Pharmacokinetics of Anti-hepcidin Monoclonal Antibody Ab 12B9m and Hepcidin in Cynomolgus Monkeys

Abstract

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.

Hepcidin in Human Iron Disorders: Diagnostic Implications

“…The results of this study suggest that administration of antihepcidin therapies alone or in combination with erythropoiesis-stimulating agents may improve patients' erythropoietic response and allow the use of lower EPO doses to avoid the potential detrimental effects of high EPO concentrations. Notably, monitoring of the bioactive serum hepcidin during treatment by these hepcidin antagonists appears to be complicated by the interference of the compounds in the assays (219 ).…”

Manipulation of the hepcidin pathway for therapeutic purposes

“…The hepcidin peptide itself does not have desirable pharmacological properties as the synthesis of bioactive hepcidin is difficult and costly and the peptide has a relatively short halflife in circulation (several minutes). 56 …”

“…101 The main challenge for the efficacy of hepcidin binding molecules may be the high rate of hepcidin production. Xiao et al 56 estimated hepcidin production in macaque monkeys at 7.6 nmole/kg/h (20.5 μg/kg/h). Scaled to humans, the estimated hepcidin production in a 75 kg man would be 12 mg/day (20.5 μg/kg/h x 75kg x 24h x 12/37*) (*a conversion factor to estimate human equivalent dose based on the differences in body surface area).…”

Role of hepcidin in the diagnosis of sepsis and septic shock in children

“…Moreover, we were not able to examine WBC, CRP, and PCT levels due to inadequate blood volume collected from the healthy children. The levels of the biomarkers at the time the samples were taken may not reflect their actual levels because our data are cross-sectional, the half-lives of sepsis markers are different (14,(25)(26)(27), and the majority of patients had received antibiotic and fluid therapy prior to the PICU. Hepcidin is severely affected by anemia parameters such as serum and storage iron levels of patients regardless of the level of inflammation.…”