Doctor of Philosophy (PhD)
Pharmacology and Experimental Neuroscience
Dr. Howard E. Gendelman
Antiretroviral therapy (ART) requires lifelong daily dosing to suppress viral replication, restore or maintain immune function and improve quality of life. As an alternative, long-acting (LA) antiretrovirals (ARVs) aim to deliver therapeutic drug concentrations over an extended period, ultimately requiring monthly or even more extended dosing intervals. Specifically, the success of recent clinical trials examining LA cabotegravir and rilpivirine (CAB and RPV LA) highlight the advent of these novel HIV-1 therapeutics. Further optimization of LA dosage forms are required and rests upon improving dosing frequency, injection volumes and tissue distribution to viral compartments. To this end, we report the synthesis of a library of RPV prodrugs specifically designed to provide sustained drug plasma concentrations and enhance tissue distribution. Lead prodrug candidate M3RPV was nanoformulated to develop a stable LA injectable dosage form (NM3RPV). Specifically, NM3RPV provided RPV plasma concentrations above the PA-IC90 for 25 weeks, while concurrently generating a substantial tissue depot after in single injection in BALB/cJ mice. Furthermore, NM3RPV provided 13 and 26-fold increases in t1/2 and MRT compared with NRPV respectively. Therefore, these results provide proof-of-concept nanoformulated RPV prodrugs can effectively extend the apparent half-life and improve tissue distribution compared to nanoformulated RPV (NRPV), warranting further investigation and optimization.
Hilaire, James R., "Synthesis and Characterization of Long-Acting Rilpivirine Prodrugs" (2019). Theses & Dissertations. 390.