Preclinical Evaluation of Long-Acting Emtricitabine Semi-Solid Prodrug Nanoparticle Formulations

Abstract

Long-acting injectable (LAI) formulations promise to deliver patient benefits by overcoming issues associated with non-adherence. A preclinical assessment of semi-solid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) is reported here. Pharmacokinetics over 28 days were assessed in Wistar rats, New Zealand white rabbits, and Balb/C mice following intramuscular injection. Two lead formulations were assessed for the prevention of an HIV infection in NSG-cmah−/− humanised mice to ensure antiviral activities were as anticipated according to the pharmacokinetics. Cmax was reached by 12, 48, and 24 h in rats, rabbits, and mice, respectively. Plasma concentrations were below the limit of detection (2 ng/mL) by 21 days in rats and rabbits, and 28 days in mice. Mice treated with SSPN formulations demonstrated undetectable viral loads (700 copies/mL detection limit), and HIV RNA remained undetectable 28 days post-infection in plasma, spleen, lung, and liver. The in vivo data presented here demonstrate that the combined prodrug/SSPN approach can provide a dramatically extended pharmacokinetic half-life across multiple preclinical species. Species differences in renal clearance of FTC mean that longer exposures are likely to be achievable in humans than in preclinical models.

The Application of Prodrugs as a Tool to Enhance the Properties of Nucleoside Reverse Transcriptase Inhibitors

“…Plasma concentrations fell below the detectable threshold of 2 ng/mL by day 21 in rats and rabbits and by day 28 in mice. Even 28 days after infection, HIV RNA remained undetectable in the plasma, spleen, lung, and liver samples [94].…”

“…Extended-release injectable (ERI) formulations have been investigated for the treatment of several diseases, including AIDS, as they can address challenges linked to medication nonadherence. For HIV treatment, the approval of ERI containing rilpivirine and cabotegravir provided a formulation that allowed therapeutic plasma concentrations of the drug for up to 20 weeks [93,94] Three FTC prodrugs (48-50) (Figure 11) were synthesized by Curley et al (2023), where they were incorporated into injectable aqueous semisolid prodrug nanoparticles (SSPNs) [94]. The pharmacokinetics of SSPNs containing prodrugs were evaluated over 28 days through intramuscular injection in Wistar rats, New Zealand white rabbits, and Balb/C mice.…”