Antiretroviral therapy (ART) requires lifelong daily dosing to attain durable viral suppression. However, regimen adherence dictates effective long-term clinical response by precluding viral rebound. To improve ART effectiveness and ensure adherence, long-acting injectables of cabotegravir and rilpivirine (CAB and RPV LA) were developed. Nonetheless, limitations include high injection volumes, limited drug tissue distribution, and frequent administrations have limited their utility. Intending to prolong the apparent half-life of ART, our laboratories developed prodrug libraries encased in biocompatible surfactants. Herein, we report the characterization of one of these for dolutegravir (DTG). A prodrug library for DTG was characterized then screened for sustained plasma concentrations and tissue biodistribution. The goal was to achieve DTG levels at or above the protein-adjusted (PA) IC90 of 64 ng/mL after a single intramuscular (IM) injection for a year or longer.
A prodrug library of DTG was synthesized by esterification using aliphatic lipid chains. This yielded 14 (MDTG), 18 (M2DTG), and 22 (M3DTG) carbon-modified lipophilic prodrugs. A 18 carbon prodrug carrying two DTG molecules on a lipid chain and native DTG completed the drug library. Solid prodrug nanoparticles in aqueous suspension were manufactured by high-pressure homogenization. Particle size, homogeneity, and the surface charge were assessed prior to human monocyte-derived macrophage (MDM) uptake, retention, cytotoxicity, and antiretroviral activity assays. A single 45 mg DTG-equivalents/kg IM dose of prodrug formulations was administered to Balb/cJ mice, SD rats and rhesus macaques. Release and hydrolysis profiles of NM2DTG were investigated.
NM2DTG was retained and provided protection beyond 30 days in cultured MDM challenged with HIV-1ADA at a multiplicity of 0.1 infectious particles. A single intramuscular injection of NM2DTG elicited DTG levels at or above the PA-IC90 for one year in rodents. Replicate PK profiles were recorded in rhesus macaques. Rat spleen, lymph node, liver, and muscle tissues showed 72, 74, 58.5, and 1.1×10ˆ6 ng/g of DTG prodrug at a year. The observed extended PK profile of NM2DTG was linked to prodrug nanocrystal tissue dissolution and pH.
The extended NM2DTG PK profile paralleled nanocrystal dissolution and pH-dependent prodrug activation. NM2DTG produced plasma DTG levels at or above the PA-IC90 for one year following a single intramuscular injection in rodents.