 (20.2) 0.16 (51.1) 0.02 (26.1)
AUCtau
(microgram∙hour per mL) 22.8 (34.7) 9.5 (33.9) 11.7 (16.6) 0.21 (71.8) 0.29 (27.4)
Ctrough
(microgram per mL) 0.29 (61.7) 0.02 (85.2) 0.10 (46.7) NA 0.01 (28.5)
Special Populations
Patients with Renal Impairment
The pharmacokinetics of GENVOYA in HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method) were eva luated in a subset |
