Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma.

ABSTRACT

INTRODUCTION: Benralizumab, an interleukin-5 receptor alpha-directed cytolytic anti-eosinophil monoclonal antibody, was recently approved as add-on maintenance treatment for patients aged 12 years and older with uncontrolled asthma with eosinophilic inflammation. METHODS: Pharmacokinetic (PK) data from nine clinical trials for patients with asthma were pooled and analyzed to further characterize the PK of benralizumab and evaluate demographic covariate effects. RESULTS: Population modeling results demonstrated that the PK of benralizumab were dose-proportional across a wide dosage range and were adequately described by a two-compartment model with first-order absorption from the subcutaneous dosing site and a first-order elimination pathway from the central compartment. Following subcutaneous administration, the absorption half-life of benralizumab was 3.54 days, and the absolute bioavailability was 58.9%. Estimated clearance (CL; 0.291 L/day), central volume of distribution (Vc; 3.13 L), and peripheral volume of distribution (Vp; 2.52 L) were typical for therapeutic immunoglobulins. Elimination half-life was approximately 15.5 days for patients with asthma. Age, sex, race, liver function, renal function, baseline blood eosinophil count, anatomic injection site, and commonly used small-molecule drugs had no clinically relevant impact on benralizumab CL. Only body weight and antidrug antibodies (ADAs) were identified as relevant PK covariates. Power parameters (exponent) of body weight on CL, Vc, and Vp were 0.807, 0.803, and 0.528, respectively, and the presence of ADAs increased benralizumab CL by 124%. CONCLUSIONS: Over 5-20 weeks, the PK of benralizumab were dose-proportional across a dosage range of 0.03-3 mg/kg intravenously and 2-200 mg subcutaneously administered every 4 weeks or every 8 weeks (first three doses every 4 weeks). Body weight and ADA status were identified as relevant PK covariates. Baseline eosinophil count, hepatic and renal functions, anatomical subcutaneous injection site, and commonly used small-molecule drugs had no impact on the PK of benralizumab.