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

Abstract

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 (IgG2 ) 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 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.

Population pharmacokinetics of brodalumab in patients with moderate to severe plaque psoriasis

“…Data from six clinical trials (2 phase I, 1 phase II and 3 phase III) were included (Table ). Except for the open‐label extension part of the phase II trial (NCT01101100) and a phase I drug‐drug interaction (DDI) trial (NCT01937260), trial design details have been presented elsewhere . For the DDI trial, briefly, the trial objective was to characterize the effect of Brodalumab on the pharmacokinetics of midazolam.…”

“…The pharmacokinetic fate of Brodalumab has previously been described in healthy individuals as well as in patients with moderate to severe plaque psoriasis following single and multiple doses . It is clear from these initial phase I and II trials that Brodalumab displays non‐linear kinetics and other hallmark features of a monoclonal IgG2 antibody interacting with a cell surface receptor such as half‐life in the duration of days and low systemic clearance .…”

Spotlight on brodalumab in the treatment of moderate-to-severe plaque psoriasis: design, development, and potential place in therapy

“…Using a phase 1 single-dose study design, Salinger et al22 were the first to characterize the PK and PD of brodalumab. A total of 57 healthy subjects and 25 moderate-to-severe psoriasis patients were randomized to receive single placebo or brodalumab doses (7–700 mg) via SC and intravenous (IV) routes of administration.…”

Network biology in development of monoclonal antibody therapeutics

“…Administration of placebo to some patients with psoriasis resulted in significant effect on PASI score in multiple clinical studies; thus, these patients are not candidates for treatment. The time-course of the placebo effect on PASI score was captured in an empirical function form with an indirect response model along with that observed following administration of ustekinumab and brodalumab [54,44]. Since placebo effect could only be described by an empirical function and not a mechanistic model, the predictions based on the final model were uncertain.…”

“…For example, interspecies scaling of mAbs [29] is indispensable for determination of the first-in-human dose [33]. Moreover, indirect response modeling provides insights into determination of efficacious dose and dose escalations for clinical studies [44].…”