Background:
Long-acting injectables (LAIs) for HIV PrEP can increase user acceptability, adherence, and reduce stigma. Current LAIs are not removable and elicit a long pharmacokinetic (PK) tail. In previous studies, investigational LAI Dolutegravir (DTG) formulations failed to sustain plasma DTG concentrations above the 4× PA-IC90 beyond two months. To overcome these limitations, we propose to develop an ultra-long-acting (ULA) biodegradable and removable in-situ forming implant (ISFI) with DTG. Here, we performed long-term safety and PK studies evaluating time-to-completion (ongoing), depot removal at various intervals, PK tail, and drug biodistribution in plasma, tissues, and organs post implant removal.
Methods:
ISFIs were comprised of high concentration DTG (350 mg/mL) in a stable suspension. Female BALB/c mice (n=6) were injected subcutaneously (SC) with 50 µL of DTG ISFI formulation. Plasma samples were collected longitudinally to quantify drug concentration and TNF-α and IL-6 levels over ≥180 days. At day 30, 90, and 180 post administration, implants were removed via a small skin incision to quantify residual DTG and determine implant degradation over time. Plasma samples were collected longitudinally post-implant removal to assess the PK tail. Biodistribution of DTG in plasma, organs, and SC tissue was assessed post implant removal.
Results:
ULA DTG ISFIs sustained plasma DTG concentrations well above the 4× PA-IC90 for ≥180 days (Fig A) and with low plasma TNF-α and IL-6 concentrations. Significant decrease in plasma DTG was achieved within 1 week post implant removal with 17-, 22-, and 24-fold decrease for implants removed at 30, 90, and 180 days respectively; however, complete elimination of DTG was not yet achieved post depot removal (Fig B). Tissue DTG concentrations revealed high DTG accumulation in the proximal SC tissue as a likely explanation of the long PK tail. ISFIs were easily retrievable at 30, 90, and 180 days post-injection with ~69%, ~45%, and ~41% DTG remaining and ~13%, 49%, and 58% decrease in implant mass at 30, 90, and 180 removal respectively.
Conclusions:
Here we report a biodegradable, removable, and ULA DTG ISFI and demonstrated safety and plasma PK for ≥180 days and assessed the PK tail. We demonstrated the first ULA injectable of DTG for HIV PrEP that can be removed if needed. This comprehensive study further characterized the PK tail via a full biodistribution, and future directions include safety, PK and efficacy studies in non-human primates.
