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Pharmacokinetic modeling to guide preclinical development of an islatravir-eluting reservoir-style biodegradable implant for long-acting HIV PrEP
Kinsale, T. S., Cottrell, M. L., Li, L., Brand, R., Gatto, G., Luecke, E., Norton, C., Krovi, A., Dumond, J. B., Rao, G., Yeshwante, S., Van Horne, B., van der Straten, A., Kashuba, A. D. M., & Johnson, L. M. (2024). Pharmacokinetic modeling to guide preclinical development of an islatravir-eluting reservoir-style biodegradable implant for long-acting HIV PrEP. Pharmaceutics, 16(2), Article 201. https://doi.org/10.3390/pharmaceutics16020201
Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(epsilon-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL's unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (n = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 +/- 0.024 mg/day, and cumulative mass at 154 days was 8.67 +/- 3.22 mg. ISL absorption was well-described by zero-order (r2 = 0.95) and Ritger-Peppas (r2 = 0.98). Our zero-order ISL-release poly(epsilon-caprolactone) implant is projected to achieve clinical PK above ISL-tp's PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted.
