Pharmacokinetic Dynamic Relationships
Predicted heart rate effect of inhaled PF-00610355, a long acting β-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease
Article first published online: 21 OCT 2013
© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 76, Issue 5, pages 752–762, November 2013
How to Cite
Diderichsen, P. M., Cox, E., Martin, S. W., Cleton, A. and Ribbing, J. (2013), Predicted heart rate effect of inhaled PF-00610355, a long acting β-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease. British Journal of Clinical Pharmacology, 76: 752–762. doi: 10.1111/bcp.12080
- Issue published online: 21 OCT 2013
- Article first published online: 21 OCT 2013
- Accepted manuscript online: 17 JAN 2013 06:40AM EST
- Manuscript Accepted: 13 JAN 2013
- Manuscript Received: 23 JUL 2012
- Pfizer Inc
- long-acting β2 agonist;
To assess the cardiovascular effects of a new inhaled long-acting β-adrenoceptor agonist PF-00610355 in COPD patients.
Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics and concomitant medication was evaluated using non-linear mixed-effects models. The median heart rate increase in COPD patients for doses of PF-00610355 up to 280 μg once daily was simulated with the final pharmacokinetic/pharmacodynamic (PKPD) model.
An Emax model accounting for delayed on-and off-set of the PF-00610355-induced change in heart rate was developed. The predicted potency in COPD patients was three-fold lower compared with healthy volunteers, while no difference in maximum drug effect was identified. Simulations suggested a maximum placebo-corrected increase of 2.7 (0.90–4.82) beats min−1 in COPD patients for a PF-00610355 dose of 280 μg once daily, with 19% subjects experiencing a heart rate increase of more than 20 beats min−1 compared with 8% in the placebo group.
This PKPD analysis supports the clinical observation that no relevant effects of PF-00610355 on heart rate in COPD patients should be expected for doses up to 280 μg once daily.