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ICAAC 2014: PK Study Shows Feasibility of Long-acting Integrase Inhibitor Cabotegravir


A pharmacokinetic (PK) analysis presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy this week in Washington, DC, confirmed that the long-acting HIV integrase inhibitor cabotegravir (formerly GSK1265744) reaches adequate target levels in the blood, setting the stage for efficacy trials for HIV treatment and pre-exposure prophylaxis (PrEP).

Cabotegravir, being developed by GlaxoSmithKline, has shown good antiviral activity and has appeared safe and well-tolerated in clinical trials to date, both as a daily pill and as a long-acting nanosuspension injection that may be administered monthly or even quarterly. Such a long-acting agent could be used for simplified maintenance therapy for people with HIV, and might help overcome adherence concerns if used for PrEP. Monthly cabotegravir injections for PrEP have already been studied with promising results in monkeys.

The study presented at ICAAC by Susan Ford of GlaxoSmithKline used a population pharmacokinetic approach to establish appropriate doses of long-acting injectable cabotegravir for use in Phase 2b trials.

In early studies of healthy HIV negative volunteers, single 100 mg to 800 mg injections of long-acting cabotegravir maintained plasma drug concentrations for up to 52 weeks, while repeated monthly and quarterly injections achieved plasma concentrations equivalent to those associated with antiviral activity following oral administration, the researchers noted as background.

This PK analysis used data from 8 Phase 1 and 2a/b studies of cabotegravir administered orally or as long-acting injections. Data were fed into a statistical model to simulate long-acting dosing regimens for future studies.


  • A total of 346 participants and 4482 observations were included in the population PK analysis.
  • About 80% were men, 70% were white, 25% were black, 55% were HIV positive, the median age was 34 years, and the median body mass index (BMI) was 25.5 ("overweight").
  • Both oral and long-acting injectable cabotegravir formulations were well described by a 2-compartment, first order absorption model, with a lag time for the oral formulation.
  • 3 factors were found to have a statistically significant effect on plasma drug levels: sex, BMI, and oral vs injectable administration route.
  • Absorption of long-acting cabotegravir was reduced by 20% for men and by 24% for women with BMI >30 -- indicating obesity -- relative to those with median BMI.
  • Conversely, absorption increased by 35% and 43%, respectively, for men and women with BMI <22-23 -- or "healthy" weight -- relative to those with median BMI.

The dosing model was used to simulate an initial cabotegravir "loading dose" of 800 mg by intramuscular injection, followed by 3 subsequent dosing regimens: 400 mg monthly injections, 600 mg bimonthly injections (every other month), or 800 mg quarterly injections (every 3 months).

All 3 dosing schedules led to mean plasma steady-state trough concentrations -- the lowest level between doses -- above therapeutic targets previously established for HIV treatment and prevention (3.35, 2.02, and 1.57 mg/mL, respectively).

These findings support the use of dosing regimens in Phase 2b trials of long-acting cabotegravir for treatment of HIV positive people and prevention for HIV negative people, the researchers concluded. To see if it is suitable for PrEP, however, it will be necessary to determine not only blood drug levels, but also rectal and vaginal levels.



SL Ford, J Chiu, M Lovern, et al. Population PK Approach to Predict Cabotegravir (CAB, GSK1265744) Long-Acting Injectable Doses for Phase 2b (Ph 2b). 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract H-645.