(C-103) Fully synthetic long-acting injectable depot with tunable pharmacokinetics for HIV PrEP

Introduction:: Long-acting injectable depot of anti-HIV drug for HIV pre-exposure prophylaxis (PrEP) can be a preferred option in some settings over pill or implant regimens. For the increased comfort of the injection recipient, high drug content in a small volume, low viscosity and the prevention of a burst release at both early and late stages are required in order to decrease injection frequency, be able to use a narrow needle to reduce pain upon injection, and be able to maintain a controlled release, respectively. To achieve those requirements, here we developed drug-conjugated polymers. The target drug we focused on was islatravir (ISL), which is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI). Then, we synthesized its vinyl monomers, which can release ISL in the physiological condition, and polymerized them to obtain the ISL-conjugated polymer. In addition, we prepared copolymers of the ISL monomers and a hydrophilic monomer, 2-(methylsulfinyl) ethyl methacrylate (MSEMA) to control the ISL release. In this research, we performed pharmacokinetic studies using rats to investigate the effects of linker structure, monomer composition, and molecular weights in the release of islatravir from the injected polymer in the subcutaneous space.


Materials and Methods:: ISL-conjugated monomers were synthesized with two different linkers which were expected to have different drug release rates. They were then polymerized by the RAFT polymerization technique to obtain homopolymers or copolymers with MSEMA. ¹H NMR spectroscopy was used to determine the drug wt% in the purified polymer by adding an internal standard (levofloxacin) in the polymer solution in DMSO-d₆. The polymer was formulated in DMSO (110 µL or 158 µL) at a dosage of 20 mg islatravir-equivalent, then subcutaneously injected to a right flank of a rat with a 25G × 5/8” tuberculin syringe. The rat plasma was collected by tail prick and islatravir concentration was quantified by LC-MS/MS.


Results, Conclusions, and Discussions:: Firstly, five polymers with similar molecular weights but different linkers and monomer compositions were assessed. Although the homopolymers did not release islatravir enough to be quantified over 7 months, one polymer with 50 mol% MSEMA (monomer composition) exhibited a stable 0-order release for 7 months. In addition, higher islatravir concentration was observed as MSEMA was increased to 75 mol%, of which the working period was shorter than the 50 mol% MSEMA polymer. Compared with the slow-release linker, the fast-release linker tended to show higher islatravir concentration. It demonstrated the tunability of the pharmacokinetics of the islatravir-conjugated polymer depot by linker chemistry and the monomer composition. To further extend the working period of the depot, we focused on the molecular weight of the polymer, then two more polymers were synthesized, which had about a 2 times or 4 times (4X) larger molecular weight compared to the 75 mol% MSEMA polymer with the fast-release linker. It was found that the larger molecular weight polymer had the longer working period, but the islatravir concentration at the 0-order release phase was lower especially in the 4X polymer. As another strategy to extend the working period, some MSEMA were replaced with hydrophobic butyl methacrylate (BMA) which was expected to show the hydrophobic anchor property in the subcutaneous space. Compared to the original 75 mol% MSEMA polymer, the BMA polymer extended the working period by about 50 days. These results could give insight on the design of a long-acting injectable depot for HIV PrEP.

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