Population Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Analysis for Clazakizumab in Patients With End-Stage Kidney Disease Undergoing Dialysis.

The inflammatory cytokine interleukin-6 (IL-6) plays a significant role in the progression of cardiovascular disease (CVD). We evaluated the impact of clazakizumab, a monoclonal antibody targeting the IL-6 ligand, upon high-sensitivity C-reactive protein (hs-CRP) as part of the dose-finding phase 2b trial. In this randomized, double-blind trial, adults with cardiovascular disease and/or diabetes receiving maintenance dialysis and having hs-CRP ≥ 2 mg/L at baseline received clazakizumab (2.5 mg, 5 mg, or 10 mg, n = 32 per dose group) or placebo (n = 31) every 4 weeks. These data were used to develop a population pharmacokinetics (popPK) and a longitudinal PK-pharmacodynamic (PK-PD) model to characterize the relationship between clazakizumab and hs-CRP to support Phase 3 dose selection. A 2-compartment model with linear elimination well described clazakizumab PK. PK-PD was best described by an indirect-response inhibitory model, where clazakizumab concentrations inhibited the kin (zero-order rate of production) of hs-CRP. Simulations predicted that all doses (2.5, 5, and 10 mg IV every 4 weeks) would result in the majority (> 80%) of subjects experiencing at least an 80% decrease in baseline hs-CRP (80.9%, 83.4%, and 88.1%, respectively). In addition, the proportion of subjects with hs-CRP concentrations below 2 mg/L at Week 12 was predicted to be 67.7%, 76.7%, and 82.6%, respectively, for these 3 dose groups. These modeling and simulation results support the dose selection of clazakizumab 5 mg IV every 4 weeks in the phase 3 placebo-controlled trial to evaluate the impact of IL-6 inhibition via clazakizumab administration upon cardiovascular events.