title: A mechanistic PK/PD model for two anti-IL13 antibodies explains the difference in total IL-13 accumulation observed in clinical studies.
abstract: IMA-638 and IMA-026 are humanized IgG1 monoclonal antibodies (mAbs) that target non-overlapping epitopes of IL-13. Separate first-in-human single ascending dose studies were conducted for each mAb. These studies had similar study designs, but mild to moderate asthmatics were recruited for the IMA-638 study and healthy subjects were recruited for the IMA-026 study. IMA-638 and IMA-026 showed similar pharmacokinetic (PK) profiles, but very different total IL-13 (free and drug bound IL-13) profiles; free IL13 was not measured. IMA-026 treatment induced a dose-dependent accumulation of total IL-13, while IMA-638 treatment led to a much smaller accumulation without any clear dose-response. To understand the differences between the two total IL-13 profiles and to predict the free IL-13 profiles for each mAb treatment, a mechanistic PK/pharmacodynamic model was developed. PK-related parameters were first fit to the mean PK profiles of each mAb separately; thereafter, the target-related parameters were fit to both total IL-13 profiles simultaneously. The IL-13 degradation rate was assumed to be the same for asthma patients and healthy subjects. The model suggests that an approximately 100× faster elimination of IL-13-IMA-638 complex than IL-13-IMA-026 complex could be responsible for the differences observed in total IL-13 profiles for the two mAbs. Furthermore, the model predicts that IMA-638 administration results in greater and more prolonged free IL-13 inhibition than equivalent dosing of IMA-026 despite similar binding KD and PK profile. In conclusion, joint modeling of two similar molecules provided mechanistic insight that the elimination rate of mAb-target complex can regulate the degree of free target inhibition.
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, New Biological Entities, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: b Inflammation and Immunology Research Unit, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Kasaian
authors.affiliation: c Quantitative Clinical Sciences, PharmaTherapeutcis R&D, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Heatherington
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, New Biological Entities, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.affiliation: c Quantitative Clinical Sciences, PharmaTherapeutcis R&D, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Hua
mesh_terms: D000328:Adult; D018927:Anti-Asthmatic Agents / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D001249:Asthma / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D018793:Interleukin-13 / Q000037:antagonists & inhibitors*; D008297:Male; D008962:Models, Theoretical
chemical_list: D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C578095:IL13 protein, human; D007074:Immunoglobulin G; D018793:Interleukin-13; C000599521:anrukinzumab
keywords: Anti-IL-13 antibody; IL-13; PKPD model; human pharmacokinetics