Impact of Target-Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9).

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target-mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low-density lipoprotein cholesterol (LDL-C). Data were pooled from 2 clinical studies: a single-dose escalation study in healthy subjects (7-420 mg SC; n = 44) and a multiple-dose escalation study in statin-treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57). A TMDD model described the time course of unbound evolocumab concentrations and removal of unbound PCSK9. The estimated linear clearance and volume of evolocumab were 0.256 L/day and 2.66 L, respectively, consistent with other monoclonal antibodies. The time course of LDL-C reduction was described by an indirect response model with the elimination rate of LDL-C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half-maximal inhibition (IC50 ) of LDL-C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420 mg QM were predicted to achieve a similar time-averaged effect of 69% reduction in LDL-C in patients on statin therapy, suggesting that an approximate 3-fold dose increase is required for a 2-fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420 mg QM were predicted to result in comparable reductions in LDL-C over a monthly period, consistent with results from recently completed phase 3 studies.