Pharmacokinetics, safety and tolerability of CHF5993 a triple pMDI in renal impaired patients

Background: CHF 5993 pMDI is a new extrafine fixed dose combination of Beclometasone Dipropionate (BDP), Formoterol Fumarate (FF) and Glycopyrronium bromide (GB), being developed as twice-daily treatment in COPD and asthma. We investigated the pharmacokinetics, safety and tolerability of CHF5993 pMDI in renal impaired (RI) patients. Methods: Non-randomised, open-label, parallel group study. Four inhalations of CHF5993 pMDI (BDP/FF/GB total dose 400/24/100 µg) were administered to mild, moderate and severe RI patients and to matched (in terms of sex, age and BMI) healthy volunteers (HV). Results: Nine mild, 7 moderate, 9 severe RI patients and 17 HVs aged 40-64 years were treated. GB systemic exposure increased with decreasing renal function, mainly in severe RI patients. GB renal clearance decreased proportionally with renal function. The degree of renal impairment had no impact on formoterol systemic exposure, while C max was reduced by about 50% in all groups of RI patients as compared to HVs. No clear relationship between renal function and renal clearance of total formoterol was found. B17MP (BDP main metabolite) systemic exposure was lower in RI patients as compared to HVs; however, differences tended to decrease with increasing degree of renal impairment. CHF5993 pMDI showed good and similar safety profiles in all RI and HVs as assessed by adverse events, laboratory parameters, vital signs and ECG. Conclusion: Despite a higher exposure to GB in severe RI patients, the GB non-renal clearance offsets the reduced elimination in mild and moderate RI patients. Therefore, CHF5993 pMDI displays a good safety profile without relevant differences between groups.