Background: New options for the prevention and treatment of HIV infection that allow infrequent dosing will facilitate adherence and likely improve long-term outcomes. Elsulfavirine (Elpida®, VM1500) is the prodrug of VM1500A, a new, potent non-nucleoside reverse transcriptase inhibitor (NNRTI), currently under review for registration as an oral QD regimen for HIV/AIDS treatment. Unique pharmacokinetic properties (T1/2 is ~8 days) of VM1500A suggest a possibility for long-acting formulation development.
Methods: Aqueous nanosuspensions of Elsulfavirine or VM1500A (particle size between 200 and 900 nm) were prepared by wet milling. Different surfactants and drug to surfactant ratios were used. Formulation safety and pharmacokinetics (PK) were studied in beagle dogs, following single (5, 10 or 20 mg/kg) dose administration by intramuscular (IM) or subcutaneous (SC) injection. Three animals were studied per dose and route of administration. Blood samples were collected frequently up to 72 h after administration and every week up to 3 months. Elsulfavirine and VM1500A plasma concentrations were measured using LC-MS/MS.
Results: All studied formulations were well-tolerated at all doses, no adverse reactions were observed, including at the injection site. The PK analysis showed that dosing with VM1500A provided more stable drug plasma concentrations than dosing with the prodrug Elsulfavirine from these administration routes. Following a single 10 mg/kg dose of VM1500A (either IM or SC), its plasma levels were maintained above 50 ng/ml for at least 4 weeks (the latest data point collected at the time of this abstract submission). These levels exceeded the clinically-efficacious VM1500A plasma concentrations. The graph plots VM1500A plasma concentrations over time after single IM or SC injections of 10 mg/kg Elsulfavirine or VM1500A.

Fig. 1. Dog plasma VM1500A concentrations.
[Fig. 1. Dog plasma VM1500A concentrations.]

Conclusions: This study provides proof-of-concept that VM1500A nanosuspensions could be developed into long-acting injectable formulations to enable infrequent dosing. Further pre-clinical development of these formulations is warranted.

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