Dose Optimization of rhIL-7-hyFc for Patients With Lymphopenia Using a Neonatal Fc Receptor-Mediated Recycling-Based and Target-Mediated Drug Disposition Pharmacokinetic Model.

Recombinant human interleukin-7 hybrid Fc (rhIL-7-hyFc) is a homodimer of rhIL-7 fused to a hyFc. Exogenous IL-7 promotes T cell proliferation and increases lymphocyte count, making it a potential treatment option for lymphopenia and cancer. To improve therapeutic efficacy, rhIL-7-hyFc was developed as a long-acting IL-7. This study aimed to create a pharmacokinetic model for rhIL-7-hyFc by incorporating neonatal Fc receptor (FcRn)-mediated recycling and target-mediated drug disposition (TMDD) of the IL-7 receptor. Data were collected from a randomized, double-blind, placebo-controlled phase 1 trial involving 30 healthy volunteers who received single doses of rhIL-7-hyFc. Volunteers received 20 or 60 mg/kg subcutaneously, 60 mg/kg intramuscularly (IM), or a placebo. Clinical data were provided by Genexine Inc. (Seoul, Republic of Korea). A TMDD-FcRn-mediated recycling pharmacokinetic model was developed using NONMEM 7.5 software, assisted by PsN 5.3.1 software. A quasi-steady-state approximation was used to describe drug-receptor and drug-FcRn interactions. The model evaluation included goodness of fit, visual predictive checks, and bootstrap analysis. Based on the pharmacokinetic parameters of the final model, a simulation was conducted to select the dosage regimen, ensuring a probability of at least 0.8 for meeting both safety and efficacy criteria. The model successfully described the pharmacokinetic profiles of 24 patients administered rhIL-7-hyFc. Based on the simulation results, 670-800 μg/kg every 3 weeks, 1010-1530 μg/kg every 6 weeks, and 1510-2190 μg/kg every 9 weeks IM were proposed. These results may help further understand rhIL-7-hyFc characteristics and, moreover, provide guidance for selecting the appropriate dosing regimen in future clinical trials.