title: Pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD).
abstract: OBJECTIVE
  NVA237 (glycopyrronium bromide) is a once-daily longacting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild-tomoderate COPD patients.
  
  
  METHODS
  In this double-blind, parallel-group study, COPD patients were randomized to a 14-day treatment with NVA237 (25, 50, 100 or 200 μg) or placebo. Plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14.
  
  
  RESULTS
  The median time to reach maximal plasma concentration (tmax) was 5 or 6.5 min postinhalation. At steady state (Day 14), total and maximum systemic exposure (AUC0-24, Cmax) to NVA237 and urinary excretion of unchanged drug (Ae0-24) was approximately dose proportional over the 50 - 200 μg dose range. The average exposure was 1.4- to 1.7- fold higher on Day 14 compared with Day 1. The mean terminal elimination half-life (t1/2) of NVA237 ranged between 13 and 22 h. Steady-state plasma concentrations were reached within 1 week of treatment. Renal clearance (CLR) was similar across doses both after single and repeated dosing, ranging between 17.4 and 20.6 l/h. Urinary excretion of NVA237 enantiomers ([3S,2R]- and [3R,2S]-stereoisomers) was similar with respect to the amount excreted within 24 h and the excretion rate.
  
  
  CONCLUSIONS
  The pharmacokinetics of NVA237 were consistent between doses with limited systemic accumulation at steady state after repeated once-daily inhalation.
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland. romain.sechaud@novartis.com
authors.forename: Romain
authors.initials: R
authors.lastname: Sechaud
authors.forename: Didier
authors.initials: D
authors.lastname: Renard
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang-Auberson
authors.forename: Stephan de la
authors.initials: Sde L
authors.lastname: Motte
authors.forename: Anton
authors.initials: A
authors.lastname: Drollmann
authors.forename: Guenther
authors.initials: G
authors.lastname: Kaiser
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D013237:Stereoisomerism
chemical_list: D018727:Muscarinic Antagonists; D006024:Glycopyrrolate