A Semi-Mechanistic Model to Characterize the Pharmacokinetics and Pharmacodynamics of Brodalumab in Healthy Volunteers and Subjects With Psoriasis in a First-in-Human Single Ascending Dose Study

Pharmacokinetic-pharmacodynamic (PK-PD) modeling can provide a framework for quantitative learning and confirming from studies in all phases of drug development. Brodalumab is a human monoclonal antibody (IgG(2)) targeting the IL-17 receptor A that blocks signaling by cytokines thought to play a central role in the pathogenesis of psoriasis (IL-17A, IL-17F, and IL-17A/F). We used semi-mechanistic modeling of single dose, first-in-human data to characterize the exposure-response relationship between brodalumab and the Psoriasis Area and Severity Index (PASI) in a Phase 1 clinical trial. Fifty-seven healthy volunteers and 25 subjects with moderate to severe psoriasis received single intravenous or subcutaneous administration of placebo or brodalumab (7-700 mg). A two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination pathways described brodalumab PK. The PK-PASI relationship was characterized by linking a signaling compartment with an indirect response model of psoriatic plaques, where signaling suppressed plaque formation. The concentration of half-maximal inhibition IC50 was 2.86 mu g/mL (SE: 50%). The endogenous psoriatic plaque formation rate of 0.862 (SE: 40%) PASI units/day was comparable with literature precedent. Despite the small sample size and single administration data, this semi-mechanistic modeling approach provided a quantitative framework to inform design of dose-ranging Phase 2 studies of brodalumab in psoriasis.