title: 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.
authors.affiliation: Amgen Inc, Seattle, WA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Salinger
authors.affiliation: Amgen Inc, Seattle, WA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Endres
authors.affiliation: Amgen Inc, Seattle, WA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Martin
authors.affiliation: Amgen Inc, Seattle, WA, USA.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Gibbs
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001315:Australia; D002170:Canada; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011565:Psoriasis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; C571216:brodalumab
keywords: PK/PD model; brodalumab; interleukin 17 receptor; monoclonal antibody; psoriasis