Pharmacokinetics and Pharmacodynamics of Fluticasone Propionate and Salmeterol Delivered as a Combination Dry Powder from a Capsule-Based Inhaler and a Multidose Inhaler in Asthma and COPD Patients

被引:28
作者
Daley-Yates, Peter T. [1 ]
Mehta, Rashmi [2 ]
Chan, Robert H. [1 ]
Despa, Simona X. [2 ]
Louey, Margaret D. [2 ]
机构
[1] GlaxoSmithKline, Uxbridge UB11 1BT, Middx, England
[2] GlaxoSmithKline, Res Triangle Pk, NC USA
关键词
fluticasone propionate; salmeterol; dry powder inhaler; pharmacokinetics; asthma; chronic obstructive pulmonary disease; ESTABLISHING BIOEQUIVALENCE; IN-VITRO;
D O I
10.1089/jamp.2013.1040
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
Background: The object of this study was to assess whether a capsule-based and multidose dry powder inhaler containing salmeterol (as xinafoate salt) 50 mu g plus fluticasone propionate (FP) 250 mu g [combination (SFC 50/250)] could be equivalent in terms of in vivo drug delivery and systemic exposure. Methods: This was a randomized, double-blind, double-dummy, replicate treatment design comparative bioavailability study of SFC 50/250 delivered in a capsule-based inhaler (Rotahaler (R)) and a multidose dry powder inhaler (Diskus (R)). Subjects with asthma or chronic obstructive pulmonary (COPD) disease (n=60) were randomized to receive twice-daily SFC 50/250 via a Rotahaler and via Diskus each for two 10-day treatment periods (GlaxoSmithKline Protocol ASR114334). Results: For FP and salmeterol, the in vitro aerodynamic particle size profiles were within +/- 15% of Diskus for the fine particle mass (FPM) and emitted dose (ED) using the Andersen Cascade Impactor, and ED, mass median aerodynamic diameter, and geometric standard deviation using the New Generation Impactor (NGI). This was also the case for FP but not salmeterol for FPM and fine particle dose using the NGI. For the combined asthma and COPD subjects, the plasma AUC and C-max for FP and salmeterol were higher for Rotahaler:Rotahaler/Diskus geometric mean ratios (90% confidence intervals) for FP AUC(0-tau) of 1.52 (1.37-1.67) and C-max of 1.94 (1.75-2.10) and salmeterol AUC(0-tau) of 1.15 (1.09-1.21) and C-max of 1.56 (1.42-1.67). Corresponding values for the primary pharmacodynamic endpoint, weighted mean (0-12 hr) serum cortisol, were 0.928 (0.886-0.971). Inhaled FP/salmeterol via both inhalers was well-tolerated. One serious adverse event, considered possibly related to study medication, resulted in subject withdrawal from the study. Conclusions: The in vitro tests and systemic pharmacodynamic endpoints revealed no major differences between the two inhalers, but lacked predictive power and sensitivity to guide in vivo drug delivery performance and systemic exposure. Based on pharmacokinetic endpoints, the inhalers were not considered bioequivalent in terms of systemic exposure. Further studies to refine the Rotahaler performance are ongoing.
引用
收藏
页码:279 / 289
页数:11
相关论文
共 12 条
  • [1] [Anonymous], 2006, GLOB STRAT ASTHM MAN
  • [2] [Anonymous], GLOB STRAT DIAGN MAN
  • [3] Design, validation and initial testing of the Electronic Lung™ Device
    Burnell, PKP
    Malton, A
    Reavill, K
    Ball, MHE
    [J]. JOURNAL OF AEROSOL SCIENCE, 1998, 29 (08) : 1011 - 1025
  • [4] Byron PR, 2008, RESP DRUG DELIVERY, V1, P125
  • [5] Particle deposition in a cast of human oral airways
    Cheng, YS
    Zhou, Y
    Chen, BT
    [J]. AEROSOL SCIENCE AND TECHNOLOGY, 1999, 31 (04) : 286 - 300
  • [6] Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer
    Clearie, Karine L.
    Williamson, Peter A.
    Vaidyanathan, Sriram
    Du Bois, Jeannine
    Nell, Haylene
    Lipworth, Brian J.
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2010, 69 (06) : 637 - 644
  • [7] Daley-Yates P., 2010, Respir. Drug Delivery, V1, P273
  • [8] Establishing bioequivalence for inhaled drugs; weighing the evidence
    Daley-Yates, Peter T.
    Parkins, David A.
    [J]. EXPERT OPINION ON DRUG DELIVERY, 2011, 8 (10) : 1297 - 1308
  • [9] Pharmacokinetic, Pharmacodynamic, Efficacy, and Safety Data From Two Randomized, Double-Blind Studies in Patients With Asthma and an In Vitro Study Comparing Two Dry-Powder Inhalers Delivering a Combination of Salmeterol 50 μg and Fluticasone Propionate 250 μg: Implications for Establishing Bioequivalence of Inhaled Products
    Daley-Yates, Peter T.
    Parkins, David A.
    Thomas, Marian J.
    Gillett, Benjamin
    House, Karen W.
    Ortega, Hector G.
    [J]. CLINICAL THERAPEUTICS, 2009, 31 (02) : 370 - 385
  • [10] NEWHOUSE MT, 1998, P REPS DRUG DEL, P389