Population Pharmacokinetics and Pharmacodynamics of Crizanlizumab in Healthy Subjects and Patients with Sickle Cell Disease.

ABSTRACT

BACKGROUND AND OBJECTIVES: Crizanlizumab is a humanized monoclonal antibody against P-selectin for the prevention of vaso-occlusive crises in sickle cell disease (SCD). The objective of this study was to investigate crizanlizumab population pharmacokinetics (PK) and pharmacodynamics (PD), as well as influential covariates. METHODS: A population PK model for crizanlizumab was developed from healthy volunteer and SCD patient data, using a two-compartment intravenous infusion model utilizing a target-mediated drug disposition (TMDD) approach. The relationship between crizanlizumab concentration and ex vivo P-selectin inhibition was fitted to a non-linear sigmoidal Emax model. Covariate selection was performed in a stepwise manner. RESULTS: Crizanlizumab exhibits nonlinear pharmacokinetics in the wide dose range of 0.2-8 mg/kg body weight. The population pharmacokinetic base model incorporated body weight as covariate in the form of allometric scaling wherein the exponents were fixed to 0.8. SCD patients had higher baseline soluble P-selectin concentration, resulting in a higher estimated initial target concentration. The typical individual in the model is a 70 kg SCD patient with normal renal function and a baseline albumin of 43 g/L; CL was 0.012 L/h while Vss was 5.2 L. For the population PD model, none of the identified additional factors beyond PD assay and covariates, such as body weight at baseline nor patient type differences, led to relevant differences in P-selectin % inhibition. CONCLUSIONS: Renal and hepatic impairments, concomitant hydroxyurea usage, and presence of anti-drug antibody are not expected to impact the exposure of crizanlizumab. The model allows for extrapolating the PK of crizanlizumab to pediatric population and evaluation of alternative regimens and route of administration. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION] SUSTAIN (CSEG101A2201 Phase 2), ClinicalTrials.gov identifier NCT01895361 [10 July 2013]; CSEG101A2202 (Phase 2), ClinicalTrials.gov identifier NCT03264989 [29 August 2017].