Pharmacodynamic (PD) model of neutrophil margination to describe transient effect of sarilumab on absolute neutrophil count (ANC) in patients with rheumatoid arthritis (RA) after single-dose administration
Pavel Kovalenko (1), Anne Paccaly (1), Anita Boyapati (1), Christine Xu (2), John D. Davis (1), A. Thomas DiCioccio (1)
(1) Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA, (2) Sanofi Genzyme, Bridgewater, NJ, USA
Objectives: To present a PD model that explains the time course of the decrease and recovery of ANC, describes potential margination of neutrophils from vascular circulation, and accounts for the rapid development of ANC-specific tolerance, after a single dose of sarilumab, a human mAb blocking the IL-6Rα that is being developed for the treatment of rheumatoid arthritis.
Methods: In a phase 1 PK/PD study, 56 patients received a dose of sarilumab 150 or 200 mg SC. Sarilumab concentration and ANC were measured until 42 days postdose. Data were analyzed using stochastic approximation expectation-maximization and importance sampling methods.
Results: The PD model for ANC value and time course that described the observed nadir and return to baseline was a margination model (MM) that also accounted for tolerance. Margination of ANC, where neutrophils are excluded from the circulation in blood (central compartment), is a plausible mechanism to describe the transient effect of IL-6 inhibitors on neutrophils without affecting their function. Tolerance accounts for an attenuation of sarilumab effect on ANC over time [1]. The tolerance is specific to ANC. The MM was represented by ANC circulating between central blood and margination compartments. A link function was imposed on the rate from the central to margination compartment. Estimated parameters included tolerance rate, 0.169 d-1; EC50, 6.59 mg/L; Emax, 4.02; and baseline rate between central and margination compartments, 6.45 d-1. Observed tolerance was manifested by a nadir in ANC that precedes the maximal drug concentrations and counterclockwise hysteresis or by absence of plateau in nadir when ANC response was saturated. Accounting for tolerance led to a substantial decrease of 143.60 in objective function value. The MM is the biologically plausible model, considering the margination of neutrophils to be the underlying mechanism for the decrease in ANC observed with IL-6 inhibitors. The margination and tolerance are consistent with the absence of both impairment in neutrophil activity [2] and lack of association of decrease in ANC with increased risk of infection [3, 4].
Conclusions: A PD model that implements neutrophil margination with ANC-specific tolerance and describes the mechanism of transient decreases in ANC observed with IL-6 inhibitors was constructed. The MM describes the data well and is consistent with known neutrophil dynamics.
References:
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[2] Wright HL, Cross AL, Edwards SW, Moots RJ. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford) (2014) 53(7): 1321-31.
[3] Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol (2015) 67(6): 1424-37.
[4] Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum (2006) 54(9): 2817-29.
