Depot Formulation of Rilpivirine (TMC278) May Offer Months of Sustained Anti-HIV Activity with a Single Injection

By Liz Highleyman

Researchers at the XVII International AIDS Conference this month in Mexico City reported data from studies of new non-nucleoside reverse transcriptase inhibitors (NNRTIs), of which rilpivirine (TMC278) is furthest along in the development pipeline.

As previously reported, rilpivirine continued to demonstrate good efficacy at 96 weeks; 73% of patients taking rilpivirine as part of a combination antiretroviral regimen had HIV RNA < 50 copies/mL, compared with 71% of those taking efavirenz (Sustiva).

In a poster presentation at the conference, investigators from Tibotec reported data from an early clinical trial of a "depot" formulation of rilpivirine in HIV negative volunteers. Depot drugs are injected into the body and released slowly over time, allowing them to be administered less often.

As background, the researchers suggested that depot TMC278 potentially could be used for maintenance therapy or pre-exposure prophylaxis (PrEP), assuming it can be combined with other antiretroviral agents in a similar long-acting formulation.

In the present trial, they investigated the pharmacokinetics (PK) and tolerability of subcutaneous (SC) and intramuscular (IM) injections of a nanosuspension formulation of TMC278, consisting of miniscule crystals of the drug in a liquid base.

The study included 51 HIV negative volunteers who received a single abdominal subcutaneous or gluteal (butt) intramuscular injection at doses of 200, 400, or 600 mg, or else placebo. A further group of 9 volunteers received a single 400 mg injection into the deltoid (shoulder) rather than gluteal muscle.

Results

• As intended, TMC278 was released slowly from the injection site.

• Plasma concentrations of TMC278 reached a maximum after about 3 days.

• At week 8, the concentration was about 20 ng/mL.

• Concentrations fell biphasically from day 3 to below 10 ng/mL by 12 to 26 weeks.

• Mean PK parameters were similar after 400 mg SC, gluteal IM, and deltoid IM injections:

• Maximum concentration (Cmax): 70, 99, and 80 ng/mL, respectively.

• Area under the curve (AUC0-week 12): 57,600, 61,400, and 63,780 ng.h/mL, respectively.

• Serious (grade 3-4) adverse events were not observed.

• Injection site reactions consisting of redness, bruising, pain, and sometimes induration (hard swelling) were more common after TMC278 than after placebo injections.

• IM injections were better tolerated than SC injections.

• For IM injections, the gluteal site was better tolerated than the deltoid.

• At the 400 mg dose, deltoid injections induced more spontaneous pain and pain to the touch (occurring in 6 of 6 volunteers) than gluteal injections (2 of 6 volunteers).

These findings led the investigators to conclude that "TMC278 long-acting depot formulation administered in single doses provided prolonged exposure to TMC278 for several months and was well tolerated."

They added, "Based on a greater number of injection site reactions with the SC versus the IM route, IM injection was better tolerated than SC injection."

"Injectable long-acting formulations may provide a new paradigm in antiretroviral use and may facilitate long-term compliance," they suggested.

The researchers plan to conduct a multiple-dose trial in HIV negative volunteers, followed by studies in HIV positive individuals if they continue to obtain promising results. They also intend to explore a more concentrated formulation that may allow for higher or longer-lasting drug levels in the body.

Tibotec BVBA, Mechelen, Belgium; Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium; Johnson & Johnson Pharmaceutical Research and Development, Merksem, Belgium.

8/29/08

Reference
R Verloes, G van't Klooster, L Baert, and others. TMC278 long acting - a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteers. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract TUPE0042.