Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches

Abstract Background Indacaterol is a once-daily long-acting inhaled β2-agonist indicated for maintenance treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD). The large inter-patient and inter-study variability in forced expiratory volume in 1 second (FEV1) with bronchodilators makes determination of optimal doses difficult in conventional dose-ranging studies. We considered alternative methods of analysis. Methods We utilized a novel modelling approach to provide a robust analysis of the bronchodilatory dose response to indacaterol. This involved pooled analysis of study-level data to characterize the bronchodilatory dose response, and nonlinear mixed-effects analysis of patient-level data to characterize the impact of baseline covariates. Results The study-level analysis pooled summary statistics for each steady-state visit in 11 placebo-controlled studies. These study-level summaries encompassed data from 7476 patients at indacaterol doses of 18.75-600 μg once daily, and showed that doses of 75 μg and above achieved clinically important improvements in predicted trough FEV1 response. Indacaterol 75 μg achieved 74% of the maximum effect on trough FEV1, and exceeded the midpoint of the 100-140 mL range that represents the minimal clinically important difference (MCID; ≥120 mL vs placebo), with a 90% probability that the mean improvement vs placebo exceeded the MCID. Indacaterol 150 μg achieved 85% of the model-predicted maximum effect on trough FEV1 and was numerically superior to all comparators (99.9% probability of exceeding MCID). Indacaterol 300 μg was the lowest dose that achieved the model-predicted maximum trough response. The patient-level analysis included data from 1835 patients from two dose-ranging studies of indacaterol 18.75-600 μg once daily. This analysis provided a characterization of dose response consistent with the study-level analysis, and demonstrated that disease severity, as captured by baseline FEV1, significantly affects the dose response, indicating that patients with more severe COPD require higher doses to achieve optimal bronchodilation. Conclusions Comprehensive assessment of the bronchodilatory dose response of indacaterol in COPD patients provided a robust confirmation that 75 μg is the minimum effective dose, and that 150 and 300 μg are expected to provide optimal bronchodilation, particularly in patients with severe disease.</p

Pharmacokinetic-Pharmacodynamic Characterization of the Cardiovascular, Hypnotic, EEG and Ventilatory Responses to Dexmedetomidine in the Rat 1 ABBREVIATIONS: MAP, mean arterial pressure; PK, pharmacokinetic; PD, pharmacodynamic; bpm, beats per minute

ABSTRACT This study characterizes the pharmacokinetic-pharmacodynamic (PK-PD) relationships of the cardiovascular, EEG, hypnotic and ventilatory effects of the alpha-2 adrenergic agonist dexmedetomidine in rats. Dexmedetomidine was administered by a single rapid infusion (n ϭ 6) and by an infusion regimen of gradually increasing rate (n ϭ 8). HR, mean arterial pressure (MAP) and EEG signals were recorded continuously, as was the time at which the rats woke up spontaneously from druginduced sleep, a measure of hypnosis. Arterial concentrations of dexmedetomidine and blood gases were determined regularly. A sigmoidal E max model was used to describe the HR, MAP and EEG concentration-effect relationships, with the EEG effect (activity in 0.5-3.5-Hz frequency band) linked to an effect-site model. The PK of dexmedetomidine could be described by a two-compartment model, with similar PK parameters for both infusion regimens. Plasma protein binding was 84.1[0.7]%. Because of complex cardiovascular homeostatic reflex mechanisms, HR and MAP could only be analyzed during gradually increasing infusions. The maximal decrease in HR was 35(2)%, and the maximal increase in MAP was 37(2)%. For both infusion regimens, similar PD parameters were found for the EEG and the hypnotic measure. These data suggest the absence of active metabolites or tolerance of the EEG and hypnotic effects. Judging on the basis of concentrations of dexmedetomidine (mean (S.E.M.)), HR decrease was the most sensitive response [EC 50 of 0.65(0.09) ng/ml], followed by increase in MAP [EC 50 of 2.01(0.14) ng/ml], change in EEG activity [EC 50 of 2.24(0.16) ng/ml] and the hypnotic measure [C wake-up of 2.64(0.10) ng/ml]. Ventilatory effects were minor. Alpha-2 adrenergic agonists, such as clonidine, have been used in clinical practice as antihypertensive agents for almost 30 years. Recently, clonidine and a more selective alpha-2 adrenergic agonist, dexmedetomidine, have received considerable attention in anesthetic practice because of their analgesic, sedative, hypnotic and anxiolytic effects In order to develop a safe and rational dosing regimen for dexmedetomidine, most researchers have followed its effects over time as a function of dose in human subjects or in animals. An alternative approach is to study dexmedetomidine&apos;s pharmacology on the basis of concentrations rather than dose to establish PK-PD relationships for its desired anesthetic effects, such as sedation and hypnosis, and its unwanted side effects, such as blood pressure increase and HR decrease. This would make it possible to predict the time-course of therapeutic and side effect profiles of dexmedetomidine for i.v. dosing strategies. However, the design of such PK-PD experiments is often restricted in human subjects, because they require the evaluation of multiple effect measures at a wide range of concentrations (e.g.