Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Modeling of Weight-Based Intravenous Reslizumab Dosing

摘要

Reslizumab 3.0 mg/kg has demonstrated efficacy in clinical studies of patients with eosinophilic asthma and a history of exacerbations.A population pharmacokinetic (PK) model was developed to determine whether 3.0 mg/kg weight-based dosing is appropriate to obtain consistent reslizumab exposures in all patients. PK data in healthy volunteers and patients >= 12 years with moderate to severe asthma,eosinophilic asthma,or nasal polyposis were analyzed from 4 phase 1,2 phase 2, and 2 phase 3 studies of intravenous (IV) reslizumab (N = 804). Covariates evaluated included age, race, sex, baseline weight, renal and liver function, concomitant medications, and antidrug antibody status. Exposure-response models were developed to characterize key efficacy (blood eosinophil levels,forced expiratory volume in 1 second [FEV|],Asthma Control Questionnaire [ACQ-7] scores),and safety end points (muscle disorder adverse events [AEs]). Vial-based dosing was evaluated as an alternative to weight-based dosing. IV reslizumab PK was accurately described by a 2-compartment PK model with 0-order input and first-order elimination. Body weight was the only covariate that significantly influenced PK parameters. However,with weight-based dosing,comparable steady-state exposures were observed across high and low body weights. Greater eosinophil lowering and longer response duration were observed with increasing dose; exposure-related effects on FEV| and ACQ-7 were also seen, demonstrating the clinical importance of a dosing regimen to optimize reslizumab exposure. The probability of a muscle disorder AE appeared to increase with increasing exposure.Steady-state exposure measures were similar for both dosing regimens,showing vial-based dosing as an alternative method of achieving the benefits of weight-based dosing.