Frequency-domain response analysis for quantitative systems pharmacology models
Pascal Schulthess (1), Teun Post (1,2), James Yates (3), and Piet Hein van der Graaf (1,4)
(1) Systems Pharmacology, Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (2) Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P) Leiden, The Netherlands, (3) AstraZeneca, IMED Oncology DMPK, Hodgkin Building, Chesterford Research Park, United Kingdom, (4) Certara QSP, Canterbury Innovation House, Canterbury, United Kingdom
Objectives: It was recently demonstrated that key biological control systems (such as the MAPK pathway) are highly sensitive to the frequency of external stimuli in a non-intuitive manner which cannot be predicted by conventional pharmacometrics approaches [1]. This suggests that quantitative systems pharmacology (QSP) can provide novel insights into optimal dosing regimens which could add a new dimension to the design of novel treatments. However, methods for such an approach are currently lacking. We therefore apply frequency-domain response analysis (FdRA), a method widely used in electrical and control engineering and already employed for systems biology models in S. cerivisae [1-3], to optimise drug treatment regimen of drug tolerance QSP models.
Methods: FdRA informs on the response of a QSP model to a wide range of perturbations as used in repetitive drug treatment regimen and enables the identification of treatment frequencies that amplify or attenuate the drug response. Here FdRA is analytically and exemplarily applied to four distinct classes of QSP models: indirect response, autoregulation, pool-precursor and moderator-mediated feedback [4]. Additionally, we explore the potential of FdRA for QSP models by combining the pharmacodynamic models with short and long half-life pharmacokinetic profiles.
Results: We show that the pool-precursor model as well as the moderator-mediated feedback model with two transit compartments attenuate slow perturbation drug treatment regimen while all other models amplify such a regimen. Rapid drug treatment regimen on the other hand are only amplified by the autoregulation model. Additionally, the moderator-mediated feedback model with two transit compartments possesses only one drug dosing frequency at 0.45 h-1 that results in an amplification of the drug response, i.e. only twice per hour drug treatments get amplified by the model while all others are attenuated.
Conclusions: As a novel analytical method in systems pharmacology FdRA facilitates not only the characterisation of QSP model dynamics with respect to the presence and magnitude of time-delays, model stability and performance but also aids the understanding of the pharmacological system and the optimisation of drug treatment regimen.
References:
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