Rilpivirine

A highly potent nonnucleoside inhibitor (NNRTI) of HIV-1 reverse trK7912:M7912anscriptase with IC50 of 0.4 nM for WT HIV-1 in cell-based assay; shows activity against a panel of single and double HIV-1 site-directed mutant (IC50=0.3-2 nM) ; orally active.HIV Infection Approved (In Vitro) :R278474 is active against wild-type HIV-1 (EC50=0.4 nM) and all single and double mutants tested (EC50=0.1-2.0 nM) .R278474 (10-5000 nM; 30 d) does not observe the sign of wild-type HIV-1 breakthrough at 1 μM within 30 days.R278474 inhibits 81% of clinical isolates (about 1200 recombinant clinical isolates) at a 50% inhibitory concentration (EC50) less than 1 nM, and inhibits 94% at EC50 less than 10 nM.TMC278 shows subnanomolar EC50s against wild-type HIV-1 group M isolates (0.07-1.01 nM) and nanomolar EC50s against group O isolates (2.88-8.45 nM) in MT4 T-cells. (In Vivo) :R278474 (10-160 mg/kg; p.o. for 1 month) does not produce abnormal effects in rat, apart from liver weight increase and species-specific thyroid hypertrophy, both at the higher dose levels.R278474 (i.v.) exhibits elimination half-life ranges from 4.4 h in rat to 31 h in dog, and exposure (AUCinf) amounts to 3.1 μg h/mL (4 mg/kg) in rat, 8.7 μg h/mL (1.25 mg/kg) in dog, 1.4 μg h/mL (1.25 mg/ kg) in monkey, and 44 μg h/mL (1.25 mg/kg) in rabbit.R278474 (p.o.) exhibits half-life ranges between 2.8 h in rat and 39 h in dog, and oral bioavailability of 32% and 31% in rat and dog.