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Keywords:

  • long-acting β2 agonist;
  • nonmem;
  • PF-610355;
  • PKPD;
  • salmeterol;
  • tachycardia

Aim

To assess the cardiovascular effects of a new inhaled long-acting β-adrenoceptor agonist PF-00610355 in COPD patients.

Methods

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.

Results

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.

Conclusions

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.