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Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations.

ABSTRACT: BACKGROUND: Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two intranasal budesonide formulations for the treatment of rhinitis. METHODS: Eighteen healthy volunteers participated in this randomised, controlled, crossover, clinical trial. On two separated days, subjects received a single dose of 512 mug budesonide (4 puffs per nostril) from each of the assayed devices (Budesonida nasal 64(R), Aldo-Union, Spain and Rhinocort 64(R), AstraZeneca, Spain). Budesonide availability was determined by the measurement of budesonide plasma concentration. The pharmacodynamic effect on the hypothalamic-adrenal axis was evaluated as both plasma and urine cortisol levels. Adverse events were tabulated and described. Budesonide availability between formulations was compared by the calculation of 90%CI intervals of the ratios of the main pharmacokinetic parameters describing budesonide bioavailability. Plasma cortisol concentration-time curves were compared by means of a GLM for Repeated Measures. Urine cortisol excretion between formulations was compared through the Wilcoxon's test. RESULTS: All the enrolled volunteers successfully completed the study. Pharmacokinetic parameters were comparable in terms of AUC(t) (2.6 +/- 1.5 vs 2.2 +/- 0.7), AUC(i) (2.9 +/- 1.5 vs 2.4 +/- 0.7), t(max) (0.4 +/- 0.1 vs 0.4 +/- 0.2), C(max)/AUC(i) (0.3 +/- 0.1 vs 0.3 +/- 0.0), and MRT (5.0 +/- 1.4 vs 4.5 +/- 0.6), but not in the case of C(max) (0.9 +/- 0.3 vs 0.7 +/- 0.2) and t(1/2) (3.7 +/- 1.8 vs 2.9 +/- 0.4). The pharmacodynamic effects, measured as the effect over plasma and urine cortisol, were also comparables between both formulations. No severe adverse events were reported and tolerance was comparable between formulations. CONCLUSION: The systemic availability of intranasal budesonide was comparable for both formulations in terms of most pharmacokinetic parameters. The pharmacodynamic effect on hypothalamic-pituitary-adrenal axis was also similar. Side effects were scarce and equivalent between the two products. This methodology to compare different budesonide-containing devices is reliable and easy to perform, and should be recommended for similar products intented to be marketed or already on the market. TRIAL REGISTRATION: No Eudra CT: 2005-003727-39.

SUBMITTER: Algorta J

PROVIDER: S-EPMC2453102 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations.

Algorta Jaime J Pena Maria Angeles MA Francisco Silvia S Abajo Zurine Z Sanz Emilio E

Trials 20080609

<h4>Background</h4>Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two i ...[more]

PMID: 18541030

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Project description:Background and objectivesCurrently, there are no US FDA-approved therapies for eosinophilic esophagitis (EoE). Budesonide oral suspension (BOS; SHP621, TAK-721) is a viscous, muco-adherent, oral formulation of budesonide that is in phase III development for the treatment of EoE. BOS 2 mg twice daily was studied in 12- and 36-week phase III studies for the induction and maintenance of clinical remission in adults and adolescents with EoE (NCT02605837 and NCT02736409). ENTOCORT EC is a gelatin capsule formulation of budesonide that is FDA-approved for the treatment of mild-to-moderate active Crohn's disease (CD) in adults and children. This study compared the systemic exposure to budesonide from BOS with that from ENTOCORT EC, aiming to provide the pharmacokinetic (PK) bridge to the safety data of ENTOCORT EC.MethodsHealthy adult volunteers (n = 22) were enrolled in an open-label, single-center, crossover study. Participants received a single oral dose of BOS 2 mg and a single oral dose of ENTOCORT EC 9 mg under fasting conditions in a randomized sequence, with a 48-h washout period between treatments. PK parameters were calculated by non-compartmental analysis and compared between treatments using a mixed-effects model with sequence and treatment as fixed effects and individuals within sequence as a random effect.ResultsPlasma budesonide concentrations showed that budesonide was absorbed significantly faster from BOS 2 mg than from ENTOCORT EC 9 mg, with peak concentrations reached at 1.5 and 4 h, respectively (p < 0.001). Systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that observed after a single oral dose of ENTOCORT EC 9 mg; the least squares geometric mean maximum plasma concentration and the area under the concentration-time curve from the time of dosing to infinity and from the time of dosing to the last measurable concentration of budesonide after BOS 2 mg were 71.1%, 33.5%, and 33.6% of those after ENTOCORT EC 9 mg, respectively. No notable differences in treatment-emergent adverse events were observed between individuals treated with either drug; all events were mild and none resulted in discontinuation from the study.ConclusionsThis study demonstrated that systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that after a single oral dose of ENTOCORT EC 9 mg. These results provide PK bridging data to compare BOS with therapeutic doses of ENTOCORT EC with respect to safety information.

Project description:Background and objectiveA 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.MethodsThis 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.ResultsA 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).ConclusionsBoth products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.

Project description:BackgroundSeveral countries have used pegylation technology to improve the pharmacokinetic properties of essential drugs. Recently, a novel interferon alfa-2b protein conjugated to four-branched 12 kDa polyethylene glycol molecules was developed jointly between Cuba and Brazil. The aim of this study was to compare the pharmacokinetic properties of BIP48 (pegylated interferon alfa-2b from Bio-Manguinhos/Fiocruz, Brazil) to those of PEGASYS® (commercially available pegylated interferon alfa-2a from Roche Pharmaceutical).MethodsThis phase I, single-centre, randomized, double-blind crossover trial enrolled 31 healthy male volunteers aged 19 to 35 who were allocated to two stages, either side of a 5-week wash-out period, with each arm lasting 14 consecutive days after subcutaneous administration of 180 μg of one formulation or the other (study or comparator). The main outcome variable was serum pegylated interferon concentrations in 15 samples collected during the course of the study and tested using an enzyme immunoassay.ResultsThere were no differences between formulations in terms of magnitude or absorption parameters. Analysis of time parameters revealed that BIP48 remained in the body significantly longer than PEGASYS® (Tmax: 73 vs. 54 h [p = 0.0010]; MRT: 133 vs. 115 h [p = 0.0324]; ke: 0.011 vs. 0.013 h(-1) [p = 0.0153]; t1/2: 192 vs. 108 h [p = 0.0218]).ConclusionBIP48 showed the expected pharmacokinetic profile for a pegylated product with a branched molecular structure. Compared to PEGASYS®, the magnitude absorption was similar, but time parameters were consistent with slower elimination. Further studies should be conducted to evaluate the clinical implications of these findings. A phase II-III repeated-dose clinical trial is ongoing to study these findings in patients with chronic hepatitis C virus infection.Trial registrationThis study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 ). This trial was retrospectively registered in June 2013.

Dataset Information

Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations.

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Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations.

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