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

Abstract

IntroductionThe recommended standard dose for α1-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 α1-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. MethodsA 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. ResultsA1PI 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. DiscussionFindings 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.