Development and preclinical evaluation of a dual-drug implant for long-acting HIV prevention and contraception

Abstract

Background/Objectives: Multipurpose prevention technologies (MPTs) that combine protection against HIV and unintended pregnancy can improve women's health outcomes by simplifying use and enhancing adherence. We developed a long-acting (LA) implant for the simultaneous and sustained delivery of the antiretroviral islatravir (ISL) and the contraceptive hormone etonogestrel (ENG). Methods: Using extruded poly-ε-caprolactone (PCL) tubing, reservoir-style implants were fabricated and evaluated in three configurations: (Group 1) a two-segment implant formed by joining separate ISL- and ENG-containing tubes; (Group 2) a single tube divided into two drug compartments by a heat-sealed PCL spacer; (Group 3) separate single-drug implants. In vitro release was assessed in phosphate-buffered saline at 37 °C, and safety and pharmacokinetic (PK) profiles were evaluated in New Zealand White rabbits (n = 4/group) over approximately 90 days. Results: The average ISL daily in vitro release rates for Groups 1, 2, and 3 were 29 ± 5 µg/day, 18 ± 5 µg/day, and 47 ± 8 µg/day, respectively, and ENG daily in vitro release rates were 39 ± 9 µg/day, 41 ± 8 µg/day, and 33 ± 7 µg/day. From day 28 through the end of the study, median (IQR) plasma concentrations were 0.22 (0.18-0.27) ng/mL, 0.28 (0.24-0.33) ng/mL, and 0.31 (0.28-0.33) ng/mL for ISL in Groups 1, 2, and 3, respectively, and 0.26 (0.21-0.31) ng/mL, 0.25 (0.16-0.47) ng/mL, and 0.30 (0.23-0.38) ng/mL for ENG in Groups 1, 2 and 3, respectively. Implants across all groups were well tolerated and demonstrated favorable local tolerability over the 90-day dosing period. Conclusions: Integration of multiple indications into a single platform capable of sustained release over an extended duration holds potential to address persistent gaps in women's sexual and reproductive health needs.