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Injectable, Biodegradable, Removable
PrEP/Contraceptive Tested in Mice
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2022 CROI, February 12-16 and 22-24, 2022
Mark Mascolini
A long-acting injectable containing an antiretroviral and a hormonal contraceptive safely provided high levels of the agents when studied in mice, a first step in providing women with long-acting HIV PrEP and contraception in the same shot [1].
Researchers at the University of North Caroline (UNC) at Chapel Hill noted that 38 million people worldwide have HIV infection, and about half of all pregnancies are unplanned. Condoms remain the only technology that prevents both HIV and pregnancy, but they require planning, readiness, and agreement between sex partners. The UNC team proposed that a solution to this dilemma may be an injectable multipurpose prevention technology that remains effective for 3 months or more, can be given subcutaneously, and is both biodegradable and removable (in case problems arise).
The technology they proposed contains a biodegradable polymer (PLGA), a water-miscible organic solvent (NMP or DMSO), and agents that prevent HIV and pregnancy (an antiretroviral and a contraceptive). This analysis focused on four combinations given to 12 female BALB/c mice per group: dolutegravir (DTG, 278 mg/kg) plus medroxyprogesterone acetate (MPA, 70 mg/kg); DTG plus etonogestrel (ENG, 70 mg/kg); cabotegravir (CAB, 1215 mg/kg) plus MPA (76 mg/kg); and CAB plus ENG (151 mg/kg). Researchers delivered all combinations as a 50-uL subcutaneous injection. A fifth group of control mice got no injection. (MPA is in Depo Provera and ENG in Nexplanon.)
At multiple points through 90 days after injection, antiretrovirals always maintained concentrations above their 4X protein-adjusted 90% inhibitory concentration (IC90). Formulation with either hormone did not affect release of either antiretroviral. DTG, CAB, and MPA elicited zero-order release, while ENG elicited first-order release. (Release kinetics explained at [2] below.)
With the four antiretroviral/hormone combinations, the biodegradable polymer PLGA degraded by 40.9% to 65.1% of molecular weight through 90 days. No fibrotic tissue surrounded the depot. Residual drug could be measured in extracted depots with all four formulations. The CAB/MPA formulation retained the highest drug concentrations at 90 days, a result suggesting CAB/MPA has the greatest potential for 90-day protection.
Other research showed that a CAB in-situ forming implant (ISFI, like those tested in this study) released 4X IC90 concentrations for up to 6 months in macaque monkeys [3]. The UNC group plans to use CAB in phase 2 studies.
Local inflammation assessed by staining of the excised depot and surrounding tissue ranged from mild to nonexistent after 30 to 90 days. Systemic inflammation was mild when assessed by measuring TNF-alpha and IL-6 through 90 days.
The researchers are working toward pharmacokinetic and efficacy studies in nonhuman primates.
References
1. Young I, Pallerla A, Maturavongsadit P, et al. Long-acting injectable for prevention of HIV and unplanned pregnancy. 2022 CROI, February 12-16 and 22-24, 2022. Abstract 80.
2. Pharmacokinetics. Elimination kinetics.
https://sepia2.unil.ch/pharmacology/parameters/elimination-kinetics/
3. Massud I, Kovarova M, Wong-Sam A, et al. In situ forming implants with cabotegravir for ultra-long-acting PrEP. 2022 CROI, February 12-16 and 22-24, 2022. Abstract 855.
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