Background:
Bictegravir (BIC), is an integrase strand transfer inhibitor, effective for HIV treatment when combined with emtricitabine and tenofovir alafenamide. Another integrase inhibitor, cabotegravir, has been demonstrated to be effective in pre-exposure prophylaxis as a single agent and is available as a long-acting (LA) injectable medicine. This work describes preclinical pharmacology of a novel BIC LA solid injectable.
Methods:
A solid drug nanoparticle (SDN) formulation of BIC was manufactured using emulsion-templated freeze-drying (ETFD) prior to formation of a solid format using vacuum compression moulding (VCM). Resulting BIC formulations were injected (16.8mg BIC per animal) subcutaneously with a 12-gauge needle into the scapular region of male Sprague Dawley rats (n = 4, 250-300g). Plasma samples were collected from the lateral tail vein for 13-weeks post injection. BIC concentrations were quantified in plasma using validated LC-MS/MS and the injection site was terminally harvested for histopathological analysis.
Results:
ETFD yielded solids consisting of 70% BIC by weight, with subsequent dispersion in water yielding BIC particles with hydrodynamic diameters (Dz) between 700-850 nm, as determined by dynamic light scattering. Plasma BIC concentrations exceeded the human oral steady-state Ctrough within 3 hours of administration and remained above this level for 42 days (Tmax = 2 days; AUC0-tlast = 22427 μg.h/mL). No behavioural issues were encountered, animals gained weight throughout and no visible injection-site reactions were evident.
Conclusions:
Preclinical data for a novel BIC solid injectable demonstrated sustained therapeutic concentrations in rats for 42 days. Further work is required to understand dose linearity and proportionality, assess removability, and estimate doses and durations likely to be achievable in humans.
