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LONG-ACTING INJECTABLE FOR PREVENTION OF HIV AND UNPLANNED PREGNANCY
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CROI 2022 Feb 15
Isabella Young1, Aryani Pallerla1, Panita Maturavongsadit1, Alka Prasher1, Roopali
Shrivastava1, Stephanie Montgomery1, Amanda Schauer1, Mackenzie L. Cottrell1, Angela Kashuba1, Soumya R. Benhabbour1
1University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
program abstract
Background:
Globally 38 million people are living with HIV and half of all pregnancies are unplanned. There is an urgent need to control and prevent these global health crises as current preventative daily oral dosing regimens elicit low patient adherence. Thus, we propose to develop an injectable long-acting, biodegradable, and removable in-situ forming implant (ISFI) as a multipurpose prevention technology (MPT) for the prevention of HIV and unplanned pregnancy.
Methods:
ISFIs were generated by co-formulating PLGA, NMP, or DMSO, and APIs in a stable solution or suspension. ISFIs were loaded with one of two ARVs, dolutegravir (DTG) or cabotegravir (CAB), and one of two contraceptives, etonogestrel (ENG) or medroxyprogesterone acetate (MPA). A 90-day pharmacokinetic (PK) and safety study was conducted in female BALB/c mice with optimized MPT ISFI formulations. Mice (n=12/group) were injected subcutaneously with 50 μL of MPT ISFI formulations. Plasma samples were collected longitudinally to quantify drug concentration and TNF-α and IL-6 levels. At day 3, 7, 30, and 90, the depot and surrounding tissue were removed for H&E staining to assess local inflammation. At day 90, depots were removed to quantify residual drug, evaluate polymer degradation with gel permeation chromatography (GPC), and depot microstructure with SEM.
Results:
In vivo plasma concentrations of CAB and DTG were well above their 4x PA-IC90 for 90 days, demonstrated zero-order release kinetics, and showed no differences in drug release when formulated with either hormone. Furthermore, plasma concentrations of ENG and MPA were at, or above target levels based on their marketed products (Nexplanon® and Depo-Provera®) for 90 days and MPA demonstrated zero-order release kinetics. All formulations had mild to moderate inflammation scores with low concentrations of TNF-α (0-3 pg/mL) and IL-6 in plasma (0-20 pg/mL). Depots retrieved 90 days post euthanasia reached ∼47% degradation based on GPC analysis and contained ∼5% ENG, ∼20% DTG, 14-70% MPA and ∼85% CAB remaining.
Conclusion:
Here we report a first-in-line biodegradable, removable, and injectable MPT that elicits a clinically translational drug regimen. Our results demonstrated (1) the ability to co-formulate an ARV (DTG or CAB) and contraceptive (ENG or MPA) in a single ISFI, (2) sustained and target drug release kinetics in vivo for 90 days and (3) all formulations were safe and well-tolerated. Future studies include assessing PK and efficacy in non-human primates.
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