title: Pharmacokinetic Bioequivalence of Two Inhaled Tiotropium Bromide Formulations in Healthy Volunteers.
abstract: OBJECTIVE
  A novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 µg/capsule) while maintaining the same delivered dose (10 µg/actuation). This study describes the pharmacokinetic bioequivalence to the reference product.
  
  
  METHODS
  This randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 μg delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 μg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler(®) (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid-liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (C max), area under the concentration-time curve (AUC) from time zero hours to the last observed concentration at time t (AUC t ), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80-125 %. Safety assessment was a secondary endpoint.
  
  
  RESULTS
  A total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: C max (CI 87.26-106.60 %), AUC t (CI 101.33-111.64 %), and AUC0.5 (CI 97.95-113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration).
  
  
  CONCLUSIONS
  Both products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.
authors.affiliation: Laboratorios Liconsa, Avda. Miralcampo 7, 19200, Azuqueca de Henares, Spain. Jaime.Algorta@chemogroup.net.
authors.forename: Jaime
authors.initials: J
authors.lastname: Algorta
authors.affiliation: Laboratorios Liconsa, Avda. Miralcampo 7, 19200, Azuqueca de Henares, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Andrade
authors.affiliation: Laboratorios Liconsa, Avda. Miralcampo 7, 19200, Azuqueca de Henares, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Medina
authors.affiliation: Clinic for Internal Diseases, MHAT Tokuda Hospital Sofia EAD, Sofia, Bulgaria.
authors.forename: Valentin
authors.initials: V
authors.lastname: Kirkov
authors.affiliation: Cooperative Clinical Drug Research and Development, Hoppegarten, Germany.
authors.forename: Sacha
authors.initials: S
authors.lastname: Arsova
authors.affiliation: PPD Laboratories, Middleton, WI, USA.
authors.forename: Fumin
authors.initials: F
authors.lastname: Li
authors.affiliation: PPD Laboratories, Middleton, WI, USA.
authors.forename: Jingduan
authors.initials: J
authors.lastname: Chi
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004339:Drug Compounding; D058995:Dry Powder Inhalers; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency; D000069447:Tiotropium Bromide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D002214:Capsules; D000069447:Tiotropium Bromide