Controlled drug delivery systems can provide sustained release profiles, favorable pharmacokinetics, and improved patient adherence. Here, a reservoir-style implant comprising a biodegradable polymer, poly(ε-caprolactone) (PCL), was developed to deliver drugs subcutaneously. This work addresses a key challenge when designing these implantable drug delivery systems, namely the accurate prediction of drug release profiles when using different formulations or form factors of the implant. The ability to model and predict the release behavior of drugs from an implant based on their physicochemical properties enables rational design and optimization without extensive and laborious in vitro testing. By leveraging experimental observations, we propose a mathematical model that predicts the empirical parameters describing the drug diffusion and partitioning processes based on the physicochemical properties of the drug. We demonstrate that the model enables an adequate fit predicting empirical parameters close to experimental values for various drugs. The model was further used to predict the release performance of new drug formulations from the implant, which aligned with experimental results for implants exhibiting zero-order release kinetics. Thus, the proposed empirical models provide useful tools to inform the implant design to achieve a target release profile.

Background: Long-acting drug delivery strategies could augment pediatric human immunodeficiency virus (HIV) treatment effectiveness by bypassing population-specific challenges such as adherence. We harnessed pharmacokinetic (PK) modeling to develop a biodegradable, subcutaneous (SQ), reservoir-style implant for HIV treatment in 2–5-year-old children. Methods: Plasma was collected from New Zealand White rabbits over 30 h after a single intravenous (IV) bolus of bictegravir (BIC, 0.75 mg/kg), islatravir (ISL, 5 mg/kg) and/or emtricitabine (FTC, 30 mg/kg) then over a year after subcutaneous insertion of two to three implants eluting these antiretrovirals. Plasma antiretrovirals were quantified by HPLC-MS/MS and population PK models were fit to the IV PK profile to derive a mean unit impulse response (UIR). UIR was used to numerically deconvolve SQ absorption rate from the implant PK profile. SQ dosing rates were translated to pediatric plasma concentrations using published clinical PK parameters. Results: BIC, FTC, and ISL PK profiles were best described by two-compartment models. Each implant achieved quantifiable plasma concentrations for >360 days. Median SQ absorption rates (μg/day) at 3, 6 and 12 months of implantation were 116, 98 and 71 for BIC; 116, 37 and 5 for ISL; and 236, 116 and 24 for FTC. These 6-month dosing rates translated to pediatric plasma concentrations of 24 ng/mL BIC, 0.14 ng/mL ISL, and 0.7 ng/mL FTC. Conclusions: Our novel long-acting delivery platform exhibited antiretroviral SQ dosing rates for ≥6 months that are anticipated to achieve plasma concentrations in children within an efficacious range warranting further development for pediatric HIV treatment.