PMID- 27470430 OWN - NLM STAT- MEDLINE DCOM- 20170109 LR - 20181202 IS - 1179-1918 (Electronic) IS - 1173-2563 (Print) IS - 1173-2563 (Linking) VI - 36 IP - 9 DP - 2016 Sep TI - Pharmacokinetic Bioequivalence of Two Inhaled Tiotropium Bromide Formulations in Healthy Volunteers. PG - 753-762 LID - 10.1007/s40261-016-0441-8 [doi] AB - BACKGROUND AND 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 microg/capsule) while maintaining the same delivered dose (10 microg/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 mug delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 mug delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler((R)) (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 microg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile. FAU - Algorta, Jaime AU - Algorta J AD - Laboratorios Liconsa, Avda. Miralcampo 7, 19200, Azuqueca de Henares, Spain. Jaime.Algorta@chemogroup.net. FAU - Andrade, Laura AU - Andrade L AD - Laboratorios Liconsa, Avda. Miralcampo 7, 19200, Azuqueca de Henares, Spain. FAU - Medina, Marta AU - Medina M AD - Laboratorios Liconsa, Avda. Miralcampo 7, 19200, Azuqueca de Henares, Spain. FAU - Kirkov, Valentin AU - Kirkov V AD - Clinic for Internal Diseases, MHAT Tokuda Hospital Sofia EAD, Sofia, Bulgaria. FAU - Arsova, Sacha AU - Arsova S AD - Cooperative Clinical Drug Research and Development, Hoppegarten, Germany. FAU - Li, Fumin AU - Li F AD - PPD Laboratories, Middleton, WI, USA. FAU - Chi, Jingduan AU - Chi J AD - PPD Laboratories, Middleton, WI, USA. LA - eng PT - Journal Article PT - Randomized Controlled Trial PL - New Zealand TA - Clin Drug Investig JT - Clinical drug investigation JID - 9504817 RN - 0 (Capsules) RN - XX112XZP0J (Tiotropium Bromide) SB - IM MH - Administration, Inhalation MH - Adolescent MH - Adult MH - Area Under Curve MH - Capsules MH - Chromatography, High Pressure Liquid MH - Cross-Over Studies MH - Drug Compounding MH - Dry Powder Inhalers MH - Female MH - Healthy Volunteers MH - Humans MH - Male MH - Middle Aged MH - Therapeutic Equivalency MH - Tiotropium Bromide/administration & dosage/adverse effects/*pharmacokinetics MH - Young Adult PMC - PMC4987402 COIS- FUNDING: This study was funded by Laboratorios Liconsa. CONFLICT OF INTEREST: Jamie Algorta and Laura Andrade are employees of Laboratorios Liconsa. Marta Medina was an employee of Laboratorios Liconsa at the time the study was conducted. Sacha Arsova is an employee of Cooperative Clinical Drug Research and Development AG. Valentin Kirkov, Fumin Li, and Jingduan Chi have no conflicts of interest to declare. ETHICAL APPROVAL: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was approved by the Independent Ethics Committee of MHAT Tokuda Hospital Sofia AD, Sofia, Bulgaria. INFORMED CONSENT: Subjects were informed orally and by means of the Institutional Review Board-approved informed consent sheet. Prior to any activity in the trial, all study participants provided signed informed consent and had the right to withdraw their consent at any time, without giving reason and without detriment. EDAT- 2016/07/30 06:00 MHDA- 2017/01/10 06:00 PMCR- 2016/07/28 CRDT- 2016/07/30 06:00 PHST- 2016/07/30 06:00 [entrez] PHST- 2016/07/30 06:00 [pubmed] PHST- 2017/01/10 06:00 [medline] PHST- 2016/07/28 00:00 [pmc-release] AID - 10.1007/s40261-016-0441-8 [pii] AID - 441 [pii] AID - 10.1007/s40261-016-0441-8 [doi] PST - ppublish SO - Clin Drug Investig. 2016 Sep;36(9):753-762. doi: 10.1007/s40261-016-0441-8.