Background
Dolutegravir (DTG) is a widely used effective integrase strand transfer inhibitor with a high barrier to resistance. It is a recommended first-line treatment regimen for HIV-1-infected adults and children. However, DTG’s impact is limited by its daily dose requirements and suboptimal adherence. Long-acting formulations would improve optimal usage and reduce the emergence of drug resistance. To these ends, we focused on developing ultra-long-acting (ULA) prodrugs. One was a DTG monomeric ester prodrug formulation (NM2DTG). NM2DTG safely extended the drug’s apparent half-life [Nat. Commun., 3226 (2022)]. To further improve NM2DTG’s pharmacokinetic (PK) profile, DTG prodrug homodimers were synthesized and screened. An ULA DTG injectable dimer prodrug formulation (NM7DTG) was then identified, with the potential for or beyond a four-month dosing interval.
Methods
A library of DTG homodimers was synthesized and nanoformulated by high-pressure homogenization. Parent DTG formulations (NDTG) were prepared in parallel and used as a control. Cellular uptake and retention, antiretroviral efficacy, and cytotoxicity were evaluated in primary human monocyte-derived macrophages (MDM). The PK profile of a single intramuscular injection (IM) of 50 mg DTG equivalents/kg was then tested in Sprague Dawley (SD) rats.
Results
The DTG homodimers demonstrated distinct physicochemical properties compared to the native drug. NM7DTG formulations showed increased intracellular drug uptake, retention, and antiretroviral activities. NDTG demonstrated a suboptimal PK profile at four months, with plasma DTG levels declining rapidly below 4x the PA-IC90 at four weeks. In contrast, NM7DTG sustained therapeutic drug levels throughout this observation period and was tolerated well.
Conclusions
A single IM injection of a novel homodimeric NM7DTG formulation sustains plasma DTG levels above 4x PA-IC90 for > four months. Loading more DTG molecules per prodrug unit mass in NM7DTG could also reduce drug injection volumes.
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