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/Johnson & Johnson 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 Mary Catherine 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.
Will
Nanoparticle Technology Lead to Once Monthly HAART?
Results
