title: 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.
authors.affiliation: Informatics and Mathematical Modelling, Technical University of Denmark, Richard Petersens Plads, Building 321, Room 015, Lyngby 2800, Denmark. ruvo@novonordisk.com
authors.forename: Rune V
authors.initials: RV
authors.lastname: Overgaard
authors.forename: Mats
authors.initials: M
authors.lastname: Karlsson
authors.forename: Steen H
authors.initials: SH
authors.lastname: Ingwersen
mesh_terms: D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001663:Bilirubin / Q000097:blood; D001772:Blood Cell Count; D001810:Blood Volume / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000032:analysis / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007378:Interleukins / Q000493:pharmacokinetics / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D012156:Reticulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D000970:Antineoplastic Agents; D006454:Hemoglobins; D007378:Interleukins; D000098546:Interleukin-21; D001663:Bilirubin