Cell lines

Caco-2 cell lines

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Reaction Conditions

1 h; 20 μM

Applications

The ability of rilpivirine to inhibit ABCB1-mediated transport of digoxin was assessed using Caco-2 cell monolayers. Permeation of 1 μM digoxin in the A-to-B direction was significantly increased when it was coincubated with rilpivirine at 1 μM, 3μM, 10μM and 30μM compared with that for the rilpivirine-free controls. Permeation of 1 μM digoxin in the B-to-A direction was significantly decreased when it was coincubated with 10 μM rilpivirine and 30 μM rilpivirine compared with rilpivirine-free control incubations

Animal models

Six male beagle dogs

Dosage form

Per dog, two vials each containing 25 mg of TMC278; oral taken

Applications

In dogs, TMC278 (rilpivirine) was more slowly absorbed from tablets than from the suspended powders for reconstitution. Compared to the tablet, the relative bioavailability obtained with the powders ranged between 69% and 89% for TMC278/PVP-VA 64 1:9 (w/w) and between 85% and 157% for TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w).

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Rilpivirine is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase with IC50 value of 0.73 nM [1].

Since the existed anti-HIV compound efavirenz showed a serious of side effects including low genetic barrier to resistance and causing CNS disturbance, the alternative NNRTIs (non-nucleoside reverse transcriptase inhibitors) with the advantages (potent, well-tolerated and long plasma half-lives) of efavirenz and without these side effects have been developed. Rilpivirine is one of these new candidate compounds [2].

Rilpivirine showed inhibitory activities to both wild-type HIV (with EC50 value of 0.51 nM) and NNRTI-resistant strains. The conformational flexibility of rilpivirine allowed it to adjust different mutations of the reverse transcriptase. For the singly mutant HIV strains such as L100I, G190S, G190A and V106A, rilpivirine showed higher retained potency than efavirenz and low EC50 values blow 1 nM. In MT-4 cells infected with the K103N isolates, rilpivirine exerted the EC50 value of 0.35 nM. Besides that, rilpivirine showed EC50 values of 2.7 nM and 0.8-1.7 nM for the double-mutant strains K103N/L100I and K103N/ Y181C, respectively. Besides that, rilpivirine was found to significantly inhibit the expression or function of some drug transporters including OATP1B1, CYP3A4 and ABCB1 [2 and 3].

The long elimination half-life and high oral bioavailability of rilpivirine allowed it to be administrated in once-daily oral dose. It showed good oral absorption at dose up to 200 mg in the in vivo evaluation assay. Since rilpivirine has a poor water- and oil- solubility, a nanosuspension injectable formulation has been developed [2 and 4].

References:
[1] Moss D M, Liptrott N J, Curley P, et al.  Rilpivirine inhibits drug transporters ABCB1, SLC22A1, and SLC22A2 in vitro. Antimicrobial agents and chemotherapy, 2013, 57(11): 5612-5618.
[2] Garvey L, Winston A.  Rilpivirine: a novel non-nucleoside reverse transcriptase inhibitor. 2009.
[3] Weiss J, Haefeli W E.  Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro. International journal of antimicrobial agents, 2013, 41(5): 484-487.
[4] Baert L, van’t Klooster G, Dries W, et al.  Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. European Journal of Pharmaceutics and Biopharmaceutics, 2009, 72(3): 502-508.