The pharmacokinetics, pharmacodynamics and tolerability of PUR0200, a novel tiotropium formulation, in chronic obstructive pulmonary disease

Abstract

Aims: PUR0200 is a tiotropium bromide formulation engineered with the iSPERSE dry powder delivery technology. PUR0200 is being developed as a bioequivalent alternative to tiotropium bromide, delivered using Spiriva® HandiHaler® (HH). We investigated the bronchodilator effects, pharmacokinetics and safety of PUR0200 in patients with chronic obstructive pulmonary disease (COPD).

Methods: This was a randomized, placebo-controlled, crossover study using different PUR0200 doses and the comparator tiotropium HH. In vitro aerodynamic particle size distribution (aPSD) characterization of PUR0200 and tiotropium HH are presented. The main endpoints included forced expiratory volume in 1 s (FEV₁ ) trough and (0-24 h) and pharmacokinetic parameters.

Results: The increased fine-particle fraction of PUR0200 demonstrated by testing using the next-generation impactor increased the proportion of drug available for lung deposition compared with the tiotropium HH. There was a numerical dose-response effect for PUR0200 on FEV₁ , with 3 μg demonstrating a lower effect than higher doses. The placebo-adjusted mean (95% confidence interval) increases from baseline at 24 h postdose were 150 ml (100-200), 210 ml (160-270) and 200 ml (140-250) for 3 μg, 6 μg and 9 μg doses of PUR0200, respectively. Tiotropium HH (18 μg) caused a mean 169 ml (standard deviation 157ml) improvement in trough FEV₁ , which was not significantly different to the PUR0200 effects at any of the tested doses.

Conclusions: PUR0200 treatment caused bronchodilation in COPD patients that was similar in magnitude to that caused by tiotropium HH. This enabled a similar clinical effect on lung function to be achieved with PUR0200 using a lower metered dose of tiotropium compared with tiotropium HH.

Keywords: COPD; FEV1; PUR0200; pharmacokinetics; tiotropium.

Figure 1

Consolidated Standards of Reporting Trials (CONSORT) flow diagram showing reasons for screen failure and withdrawal after randomization

Figure 2

Mean change from baseline forced expiratory volume in 1 s (FEV₁) over 24 h after a single dose of 3 μg, 6 μg and 9 μg inhaled PUR0200, placebo and HandiHaler® (HH) 18 μg. Mean and standard deviation are shown (n = 36 for 3 μg, 9 μg and HH 18 μg, and n = 34 for 6 μg and placebo)

Figure 3

(A) Trough forced expiratory volume in 1 s (FEV₁) and (B) area under the curve from zero to 24 h (AUC_(0–24 h)) for FEV₁ (FEV₁ AUC_0–24 h) after 3 μg, 6 μg and 9 μg of inhaled PUR0200, placebo and tiotropium 18 μg. Mean and standard deviation are shown (n = 36 for 3 μg, 9 μg and HandiHaler® (HH) 18 μg, and n = 34 for 6 μg and placebo)

Figure 4

Pharmacokinetics of PUR0200 and HandiHaler® (HH) 18 μg. Geometric mean plasma concentrations of tiotropium bromide for PUR0200 and HH 18 μg over time. (A) Linear‐log plot of plasma concentrations over the first 6 h following dosing, and (B) Log–log plot of plasma concentrations over the 24 h after dosing

Figure 5

Relationship of pharmacokinetics with change (Δ) in trough forced expiratory volume in 1 s (FEV₁). (A) shows area under the curve from zero to 24 h (AUC_0–24 h) and (B) shows maximal observed plasma drug concentration (C_max). HH, HandiHaler®