Pharmacodynamic model of interleukin-21 effects on red blood cells in cynomolgus monkeys

Abstract

Interleukin-21 (IL-21) is a novel cytokine that is currently under clinical investigations as a potential anti-cancer agent. Like many other anti-cancer agents, including other interleukins, IL-21 is seen to produce a broad range of biological effects that may be related to both efficacy and safety of treatment. The present analysis investigates the observed pharmacodynamics effects on red blood cells following various treatment schedules of human IL-21 administrated to cynomolgus monkeys. These effects are described by a novel non-linear mixed-effects model that enabled separation of drug effects and sampling effects, the latter believed to be due partly to blood loss and partly to stress induced haemolysis in connection with blood sampling. Two different studies with a total of 9 different treatment groups of cynomolgus monkeys were used for model development. In conclusion, the model describes the IL-21 induced drop in red blood cells to be (1) caused by removal rather than suppression of production, consistent with increased reticulocyte concentration, and (2) considerably delayed compared to dosing, i.e. not related to the drop in red blood cells observed immediately post dose. It is believed that the structural model presented here can be used for other types of drug induced loss of red blood cells, whereas the mechanism for sampling related blood loss is relevant for investigations of anaemia in all pharmacological studies with smaller animals.

An Integrated Disease/Pharmacokinetic/Pharmacodynamic Model Suggests Improved Interleukin-21 Regimens Validated Prospectively for Mouse Solid Cancers

“…Indeed, the murine biodistribution profile in SC/IP administrations demonstrated observable multiplex transport of IL-21 into several peripheral tissues, where its concentrations were higher than plasma levels during several time points (personal communication, Dr. P. Thygesen, Novo Nordisk A/S, Denmark). Of note, similar multi-compartmental active transport was also described in prior models of IL-21-induced hematological effects in primates [46],[47], in support of this structure.…”

“…IL-2 and interferon-α, other cytokine drugs, are associated with severe hematological and neuropsychiatric side effects complicating their use [2]. Recent PK/PD models of toxic IL-21 effects on body temperature and red blood cell regulation [46],[47] present a possible framework in which our improved regimens can be confirmed for clinical safety.…”