Will Nanoparticle Technology Lead to Once Monthly HAART?

[Guest guest]

By Baker, PhD

Nanoparticles, include any type of particle with at least one dimension of less than 500 nanometers.

The next major advance in simplification of HIV therapy could be the approval of antiretrovirals in nanosuspension formulations that release drug molecules slowly, and thus may enable once-monthly (or even less frequent) injectible antiretroviral therapy. Tibotec Therapeutics' experimental NNRTI rilpivirine (aka TMC 278) is the compound furthest along in the development of this technology. At the recent 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) in Boston, Gerben van't Klooster and colleagues at Tibotec/ & Pharma R & D in Belgium presented findings on the pharmacokinetics and tolerability of intramuscular and subcutaneous injections of long-acting rilpivirine formulations. Rilpivirine as a free base and as a HCl salt were formulated as sterile nanosuspensions using Elan's NanoCrystal technology. Pharmacokinetics and injection site tolerability were evaluated after single doses up to 20 mg/kg in rats and up to 400 mg/kg in dogs. One formulation was studied in 48 HIV negative volunteers at doses of 200, 400, and 600 mg.Results

• Rilpivirine was slowly released from nanosuspension formulations, producing sustained plasma levels for 2 months in rats and as long as 6 months in dogs and humans. • In animals, but not in humans, subcutaneous application resulted in more stable plasma levels than intramuscular application, which showed more pronounced initial peaks. • High concentrations of rilpivirine were observed at the injection site for up to 3 months in dogs. • However, in 3 to 6 months, the release from the depot was complete, as demonstrated by a bioavailability of close to 100%. • Within 3 months, the tissue distribution pattern was similar to that previously observed after oral dosing, with 5-fold higher concentrations in lymphoid tissues than in plasma. • In dogs, slight swelling with induration, 2 to 3 weeks after dosing, was more frequent after subcutaneous than after intramuscular application. • Human plasma concentrations reached a maximum around 3 days, then fell to 60% of these levels by 14 days, before declining very slowly (half-life about 5 weeks) to below 10 ng/mL by 12 to 26 weeks. • The pharmacokinetics was dose-proportional and inter-subject variability was low. • Typical pharmacokinetic parameters, normalized to a 100-mg dose, were 20.9 ng/mL for Cmax and 14,500 ng.h/mL for AUC0-week12 after both subcutaneous and intramuscular injection. • There were no serious adverse events and no premature discontinuations from the study. • Injection site reactions consisting of redness, bruising, pain, and sometimes indurations -- but no other adverse events -- were more common after rilpivirine than placebo injections. • The intramuscular route was better tolerated than the subcutaneous route.

In conclusion, Dr. van't Klooster wrote, "Long-acting TMC278 [rilpivirine ] may be a useful depot formulation since single doses gave prolonged exposure to TMC278 for several months and were well tolerated, particularly when administered intramuscularly."It is possible that Tibotec may be developing a slow-release formulation of rilpivarine as therapy for chronic HIV infection and for use as pre-exposure prophylaxis and in microbicides, but the company has not commented on this possibility.Slow-release Nanoparticles with Lopinavir, Ritonavir, and Efavirenz

In an in vitro study, a research group at Creighton University in Omaha, Nebraska, created slow-release nanoparticles containing lopinavir, ritonavir (the 2 drugs in the Kaletra pill), and efavirenz (Sustiva), and tested the release of the drugs from the particles.

Samples were taken every 2 hours for 8 hours, and then at 1, 2, 3, 4, 5, 7, 9, and 14 days. Drug levels were analyzed using high performance liquid chromatography. Intra-day and inter-day variability were both < 10%. According to the investigators, "Results of these experiments demonstrate that ritonavir, lopinavir, and efavirenz release from our nanoparticle formulation occurs over at least 14 days."Further, they wrote, "[N]anoparticles could be a delivery system for multiple anti-retroviral agents in the future."HIV-1 Inhibition with Multivalent Gold Nanoparticles Finally, researchers at the University of North Carolina and the University of Colorado presented results from their "proof of principle" experiment involving the attachment of a normally inactive CCR5 antagonist to gold nanoparticles in order to create large drug/gold molecules that would act like large viral proteins.Lead author Bowman wrote of their experiment, "[Here] we report…the first application of mono-disperse gold nanoparticles as a base scaffold for inhibition of HIV infection.""This method," she added, "may allow mixed ligand nanoparticles to target intracellular protein/protein interactions that are key for the HIV life cycle (e.g., Vif) with inhibitors that otherwise cannot access the intracellular space, or drug delivery to anatomic spaces (e.g., central nervous system) or selected cell types that are currently inadequately accessed by small molecule therapeutics."2/19/08 References

G van't Klooster, R Verloes, L Baert, and others. Long-acting TMC278, a Parenteral Depot Formulation Delivering Therapeutic NNRTI Concentrations in Preclinical and Clinical Settings. 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008). Boston, MA. February 3-6, 2008. Abstract 134.

C Destache, T Belgum, G Elsasser, and others. Ritonaivr-, Lopinavir-, and Efavirenz-containing Nanoparticles: in vitro Release of ART. CROI 2008. Abstract 743. MC Bowman, E Ballard, C Akerson, and others. HIV-1 Inhibition with Multi-valent Gold Nanoparticles. CROI 2008. Abstract 744.

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