Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent

Abstract

PC945 is a novel antifungal triazole formulated for nebulized 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 characterized. Toxicokinetics were assessed following daily 2‐hour inhalation for 14 days. Potential for drug‐drug interactions was evaluated using pooled human liver microsomes. Clinical safety and pharmacokinetics were assessed following (a) single inhaled doses (0.5‐10 mg), (b) 7‐day repeat doses (5 mg daily) in healthy subjects; (c) a single dose (5 mg) in subjects with mild asthma. C max 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 (IC 50 : 1.33 µM [testosterone] and 0.085 µM [midazolam]). Geometric mean C max was 322 pg/mL (healthy subjects) and 335 pg/mL (subjects with mild asthma) 4‐5 hours (median t max ) after a single inhalation (5 mg). Following repeat, once daily inhalation (5 mg), Day 7 C max was 951 pg/mL (0.0016 µM) 45 minutes after dosing. Increases in C max and AUC 0–24h 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. 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.

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

“…Opelconazole is a novel antifungal triazole that was designed and optimized for inhalation via commonly available nebulizers [ 179 ]. After inhalation, opelconazole shows efficacy primarily in the lungs (systemic concentrations are minimal), making it a promising agent for treating pulmonary aspergillosis in non-neutropenic patients without disseminated infection.…”

“…Recent in vitro and in vivo studies have shown distinctive pharmacological characteristics, differentiating from commonly used azoles. Chemical and physical attributes of opelconazole, namely increases in lipophilic compounds and micronized drug particles, result in high local concentrations, prolonged lung retention, slow absorption form the lung, and as a consequence, low plasma concentrations [ 179 ].…”

“…Cass et al analyzed safety profiles in 29 subjects, of whom 20 were healthy and nine had mild asthma. Following inhaled single doses of 5 mg in the mild asthma cohort, single doses between 0.5 and 10 mg in healthy cohort one and repeated doses of 5 mg for 7 days in healthy cohort two [ 179 ], the geometric mean plasma C max after the 5-mg single dose did not significantly differ between healthy subjects and subjects with mild asthma. A dose-proportional increase in the AUC from 0 to 24 h and C max was found between dosages of 0.5 mg to 10 mg.…”

Advances in anti-fungal therapies

“…In a phase I trial, PC945 was well tolerated in healthy controls and subjects with mild asthma [64].…”

Allergic Diseases Caused by Aspergillus Species in Patients with Cystic Fibrosis

“…PC945 is a potent inhibitor of ergosterol synthesis, exhibiting 14-fold greater potency than voriconazole and 2.6-fold more potency than posaconazole against A. fumigatus [ 96 ]. A Phase 1 study in healthy volunteers and adult asthmatic patients (NCT02715570) showed that following inhalation, PC945 was slowly absorbed from the lung and led to low systemic exposure, suggesting an improved safety and DDI profile relative to oral itraconazole [ 97 ].…”