Background: VM1500A is a new, potent non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI). Its orally-bioavailable prodrug, Elsulfavirine (Elpida^®, VM1500), is currently marketed in Eastern Europe as an oral QD regimen for HIV/AIDS treatment. Unique pharmacokinetic properties (T_1/2 ~ 9 days) of VM1500A suggest a possibility for long-acting formulation development.
Methods: VM1500A was subjected to polymorph analysis via generation of corresponding amorphous forms and evaporative/low-temperature crystallization from 50 different solvents. Two aqueous nanosuspensions of VM1500A polymorph I with particle size distribution (PSD d90) of 306 or 411 nm were prepared by wet milling. Formulation safety and pharmacokinetics (PK) were studied in beagle dogs, following three once-monthly 10 mg/kg dose administration by intramuscular (IM) injection. Three animals were studied per formulation. Blood samples were collected frequently up to 72 h after administration and every week up to 3 months after last administration. VM1500A plasma concentrations were measured using LC-MS/MS.
Results: A total of twenty morphoforms of VM1500A were identified. Out of those, two (morphoforms I and X), were found to be stable. Morphoform I was selected for further studies. All studied formulations were well-tolerated, no adverse reactions were observed, including at the injection site. Dosing with 306 nm-formulation provided more stable drug plasma concentrations than dosing with that of 411 nm. Following three once-monthly 10 mg/kg IM injections of 306 nm VM1500A formulation, drug plasma levels were maintained above 40 ng/ml for at least for 4 month. These levels exceeded the clinically-efficacious VM1500A plasma concentrations.
Conclusions: This study supports further development of VM1500A long-acting injectable formulations to enable infrequent dosing.

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