title: Population pharmacodynamic model of the longitudinal FEV1 response to an inhaled long-acting anti-muscarinic in COPD patients.
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 FEV(1). 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 FEV(1) 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, EKD(50,) was estimated as 6.56 μg/h, and the maximum response, Emax as 0.631 L. Between-subject variability for kde, EKD(50) 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 FEV(1) response to a twice-daily regimen was higher, and the maximum FEV(1) response to once-daily regimen was higher, while the predicted average FEV(1) response was about the same.
authors.affiliation: Modeling and Simulation, Novartis Institutes for BioMedical Research, 220 Massachusetts Avenue, Cambridge, MA 02171, USA. kai.wu@novartis.com
authors.forename: Kai
authors.initials: K
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Looby
authors.forename: Goonaseelan
authors.initials: G
authors.lastname: Pillai
authors.forename: Gregory
authors.initials: G
authors.lastname: Pinault
authors.forename: Anton Franz
authors.initials: AF
authors.lastname: Drollman
authors.forename: Steve
authors.initials: S
authors.lastname: Pascoe
mesh_terms: D000280:Administration, Inhalation; D001993:Bronchodilator Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005541:Forced Expiratory Volume / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D015233:Models, Statistical; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D012129:Respiratory Function Tests; D012602:Scopolamine Derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013147:Spirometry; D013997:Time Factors
chemical_list: D001993:Bronchodilator Agents; D012602:Scopolamine Derivatives