Fredrik Öhrn, PhD, Magnus Åstrand, PhD and Adriaan Cleton, PhD
Clinical Pharmacology and Pharmacometrics, Global Medicines Development, AstraZeneca R&D Mölndal, Sweden.
Objectives: Understanding the bronchodilatory potential and dose response profile early in the development programme is important for informing future investment decisions and dosing regimens. To this end, data from single-dose cross-over studies were used to model the FEV1 (Forced Expiratory Volume during one second) effect over time.
Methods: FEV1 was measured during 26 hours after a single dose cross-over study. The placebo data was modelled as a circadian rhythm as well as a linear trend to account for any increase in time over the 26 hours. Since no PK data from the lung were available, an underlying PK profile was assumed to drive the placebo-corrected FEV1 effect. Parameters for the rate of onset and offset were estimated.
Results: An emax model with one parameter for onset of effect and one for offset was found to describe the data well. IIV and IOV variability was estimated for several parameters. A confidence interval for the mean placebo-corrected effect at trough, as well as other timepoints, was obtained by simulating from the variance-covariance matrix of the parameter estimates from the final model.
Conclusion: Longitudinal modeling of FEV1 data from the entire 26 hour profile, as well as incorporating competitor information, can be helpful for understanding the dose response profile and inform decisions about future development.
References:
[1] J. C. Nielsen, M. M. Humacher, A. Cleton, S. W. Martin, J. Ribbing. Longitudinal FEV1 dose-response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease, Journal of Pharmacokinetics and Pharmacodynamics. 2012: 39:619-634.
[2] K. Wu, M.Looby, G. Pillai, G. Pinault, A. F. Drollman, S. Pascoe. Population pharmacodynamic model of the longitudinal FEV1 response to an inhaled long-acting anti-muscarinic in COPD patients. Journal of Pharmacokinetics and Pharmacodynamics. 38:105-119, 2011.
Reference: PAGE 22 () Abstr 2965 [www.page-meeting.org/?abstract=2965]
Poster: Other Modelling Applications