BMC assays ranged from 0.09 nM to 0.61 nM.
Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of celllines including monocytes and PBMCs using standard susceptibility assays. EC50 values were inthe range of 3 to 15,000 nM (1 nM = 230 ng/mL). The EC50 values of lamivudine againstdifferent HIV-1 clades (A-G) and group O viruses ranged from 1 to 120 nM, and against HIV-2isolates from 3 to 120 nM in PBMCs.
Antiviral Activity in Combination with Other Antiviral Agents
Neither dolutegravir nor lamivudine were antagonistic to all tested anti-HIV agents.
Resistance
Cell Culture: Dolutegravir: Dolutegravir-resistant viruses were selected in cell culture startingfrom different wild-type HIV-1 strains and clades. Amino acid substitutions emerged in differentpassages; the substitution G118R emergence conferred decreased susceptibility to dolutegravir of10-fold, while substitutions E92Q, S153F or Y, G193E, or R263K conferred decreasedsusceptibility to dolutegravir of up to 4-fold.
Lamivudine: HIV-1 resistance to lamivudine involves the development of a M184V or
M184I amino acid change close to the active site of the viral RT. This variant arises both in cell culture and in HIV-1–infected patients treated with lamivudine-containing antiretroviral therapy.
Substitutions M184V or I confer high-level resistance to lamivudine.
Clinical Subjects: At Week 48, none of the 6 subjects in the dolutegravir plus lamivudine groupor the 4 subjects in the dolutegravir plus TDF/FTC group who met the protocol-definedconfirmed virologic withdrawal criteria across the pooled GEMINI-1 and GEMINI-2 trials hademergent INSTI- or NRTI-resistance substitutions.
Cross-Resistance
Dolutegravir: The susceptibility of dolutegravir was tested against 60 INSTI-resistant sitedirectedmutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions).
The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a >2-fold decreasein dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations ofmultiple substitutions T66K/L74M; E92Q/N155H; G140C/Q148R; G140S/Q148H, R or K;
Q148R/N155H; T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a >2-fold
decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).
Lamivudine: Cross-resistance conferred by the M184V or I RT has been observed within the
NRTI class of antiretroviral agents. The M184V or I substitution confers resistance toemtricitabine and to abacavir, which selects M184V or I plus additional RT substitutions K65R,L74V, and Y115F. Zidovudine maintains its antiretroviral activities against lamivudine-resistant
HIV-1. Abacavir and tenofovir maintain antiretroviral activity against lamivudine-resistant HIV-
1 harboring only the M184V or I substitution.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
Dolutegravir: Two-year carcinogenicity studies in mice and rats were conducted withdolutegravir. Mice were administered doses of up to 500 mg/kg, and rats were administereddoses of up to 50 mg/kg. In mice, no significant increases in the incidence of drug-relatedneoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposuresapproximately 26 times higher than those in humans at the recommended dose. In rats, no |
