title: Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: A phase I, open-label, single-dose clinical trial.
abstract: BACKGROUND
  Aclidinium bromide is an inhaled, long-acting muscarinic antagonist currently in development for the treatment of chronic obstructive pulmonary disease. Renal impairment may affect drug clearance.
  
  
  OBJECTIVE
  This study was conducted to evaluate the pharmacokinetic (PK) parameters, safety, and tolerability of aclidinium bromide and its metabolites in patients with normal and impaired renal function to determine whether dosing adjustments are required when renal dysfunction is present.
  
  
  METHODS
  This was a Phase I, open-label, single-center, single-dose clinical trial conducted in Munich, Germany. Adults with varying degrees of renal function were assigned to 4 groups (n = 6 for each) based on creatinine clearance, including normal renal function (>80 mL/ min), mild renal insufficiency (>50-≤80 mL/min), moderate renal insufficiency (>30-≤50 mL/min), and severe renal insufficiency (<30 mL/min). Single doses of aclidinium bromide 400 μg were administered using a multidose dry powder inhaler. Blood and urine samples were obtained before dosing and at various time points up to 48 hours after dosing to analyze the PK parameters of aclidinium bromide and its metabolites. Plasma PK Parameters were AUC₀₋(t), MJC₀₋(∞) C(max), T(max), t(½) CL/F and apparent volume of distribution during the terminal phase Xz; urinary parameters were the amount of aclidinium or acid or alcohol metabolite excreted in urine, the percentage of the dose excreted in urine (fe), and renal clearance (CL(R)). Tolerability was assessed using physical examination, vital signs, 12-lead ECG recordings, laboratory tests, and adverse-event (AE) reports. The Wilcoxon rank sum test was used to compare the median PK values between the normal and impaired renal function groups. Pearson correlation coefficients and linear regression models were used to analyze the relationship between creatinine clearance and AUC₀₋(∞) and between creatinine clearance and CL(R) for aclidinium and its metabolites.
  
  
  RESULTS
  A total of 16 men and 8 women were included in the study. All participants were white; mean (SD) age was 55 (10.7) years and weight was 70.8 (9.2) kg. Aclidinium Cmax was observed in plasma by 5 minutes after dosing (ie, median Tmax) and did not differ significantly among the renal function groups. Plasma concentrations of aclidinium declined after reaching Cmax, with median t(½) values ranging from 2.07 to 4.18 hours across all renal function groups. Most of the individual t(½) values were between 1.5 and 3.5 hours, regardless of the degree of renal insufficiency. No significant relationship between AUC₀₋(∞)) and creatinine clearance was observed (Pearson correlation coefficient = -0.0446; P = NS). Urinary excretion of aclidinium was very low, with a mean 0.090% (median 0.078%) of the dose recovered from the urine in participants with normal renal function. Eight AEs were reported in 7 participants after drug administration; all were mild to moderate in severity and resolved spontaneously. There were no serious drug-related AEs and no deaths.
  
  
  CONCLUSIONS
  The plasma PK parameters of aclidinium bromide were not significantly altered after a single inhaled dose of aclidinium bromide 400 μg in this small group of patients with various degrees of impaired renal function. The very low urinary excretion of aclidinium in all renal function groups indicates that renal function plays a minor role in aclidinium plasma clearance. Aclidinium appeared well tolerated in the population studied. These results suggest that aclidinium dose adjustment on the basis of renal function may not be necessary.
authors.affiliation: APEX GmbH, Munich, Germany. apexpkpd@aol.com
authors.forename: Karin
authors.initials: K
authors.lastname: Schmid
authors.forename: Silvia
authors.initials: S
authors.lastname: Pascual
authors.forename: Esther Garcia
authors.initials: EG
authors.lastname: Gil
authors.forename: Stephan
authors.initials: S
authors.lastname: Ortiz
authors.forename: Josep M
authors.initials: JM
authors.lastname: Jansat
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism* / Q000652:urine; D012720:Severity of Illness Index; D014326:Tropanes / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D055815:Young Adult
chemical_list: D018727:Muscarinic Antagonists; D014326:Tropanes; C542859:aclidinium bromide