Assessment of A1-PI dose-exposure and exposure-response relationships in patients with Alpha-1 antitrypsin inhibitor deficiency

Abstract

Background: Zemaira (A 1 -PI; CSL Behring) is a preparation of human alpha-1 proteinase inhibitor used for augmentation therapy in individuals with A 1 -PI deficiency (AATD) and clinical evidence of emphysema. RAPID (NCT00261833) compared the efficacy and safety of weekly 60 mg/kg of A 1 -PI with placebo. Aim: To characterize the relationship between dose and A 1 -PI concentration, and the exposure-response relationship between A 1 -PI concentration and lung density decline. Methods: The relationship between dose and A 1 -PI concentration was modeled using a linear model with weight, age and baseline A 1 -PI as covariates. The exposure-response relationship between A 1 -PI concentration and lung density at total lung capacity was assessed using a disease progression model with baseline A 1 -PI, FEV 1 , age and BMI as covariates. Disease progression rates were quantified as a function of A 1 -PI concentration using linear and multiple nonlinear models. Results: The relationship between dose and A 1 -PI concentration was linear and demonstrated consistent levels across the range of weights observed in RAPID. The relationship between A 1 -PI concentration and lung density suggested a continuously increasing exposure-response relationship across the exposure levels following 60 mg/kg weekly doses. The mean model predicted a beneficial effect of Zemaira on the rate of lung density decline (0.88 g/L/yr versus 2.17 g/L/yr for placebo patients). Conclusions: Weight-based dosing resulted in achieving consistent exposure levels. 60mg/kg dose was an effective dose. Higher levels of A 1 -PI may result in improved efficacy in some patients.