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PKPD Model of Interleukin-21 Effects on Thermoregulation in Monkeys—Application and Evaluation of Stochastic Differential Equations

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Abstract

Purpose

To describe the pharmacodynamic effects of recombinant human interleukin-21 (IL-21) on core body temperature in cynomolgus monkeys using basic mechanisms of heat regulation. A major effort was devoted to compare the use of ordinary differential equations (ODEs) with stochastic differential equations (SDEs) in pharmacokinetic pharmacodynamic (PKPD) modelling.

Methods

A temperature model was formulated including circadian rhythm, metabolism, heat loss, and a thermoregulatory set-point. This model was formulated as a mixed-effects model based on SDEs using NONMEM.

Results

The effects of IL-21 were on the set-point and the circadian rhythm of metabolism. The model was able to describe a complex set of IL-21 induced phenomena, including 1) disappearance of the circadian rhythm, 2) no effect after first dose, and 3) high variability after second dose. SDEs provided a more realistic description with improved simulation properties, and further changed the model into one that could not be falsified by the autocorrelation function.

Conclusions

The IL-21 induced effects on thermoregulation in cynomolgus monkeys are explained by a biologically plausible model. The quality of the model was improved by the use of SDEs.

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Abbreviations

ACF:

autocorrelation function

IL-21:

interleukin-21

IOV:

inter-occasion variability

ODE(s):

ordinary differential equation(s)

PKPD:

pharmacokinetic pharmacodynamic

PGE2 :

prostaglandin E2

QQ:

quantile-quantile

SDE(s):

stochastic differential equation(s)

UR:

unbound receptor

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Authors and Affiliations

  1. Informatics and Mathematical Modelling, Technical University of Denmark, Richard Petersens Plads, Building 321, Room 015, Kongens Lyngby, 2800, Denmark

    Rune Viig Overgaard & Henrik Madsen

  2. Novo Nordisk A/S, Copenhagen, Denmark

    Rune Viig Overgaard & Klaus A. Rytved

  3. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

    Rune Viig Overgaard

  4. Department of Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand

    Nick Holford

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  1. Rune Viig Overgaard
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  2. Nick Holford
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  4. Henrik Madsen
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Correspondence to Rune Viig Overgaard.

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Overgaard, R.V., Holford, N., Rytved, K.A. et al. PKPD Model of Interleukin-21 Effects on Thermoregulation in Monkeys—Application and Evaluation of Stochastic Differential Equations. Pharm Res 24, 298–309 (2007). https://doi.org/10.1007/s11095-006-9143-x

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  • DOI: https://doi.org/10.1007/s11095-006-9143-x

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