Pharmacokinetics of anti-hepcidin monoclonal antibody Ab 12B9m and hepcidin in cynomolgus monkeys.
Hepcidin is a key regulator responsible for systemic iron homeostasis. A semi-mechanistic PK model for hepcidin and a fully human anti-hepcidin monoclonal antibody (Ab 12B9m) was developed to describe their total (free + bound) serum concentration-time data after single and multiple weekly intravenous or subcutaneous doses of Ab 12B9m. The model was based on target mediated drug disposition and the IgG-FcRn interaction concepts published previously. Both total Ab 12B9m and total hepcidin exhibited nonlinear kinetics due to saturable Fc-FcRn interaction. Ab 12B9m showed a limited volume of distribution and negligible linear elimination from serum. The nonlinear elimination of Ab 12B9m was attributed to the endosomal degradation of Ab 12B9m that was not bound to the FcRn receptor. The terminal half-life, assumed to be the same for free and total serum Ab 12B9m, was estimated to be 16.5 days. The subcutaneous absorption of Ab 12B9m was described with a first-order absorption rate constant k(a) of 0.0278 h⁻¹, with 86% bioavailability. The model suggested a rapid hepcidin clearance of approximately 800 mL h⁻¹ kg⁻¹. Only the highest-tested Ab 12B9m dose of 300 mg kg⁻¹ week⁻¹ was able to maintain free hepcidin level below the baseline during the dosing intervals. Free Ab 12B9m and free hepcidin concentrations were simulated, and their PK profiles were nonlinear as affected by their binding to each other. Additionally, the total amount of FcRn receptor involved in Ab 12B9m recycling at a given time was calculated empirically, and the temporal changes in the free FcRn levels upon Ab 12B9m administration were inferred.
Xiao
Jim J
JJ
AMGEN, Thousand Oaks, California 91320, USA. jxiaofuture@yahoo.com
Krzyzanski
Wojciech
W
Wang
Yow-Ming
YM
Li
Hongyan
H
Rose
Mark J
MJ
Ma
Mark
M
Wu
Yuling
Y
Hinkle
Beth
B
Perez-Ruixo
Juan Jose
JJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D023181:Antimicrobial Cationic Peptides / Q000276:immunology*; D001682:Biological Availability; D006207:Half-Life; D064451:Hepcidins; D008252:Macaca fascicularis; D008954:Models, Biological; D053719:Tandem Mass Spectrometry
D000911:Antibodies, Monoclonal; D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins