Background and Objective A novel tiotropium bromide\nmonodose capsule dry powder inhaler (DPI) formulation\nand device have been developed. The formulation was\nbased on a spray-dried matrix that enhances the\naerosolizaton properties, allowing a less active tiotropium\nmetered dose (13 lg/capsule) while maintaining the same\ndelivered dose (10 lg/actuation). This study describes the\npharmacokinetic bioequivalence to the reference product.\nMethods This randomized, two-stage, crossover, semi-replicate\n(three-way) study was performed in healthy volunteers. In\neach study period, subjects received a single dose of two\ncapsules (20 lg delivered dose) of the study medication, separated\nby a 14-day washout period: tiotropium 10 lg delivered\ndose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler\n(Boehringer Ingelheim Pharma GmbH & Co KG, Germany).\nBlood samples were obtained up to 48 h post-dose to evaluate\nthe comparative bioavailability. Tiotropium was measured in\nplasma by means of dual stage liquidââ?¬â??liquid extraction followed\nby the two-dimensional ultra-high performance liquid\nchromatography sensitive sub-pg/mL bioanalytical method.\nThemain pharmacokinetic parameters were maximum plasma\nconcentration (Cmax), area under the concentrationââ?¬â??time curve\n(AUC) from time zero hours to the last observed concentration\nat time t (AUCt), and AUC from time zero hours to 30 min\n(AUC0.5). Bioequivalence was accepted if the 90.20 % confidence\ninterval (CI) for the ratio test/reference of the primary\npharmacokinetic parameters lay within the acceptance range of\n80ââ?¬â??125 %. Safety assessment was a secondary endpoint.\nResults A total of 30 subjects were randomized and bioequivalence\nwas demonstrated for all primary pharmacokinetic\nparameters: Cmax (CI 87.26ââ?¬â??106.60 %), AUCt (CI 101.33ââ?¬â??\n111.64 %), and AUC0.5 (CI 97.95ââ?¬â??113.49 %). Both study\ntreatmentswere well tolerated (four non-serious adverse events\n[AEs] were reported in four subjects: one AE before any product\nadministration, two AEs after test product administration;\nand one AE after reference product administration).\nConclusions Both products containing tiotropium 10 lg\ndelivered-dose DPI were bioequivalent and showed good\ntolerability and a similar safety profile.
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