In Vitro, Pharmacokinetic, Pharmacodynamic, and Safety Comparisons of Single and Combined Administration of Tiotropium and Salmeterol in COPD Patients Using Different Dry Powder Inhalers

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• 作者：Stephen T. Horhota ; Jan A. van Noord ; Cynthia B. Verkleij ; Loek J. Bour…
• 关键词：dry powder inhaler ; in vitro/in vivo relationships ; pharmacodynamics ; pharmacokinetics ; tiotropium
• 刊名：The AAPS Journal
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：17
• 期：4
• 页码：871-880
• 全文大小：717 KB
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  19.Price D, Sharma A, Cerasoli F. Biochemical properties, pharmacokinetics and pharmacological response of tiotropium in chronic obstructive pulmonary disease patients. Expert Opin Drug Metab Toxicol. 2009;5(4):
• 作者单位：Stephen T. Horhota (1) (7)
  Jan A. van Noord (2)
  Cynthia B. Verkleij (3)
  Loek J. Bour (4)
  Ashish Sharma (5)
  Michael Trunk (6)
  Piet J. G. Cornelissen (3)
  
  1. Research and Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, 06877, USA
  7. 3 Riverview Heights, Amesbury, Massachusetts, 01913, USA
  2. Department of Respiratory Diseases, Atrium Medisch Centrum, Heerlen, The Netherlands
  3. Department of Clinical Research, Boehringer Ingelheim bv, Alkmaar, The Netherlands
  4. Global Biometrics and Clinical Applications, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
  5. Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
  6. Corporate Division R&D, Non-clinical, Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim am Rhein, Germany
  
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Biotechnology; Pharmacy;
• 出版者：Springer US
• ISSN：1550-7416

文摘

In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5?μm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5?μg tiotropium/25?μg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18?μg of tiotropium (Spiriva? HandiHaler?) (TioHH) and 50?μg of salmeterol (Serevent? Diskus?) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, four-way crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration–time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and Cmax,ss. No significant differences in 8-h forced expiratory volume in 1?s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.