Population Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis of LY3015014, a Monoclonal Antibody to Protein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Healthy Subjects and Hypercholesterolemia Patients.

PURPOSE: LY3015014 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to the catalytic domain of PCSK9 and reduce low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia that is poorly controlled by maximally tolerated statin therapy. The objective of this pharmacokinetic/pharmacodynamics (PK/PD) analysis was to characterize the PK and PD properties of LY3015014 and assess the effect of covariates on the LY3015014 PK-PD profiles.
METHODS: Single and multiple dose data from three phase1 studies in healthy subjects (n = 133), as well as a phase 2 study in hypercholesterolemia patients (n = 527) were combined into a single dataset for analysis. In this dataset, healthy subjects received single intravenous (IV) doses of 0.03 to 10 mg/kg, or multiple subcutaneous (SC) doses of 1.0 to 3.0 mg/kg, administered every 2 to 4 weeks, while patients received 20 to 300 mg every 4 weeks or 100 to 300 every 8 weeks. PK/PD analysis was performed using NONMEM (ICON, software version 7.0 level 3). PK and PD modeling were conducted sequentially, with PK parameters fixed during the development of the PK/PD model. PD parameters and estimated intersubject and intrasubject variability were obtained based on pharmacological drug exposure-response relationships. Age, baseline total PCSK9, body weight, diabetes diagnosis, hypercholesterolemia disease status, dose, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and satin administration were evaluated as potential covariates in the PK model. Baseline total PCSK9, baseline LDL-C, diabetes diagnosis, disease status, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and Statin administration were evaluated as potential covariates in the PD model.
RESULTS: LY3015014 PK profile was consistent across all the studies and between healthy subjects and hypercholesterolemia patients. The PK time course data were well described by a two compartment PK model with first order absorption, and covariates identified for PK parameters included weight on both clearance (CL) and central volume (V2), dose on CL, race on bioavailability (F), and age on V2. The PD (LDL-C) was described using an indirect response model with LY3015014 acting to stimulate the elimination of LDL-C. Covariates identified to have a statistically significant impact on PD were coadministration of statins, baseline LDL-C, metabolic syndrome status and gender.
CONCLUSIONS: The population PK/PD model adequately describes the PK and PD profiles of LY3015014. Identification of clinically significant covariates will support the design and dose selection for the pivotal registration studies, ensuring that patients are dosed appropriately.