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

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Abstract
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 k in (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.

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