Population Pharmacodynamic Model of Neutrophil Margination and Tolerance to Describe Effect of Sarilumab on Absolute Neutrophil Count in Patients with Rheumatoid Arthritis

Pavel Kovalenko, Anne Paccaly, Anita Boyapati, Christine Xu, Gregory St John, Michael C Nivens, John D Davis, Ronda Rippley, A Thomas DiCioccio, Pavel Kovalenko, Anne Paccaly, Anita Boyapati, Christine Xu, Gregory St John, Michael C Nivens, John D Davis, Ronda Rippley, A Thomas DiCioccio

Abstract

Evidence suggests that effects of interleukin-6 pathway inhibitors sarilumab, tocilizumab, and sirukumab on absolute neutrophil count (ANC) are due to margination of circulating neutrophils into rapidly mobilizable noncirculating pools. We developed a population pharmacodynamic model using compartments for neutrophil margination and ANC-specific tolerance to describe rapid, transient ANC changes in blood following administration of subcutaneous sarilumab and intravenous/subcutaneous tocilizumab based on data from 322 patients with rheumatoid arthritis in two single-dose (NCT02097524 and NCT02404558) and one multiple-dose (NCT01768572) trials. The model incorporated a tolerance compartment to account for ANC nadir and beginning of recovery before maximal drug concentration after subcutaneous dosing, and absence of a nadir plateau when the ANC response is saturated after subcutaneous or intravenous dosing. The model effectively describes the ANC changes and supports neutrophil margination and tolerance as an explanation for the absence of increased infection risk associated with low ANC due to interleukin-6 pathway inhibitor treatment.

Conflict of interest statement

P.K., A.P., A.B., M.C.N., J.D.D., and A.T.D. are employees of Regeneron Pharmaceuticals, Inc., and may hold stock and/or stock options in the company. C.X. is an employee of Sanofi Genzyme and may hold stock and/or stock options in the company. G.S.J. and R.R. were employees of Regeneron Pharmaceuticals, Inc. at the time of this work, and may hold stock and/or stock options in the company.

© 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, LLC. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Structure of the MT model. ANC0, estimated baseline absolute neutrophil count; ANCBlood, absolute neutrophil count in circulation; ANCMarginal, absolute neutrophil counts not in circulation; ANCT, absolute neutrophil count in tolerance compartment; ANCT, transit, absolute neutrophil count in tolerance transit compartment; C, concentration of IL‐6R inhibitor; EC50, concentration of IL‐6R inhibitor causing half‐maximal effect; Emax, maximal effect of IL‐6R inhibitor on intercompartmental rates; IL‐6R, interleukin‐6 receptor; k, intercompartmental rate; kin, calculated production rate of neutrophils; kout, elimination rate of neutrophils based on published estimates of half‐life; ktol, tolerance rate; LF, link function; MT, margination–tolerance; PK, pharmacokinetic.
Figure 2
Figure 2
Median simulated ANC over time from covariate MT model. (a) Model training dataset and (b) sensitivity analysis dataset. The vertical dotted line indicates the last trough day. ANC, absolute neutrophil count; MT, margination–tolerance.
Figure 3
Figure 3
Diagnostic plots. (a) Population and individual observed vs. predicted ANC, (b) log‐scaled population and individual observed vs. predicted ANC, and (c) IWRES vs. time and population‐predicted ANC. ANC, absolute neutrophil count; IWRES, individual weighted residuals.
Figure 4
Figure 4
Visual predictive checks. After single doses of s.c. sarilumab (a, b), i.v. tocilizumab (c, d), and s.c. tocilizumab (e), and multiple doses of s.c. sarilumab (f, g) and i.v. tocilizumab (h). ANC, absolute neutrophil count.

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