Predicted heart rate effect of inhaled PF-00610355, a long acting β-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease

Abstract

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.

Keywords: PF-610355; PKPD; long-acting β2 agonist; nonmem; salmeterol; tachycardia.

Figure 1

Mean (95% CI) observed HR_CFB for four different subpopulations in the analysis dataset. There is no overlap between the populations. Observations are binned into groups by dose (A) or predicted plasma concentration (B). The dashed lines show E_max functions fitted to the data. , human volunteers; , asthma; , COPD; , human volunteers, MIAT (Miat monodose inhaler, model 5)

Figure 2

Goodness of fit plot for the final HR model. Population (A) and individual (C) predictions are scattered evenly around the line of unity. Epsilon shrinkage is 35%. Conditional weighted residuals of heart rate predictions (CWRES) vs. time after first dose (B), and CWRES vs. time since last dose (E, truncated to 0–24 h for clarity). CWRES vs. population predicted PF-00610355 concentration (D). CWRES in COPD patients and healthy volunteers are shown in red and black, respectively, and solid lines show loess smooth curves

Figure 3

Visual predictive check of heart rate vs. dose (upper panels) based on 1000 datasets simulated using the PKPD model, corrected for model prediction and stratified by COPD status. The dark grey scatter and the solid lines show the observed data and the corresponding median and 95% percentile intervals. The light grey boxes indicate the 95% confidence interval of model-predicted median and 95% percentile intervals. Observed samples were sorted into six bins (lower panels) containing an approximately equal number of samples according to the administered dose

Figure 4

Black solid lines and grey area illustrates the median (between replicates) median and 95% percentile intervals within replicates maximum change in HR (A) and maximum absolute HR (B) vs. dose on day 43 in COPD patients. Error bars show the 95% percentile intervals of the medians between replicates. Dashed lines show 5, 10, and 20 beats min⁻¹ change in HR (A) and 90, 100, and 110 beats min⁻¹ absolute HR (B). Open circles show observed data