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Population pharmacodynamic model of the longitudinal FEV1 response to an inhaled long-acting anti-muscarinic in COPD patients

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Abstract

The precise assessment of the dose–response to bronchodilators in the treatment of chronic obstructive pulmonary disease is hindered by the low signal to noise ratio of the typical clinical endpoint FEV1. Kinetic-pharmacodynamic (K-PD) models which use time course of response over a range of doses are in principle suited for the assessment of the dose response relationship of pulmonary administered drugs. A K-PD model was successfully developed using the longitudinal FEV1 data collected in the clinical study for a novel bronchodilator X. A superposition of two cosine functions was selected to describe the circadian variability in FEV1 at baseline. The onset (ka) and offset (kde) of drug action were described with first-order rate constants of 0.214/h and 0.141/h, respectively. Drug potency, EKD50, was estimated as 6.56 μg/h, and the maximum response, Emax as 0.631 L. Between-subject variability for kde, EKD50 and Emax were 65, 84.7 or 34.4% (expressed as coefficient variation). The model-based simulation predicted that for the same total daily dose of once-daily and twice-daily regimens, the trough FEV1 response to a twice-daily regimen was higher, and the maximum FEV1 response to once-daily regimen was higher, while the predicted average FEV1 response was about the same.

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Authors and Affiliations

  1. Modeling and Simulation, Novartis Institutes for BioMedical Research, 220 Massachusetts Avenue, Cambridge, MA, 02171, USA

    Kai Wu

  2. Novartis Pharma AG, Basel, Switzerland

    Michael Looby, Goonaseelan Pillai, Gregory Pinault, Anton Franz Drollman & Steve Pascoe

Authors
  1. Kai Wu
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  2. Michael Looby
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  3. Goonaseelan Pillai
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  4. Gregory Pinault
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  5. Anton Franz Drollman
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  6. Steve Pascoe
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Correspondence to Kai Wu.

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Wu, K., Looby, M., Pillai, G. et al. Population pharmacodynamic model of the longitudinal FEV1 response to an inhaled long-acting anti-muscarinic in COPD patients. J Pharmacokinet Pharmacodyn 38, 105–119 (2011). https://doi.org/10.1007/s10928-010-9180-2

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  • DOI: https://doi.org/10.1007/s10928-010-9180-2

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