GENVOYA(elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide)tablets(二十七)
tions. These genotypic resistance results were confirmed by phenotypic analyses.
In Virologically Suppressed Subjects:
Three virologic failure subjects were identified with emergent genotypic and phenotypic resistance to GENVOYA (all three with M184I or V and one with K219Q in reverse transcriptase; two with E92Q or G in integrase) out of 8 virologic failure subjects with resistance data in a clinical study of virologically-suppressed subjects who switched from a regimen containing emtricitabine/TDF and a third agent to GENVOYA (Study 109, N=959).
Cross-Resistance
No cross-resistance has been demonstrated for elvitegravir-resistant HIV-1 isolates and emtricitabine or tenofovir, or for emtricitabine- or tenofovir-resistant isolates and elvitegravir.
Elvitegravir: Cross-resistance has been observed among INSTIs. Elvitegravir-resistant viruses showed varying degrees of cross-resistance in cell culture to raltegravir depending on the type and number of amino acid substitutions in HIV-1 integrase. Of the primary elvitegravir resistance-associated substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced susceptibility to raltegravir (above the biological cutoff for raltegravir) when introduced individually into a wild-type virus by site-directed mutagenesis. Of the primary raltegravir resistance-associated substitutions (Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than 2.5-fold reductions in susceptibility to elvitegravir (above the biological cutoff for elvitegravir). Some viruses expressing elvitegravir or raltegravir resistance amino acid substitutions maintain susceptibility to dolutegravir.
Emtricitabine: Cross-resistance has been observed among NRTIs. Emtricitabine-resistant isolates harboring an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine.
Tenofovir Alafenamide (TAF): Tenofovir resistance substitutions, K65R and K70E, result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir.
HIV-1 with multiple TAMs (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R, showed reduced susceptibility to TAF in cell culture.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Elvitegravir
Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats for up to 88 weeks (males) and 90 weeks (females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day RTV at exposures 3- and 14 times, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27 times, respectively in male and female, the human systemic exposure.
Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabol |
