Evaluation of body weight-based dosing, alternative dosing regimens, and treatment interruptions for α1-proteinase inhibitors and implications on biochemical efficacy in patients with α1-antitrypsin deficiency.

Introduction: The recommended standard dose for α-proteinase inhibitor (A1PI) augmentation therapy is 60 mg/kg once-weekly (QW) intravenous (IV) infusions that aim to maintain systemic A1PI levels >11 μM, the biochemical efficacy threshold, in patients with α-antitrypsin deficiency (AATD). However, this standard dose may not be optimal for all patients. Body weight-based dosing, alternative dosing regimens, and treatment interruption periods were evaluated using population pharmacokinetic (PopPK) modeling and simulations.

Methods: A nonlinear mixed-effects PopPK model with covariate effects was developed using data from 3 clinical studies investigating 60 mg/kg QW IV A1PI infusions in patients with AATD (n = 65) to evaluate A1PI pharmacokinetic (PK) characteristics. Model-based simulations were conducted for predefined body weight categories, alternative dosing regimens (60-180 mg/kg QW or once every 2 weeks [Q2W]), and treatment interruption periods ranging from 3 to 14 days.

Results: A1PI PK characteristics were well described by a 2-compartment turnover model with zero-order input and linear elimination. Body weight was a statistically significant determinant of variability in central volume of distribution. Model-based simulations suggested that patients with a higher body weight may attain the 11 μM threshold quicker than patients with a lower body weight and that QW dosing was better at maintaining A1PI levels >11 μM, even when higher Q2W doses were administered. Missing a dose for as few as 3 days could result in A1PI levels <11 μM.

Discussion: Findings suggest that doses higher than 60 mg/kg administered QW might be more clinically beneficial in some patients with AATD, and that body weight should be considered in dose optimization.