ARV pipeline: long-acting formulations of rilpivirine, GSK-744 and nanoformulations

Simon Collins, HIV i-Base

A useful poster discussion focused on long-acting (LA) formulations that are in early stages of development, some of which appear to be prioritised for use for prevention rather than treatment. [1]

This session included an introduction by Marta Boffito from the Chelsea and Westminster Hospital in London. [2]

Current ARVs with long acting formulations include a monthly intramuscular (IM) injection of rilpivirine LA and injectable formulations of the integrase inhibitor GSK744 (both IM and sub-cutaneous) where therapeutic drug levels are sustained for well over a month. The monoclonal antibody ibalizumab that has been in development for many years as a potential entry inhibitor to overcome drug resistant HIV is based on intravenous delivery every 2-4 weeks.

Understanding the pharmacokinetics of these formulations in plasma and tissue and interpatient variability are essential when they are being developed for PrEP. When used as treatment, potential advantages include improved adherence (from dramatically fewer doses linked to long half-lives), reduced potential for drug interactions related to first-pass metabolism, reduced GI toxicity, reduced renal, hepatic and other toxicity due to lower doses. Many nanoformulations also require lower formulation doses, resulting in higher target cell concentrations and the potential to reduce costs in resource limited settings where the active pharmaceutical compound accounts for a significantly greater proportion of the total production costs. [3]

Pharmacokinetic profiles of long acting compared to oral formulations often include a longer time to maximum concentration (Tmax can be several days rather than hours) and a longer time with concentrations close to the Tmax (days or weeks rather than hours). This may raise different toxicity concerns to oral dosing but also suggests efficacy targets may relate to Cmax rather than Cmin levels. Drug levels are steadier, with fewer fluctuating peaks and troughs associated with most oral drugs and this may also alter drug target levels, and whether these will be in plasma or tissue.

Unless an antidote is available to enable rapid clearance, oral lead in periods and strategies for treatment discontinuation are likely to important. As long as ART remains dependent on combination therapy, long acting individual drugs have the greatest potential as part of a long-acting combination, ideally co-formulated in a single injection.

In the first poster in this session, Pavan Puliguji form University of Nebraska presented results on an nanoformulation of atazanavir/ritonavir that in a mouse study resulted in ten-fold higher concentrations in plasma and tissue (ling, liver, kidney, spleen, lymph nodes and brain) and sustained for two weeks following a single intramuscular injection. [4]

A second poster from the same research group reported on properties of more advanced “small magnetite” (super-SMART) nanoformulation of atazanavir/ritonavir developed to target monocyte and macrophage cells. [5]

Early in vitro and rat results using a solid drug nanoformulation of efavirenz developed using a freeze-dry technique at Liverpool University was presented by Neill Liptrott. [6] This formulation produced a four-fold higher absorption, with a lower Cmax and similar Cmin, but using a two-fold lower dose compared to the standard oral formulation. The Liverpool group also has nanoformulations of lopinavir/ritonavir and both molecules have the potential for parenteral formulations. Production costs for this freeze-dry technique is minimal at $4-16 per kilo and pharmacokinetic and safety studies in HIV negative human volunteers are expected to start later in 2013.

Matching the PK exposures for long-acting ARVs are more complex than bioequivilence studies that are normally used for new formulations and the session was concluded by Kimberly Strumble from the US FDA with a summary of regulatory issues related to new nanoformulations of currently licensed ARVs.

Additional data on a very long acting formulation of an analogue of the integrase inhibitor dolutegravir (compound name GSK744) was presented in an oral late breaker. [7] Although this was in the setting of PrEP the compound is also in development for use in treatment. Viral load reductions of 2.0-2.5 log copies/mL were seen following ten days monotherapy using 5 mg and 30 mg doses of the oral formulation. Parenteral formulations are nanoparticle suspensions (both subcutaneous and intramuscular injections) that support monthly or possibly quarterly injections.

Importantly, for PrEP, two intramuscular doses one month apart protected all 8/8 rhesus macaques from multiple rectal exposure to SHIV compared 0/8 animals receiving placebo injections. These early results should drive fast-track research into whether this offers a similar protection in human studies, with the potential to overcome many of the practical difficulties associated with daily oral PrEP. See the later report in this issue of HTB for details of the PrEP study. [8]


Unless stated otherwise, references are to the Programme and Abstracts for the 20th Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2013, Atlanta.

  1. New Approaches to ARV Drug Delivery. Themed Poster Discussion. Monday 4 March 2013 1:30-2:30 pm.
  2. Boffito M. Challenges and Opportunities for the Development of Long-­acting ARVs. Webcast.
  3. Siccardi M et al. Nanomedicines for HIV therapy. Future Science. February 2013, Vol. 4, No. 2, Pages 153-156 , DOI 10.4155/tde.12.156. Full free access online.
  4. Puligujj P et al. Improved biodistribution, pharmacokinetics, and ARV responses for folate-targeted nanoformulated ART. 20th CROI, 2013, Atlanta. Poster abstract 513.
  5. Guo D et al. Development of Small Magnetite ARV Nanoparticles for Targeted Drug Delivery to Viral Reservoirs. 20th CROI, 2013, Atlanta. Poster abstract 512b.
  6. Liptrott N et al. Enhanced pharmacological properties of efavirenz formulated as solid drug nanoparticles. 20th CROI, 2013, Atlanta. Poster Poster abstract 512a.
  7. Andrews C et al. Long-acting Parenteral Formulation of GSK1265744 Protects Macaques against Repeated Intrarectal Challenges with SHIV. Oral late breaker abstract 24LB.
  8. Collins S. Monthly injection protects macaques from rectal exposure: results should fast-track human studies for advanced PrEP options. HTB March/April 2013.

Links to other websites are current at date of posting but not maintained.