Safety and nonclinical and clinical pharmacokinetics of PC945, a novel
inhaled triazole antifungal agent
Abstract
Aims PC945 is a novel antifungal triazole for nebulised delivery to
treat lung Aspergillus infections. Pharmacokinetic and safety
profiles from nonclinical studies and clinical trials in healthy
subjects and subjects with mild asthma were characterised. Methods
Toxicokinetics were assessed following daily 2-hour inhalation for 14
days. Drug-drug interactions were evaluated using pooled human liver
microsomes. Clinical safety and pharmacokinetics were assessed following
(i) single inhaled doses (0.5–10 mg), (ii) 7-day repeat doses (5 mg
daily) in healthy subjects; (iii) a single dose (5 mg) in subjects with
mild asthma. Results Cmax occurred 4 hours (rats) or
immediately (dogs) after a single dose. PC945 lung concentrations were
substantially higher (>2000-fold) than those in plasma.
PC945 only inhibited CYP3A4/5 substrate metabolism
(IC50: 1.33 µM [testosterone] and 0.085 µM
[midazolam]). Geometric mean Cmax was 322 pg/mL
(healthy subjects) and 335 pg/mL (subjects with mild asthma) 4–5 hours
(median tmax) after a single inhalation (5 mg).
Following repeat, once daily inhalation (5 mg), Day 7
Cmax was 951 pg/mL (0.0016 µM) 45 minutes after dosing.
Increases in Cmax and AUC0–24h were
approximately dose proportional (0.5-10 mg). PC945 administration was
well tolerated in both healthy subjects and subjects with mild asthma.
Treatment-emergent adverse events were mild/moderate and resolved before
the study ended. No clinically significant lung function changes were
observed. Conclusions PC945 pharmacokinetics translated from nonclinical
species to humans showed slow absorption from lungs and low systemic
exposure, thereby limiting the potential for adverse side effects and
drug interactions commonly seen with systemically delivered azoles.