Population pharmacokinetics of A1-PI in patients with Alpha-1 antitrypsin deficiency

Background: Alpha 1 proteinase inhibitor (A 1 -PI; Zemaira, CSL Behring) is used for augmentation therapy in patients with A 1 -PI deficiency (AATD). RAPID, a randomized, double-blind, placebo-controlled study, demonstrated a lower rate of lung density decline in patients treated with 60mg/kg/week A 1 -PI compared to placebo. Serum A 1 -PI levels (normal range 20–53µM) were measured every 3 months over 2 years. Aim: Characterize pharmacokinetics (PK) of A 1 -PI in deficient patients enrolled in RAPID. Methods: A one-compartmental model was developed using nonlinear mixed effects modeling. Residual variability was estimated separately for samples collected 6-8 days post-dose (trough) and samples collected outside this time window. A full covariate model was used to test covariates (weight, sex, age, baseline A 1 -PI and genotype) on PK parameters. Simulation of 1,000 patients after 3 months of A 1 -PI dosing at 60mg/kg/week was used to calculate C avg , C max and C trough concentrations at steady-state (ss). Results: A 1 -PI PK was well described using a one-compartment model with parameter estimates (inter-individual variability) of 45.2mL/day (28.7%) for clearance, 10.0L (61.2%) for volume of distribution. The half-life estimate (t 1/2 ) of A 1 -PI=6.8 days and residual error for C trough was estimated to be 21.4%. No relationship could be defined between any of the covariates tested and variability in the PK parameters. The mean (90% CI) model predicted ss C avg =20.9µM (14.8–26.7), C max =28.5µM (13.3–44.7) and C trough =16.2µM (11.1–22.6). Conclusions: Weekly infusion of 60mg/kg A 1 -PI provides patients with average A 1 -PI serum concentrations well above the accepted therapeutic threshold of 11µM and at the lower end of normal.