e integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.
Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.
Pharmacodynamic effects
Antiviral activity in cell culture
The IC50 for dolutegravir against various laboratory strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).
Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median IC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited in vitro activity against HIV-2 with IC50 values ranging from 2,510 to 10,830 nM.
Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with IC50 values ranging from 0.07 to 1.01 nM and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM.
Effect of human serum and serum proteins
In 100% human serum, the dolutegravir mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 μg/mL.
A reduction in the antiviral activity of rilpivirine was observed in the presence of 1 mg/mL alpha-1-acid glycoprotein, 45 mg/mL human serum albumin, and 50% human serum as demonstrated by median IC50 rates of 1.8, 39.2 and 18.5, respectively.
Resistance
Resistance in vitro
Serial passage is used to study resistance evolution in vitro. For dolutegravir, when using the laboratory strain HIV-1 IIIB during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F; these mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432, integrase mutations E92Q (fold change [FC] 3) and G193E (FC 3) were selected. These mutations have been selected in patients with pre-existing raltegravir resistance and who were then treated with dolutegravir (listed as secondary mutations for dolutegravir).
In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two individual patients with subtype B and subtype C in the Phase III clinical program for ART experienced, INI naive subjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir in the Phase III program.
Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to primary mutations (e |
