Methods: A phase 1 study was conducted to evaluate the safety and pharmacokinetics of PC786 delivered in a suspension formulation by nebuliser (PARI LC SPRINT® device). Healthy volunteers (HVs) received placebo or PC786 as single ascending doses (0.5-20 mg, Cohort(C) 1), 5 mg BD for 7 days (C2) or 10 mg BD for 7 days (C3). Mild asthmatics received a single dose of PC786 5 mg or placebo (C4). PC786 PK was measured in plasma and in nasal mucosal lining fluid (MLF) collected using a synthetic absorptive matrix.
Results: PC786 was well tolerated, with no significant adverse clinical nor laboratory findings. Following single inhaled doses PC786 appeared rapidly in the plasma; mean plasma Cmax of 190, 571, 1760 and 3270 pg/mL, for the 0.5, 2, 8 and 20 mg doses respectively were measured on average at 0.68 to 0.93 h (Tmax) post-inhalation. Following administration of 5 mg BD (C2) the extent of accumulation was approximately 2-fold. The geometric mean apparent terminal half-life measured following 10mg BD (C3) was 97 h. The ratio of MLF:plasma concentrations ranged from 6347 (+2h ) to 1050 (+24h).
Conclusion: PC786 was well tolerated by HVs and asthmatics. The compound showed a rapid Tmax, suggesting rapid exposure of the respiratory epithelium. The PC786 concentrations in MLF exceed the IC90 for RSV, but circulating plasma concentrations were low. The MLF:plasma measured in this study was consistent with lung:plasma ratios measured in pre-clinical studies. The long plasma half-life is consistent with slow absorption from the lung being the dominant process controlling systemic kinetic behaviour. The long t½ and 2-fold accumulation ratio observed on repeat dosing supports once daily dosing in subsequent studies.
A. Murray, Pulmocide Ltd: Employee and Shareholder , Salary .
K. Woodward, Pulmocide Ltd: Consultant , Consulting fee .
K. Ito, Pulmocide Ltd: Employee and Shareholder , Salary .
P. Strong, Pulmocide Ltd: Board Member , Employee and Shareholder , Salary .
G. Rapeport, Pulmocide Ltd: Board Member , Employee and Shareholder , Salary .