Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a long-acting injectable antiretroviral formulation

Abstract

The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.

FIG. 1.

Mean plasma concentration-time profiles of rilpivirine (TMC278) after a single 5-mg/kg or 20-mg/kg dose of rilpivirine LA in male rats (n = 6, alternated sampling per treatment group) showing effect of dose and route of administration.

FIG. 2.

Six-month mean plasma concentration-time profiles of rilpivirine (TMC278) after IM and SC administration of a single 5-mg/kg dose of rilpivirine LA in male dogs (n = 3 per treatment group; LLOQ = 1 ng/ml).

FIG. 3.

Mean plasma concentration-time profiles of rilpivirine (TMC278) after administration as LA injection showing effect of dose (200 to 400 mg), route of administration, and gender on single-dose pharmacokinetics of rilpivirine LA during 1 month of follow-up (n = 3 per dosage and gender). Because of restrictions on the volume that can be injected at once in a dog, the 200-mg dose was administered as two single injections (1 site), and the 400 mg as two double injections (2 skin or muscle sites), 24 h apart.

FIG. 4.

Species comparison of rilpivirine (TMC278) plasma concentration-time profiles after single SC or IM administration of rilpivirine LA, showing (i) higher clearance rates in rats but similar rates in dogs and humans and (ii) a difference in initial plasma concentration-time profile between IM and SC dosings in dogs and, to a lesser extent, in rats but no differences in humans. (Mean data from male rats [n = 3], male and female dogs [n = 6 in total] [current studies], and humans [n = 6] [29]).