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 IC 50 was 2.86 µg/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.