Model-Informed Dose Selection for a Novel Human Immunoglobulin G4 Derived Monoclonal Antibody Targeting Proprotein Convertase Kwashiorkor Type 9: Insights from Population Pharmacokinetics–Pharmacodynamics and Systems Pharmacology

Monoclonal antibody drugs targeting proprotein convertase kwashiorkor type 9 (PCSK9) have recently demonstrated remarkable success in lipid-lowering therapies. Specifically, antibodies derived from immunoglobulin G1 (IgG1, alirocumab) and IgG2 (evolocumab) have been successfully utilized for this purpose. Recently, a novel recombinant fully human anti-PCSK9 monoclonal antibody, originally derived from IgG4 and designated as SAL003, was developed. This study aimed to explore the pharmacokinetics, efficacy, and safety of SAL003 in both single and multiple administrations. The investigation included both healthy individuals and individuals with hyperlipidemia. To comprehensively grasp the pharmacokinetic (PK) and pharmacodynamic (PD) attributes of SAL003, this study employed population PK–PD (popPK–PD) and mechanistic systems pharmacology (MSP) modeling. These models were employed for predicting low-density lipoprotein cholesterol (LDLc) concentrations and appropriate dosages across diverse potential clinical scenarios. The research results indicated that SAL003 demonstrated comparable pharmacokinetic properties to evolocumab, exhibited notable effectiveness in reducing lipid levels, and was confirmed to be safe and well-tolerated in both healthy individuals and individuals with hyperlipidemia. Notably, SAL003 displayed differing effectiveness between patients and healthy populations. This discrepancy was observed in the popPK–PD model, with a positive population influence on E max, and the MSP model, indicating elevated PCSK9 clearance and LDLr-related LDLc clearance in the healthy group. Simulation results from the popPK–PD and MSP models indicated a dosage of 140 mg of Q4W and 420 mg of Q8W for phase II/III clinical trials. Reducing the drug dose or extending the dosing intervals may result in treatment failure. Additionally, the simultaneous use of statins led to elevated PCSK9 levels and intensified fluctuations in steady-state LDLc levels during SAL003 treatment.