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Neu-Ulm, Germany

Seithel-Keuth A.,Merck KGaA | Johne A.,Merck KGaA | Freisleben A.,Merck KGaA | Kupas K.,Merck KGaA | And 2 more authors.
Clinical Pharmacology in Drug Development

The objectives of this study were to establish the basic intravenous (IV) single-dose PK of safinamide and its major human metabolites, the absolute bioavailability (BA) and food effect on safinamide tablets. Fourteen healthy adult male and female subjects received 50 mg safinamide single-dose treatments according to a randomized, 3-period, 2-sequence crossover design: immediate release (IR) tablets, administered after an overnight fast and after a standardized high-fat, high-calorie breakfast, and IV solution, administered over 30 minutes. Treatments were separated by wash-out intervals of at least 17 days. Serial blood samples were collected for 240 hours postdosing to evaluate safinamide parent drug and metabolite concentrations for the determination of PK parameters. The absolute BA of safinamide 50 mg IR tablets was high, with geoMean AUC0-∞ ratios of about 95% (90% CI: 90-99%) indicating that safinamide is virtually completely absorbed after oral administration. Safinamide IR tablets did not display a food effect on exposure parameters; both 90% CIs for the ratios fed/fasted of AUC0-∞ and Cmax were entirely within the bioequivalence acceptance margins of 80-125%. Only tmax was delayed by about 30% in the fed state. Oral and IV safinamide 50 mg single-dose administrations were generally well tolerated. © The Author(s) 2013. Source

Nakamaru Y.,Mitsubishi Group | Hayashi Y.,Mitsubishi Group | Davies M.,Mitsubishi Tanabe Pharma Europe Ltd | Jurgen Heuer H.,Nuvisan GmbH | And 2 more authors.
Clinical Therapeutics

Purpose We assessed the effects of coadministration of metformin and teneligliptin on their pharmacokinetics in steady-state conditions relative to the administration of either drug alone. Methods This was a Phase I, single-center, open-label, 2-way parallel-group study in healthy male and female subjects. Subjects in group 1 (n = 20) were administered 40 mg of teneligliptin once daily for 5 days, and 850 mg of metformin BID was added to ongoing teneligliptin for an additional 3 days. The subjects in group 2 (n = 20) were administered 850 mg of metformin BID for 3 days, and 40 mg of teneligliptin once daily was added to ongoing metformin for an additional 5 days. Pharmacokinetic outcomes were the AUC0-τ and Cmax of metformin and teneligliptin when administered alone or in combination. Findings Ten male and 10 female subjects participated in each group (mean ± SD age 39.2 ± 11.6 years [range, 19-63 years] in group 1, 47.6 ± 11.9 years [27-64] in group 2; mean ± SD BMI 23.36 ± 2.45 in group 1, 24.56 ± 2.54 in group 2). One female subject in each group was withdrawn because of an adverse event (AE) (vomiting). All 20 subjects in each group were included in the safety analyses, and 19 subjects in each group were included in the pharmacokinetic analyses. The geometric least square means ratio (teneligliptin plus metformin/teneligliptin alone) for Cmax and the AUC0-τ for teneligliptin were 0.907 (90% CI, 0.853-0.965) and 1.042 (90% CI, 0.997-1.089), respectively. The geometric least square means ratio (metformin plus teneligliptin/metformin alone) for the Cmax and AUC0-τ for metformin were 1.057 (90% CI, 0.974-1.148) and 1.209 (90% CI, 1.143-1.278). The 90% CIs were within the prespecified threshold for equivalence (0.80-1.25), except for the AUC0-τ for metformin, which was increased by teneligliptin by 20% relative to metformin alone. In group 1, nine subjects experienced 25 AEs during treatment with teneligliptin alone and 10 subjects experienced 15 AEs during treatment with teneligliptin plus metformin. In group 2, eight subjects experienced 11 AEs during treatment with metformin alone and 11 subjects experienced 18 AEs during treatment with metformin plus teneligliptin. Two AEs in each treatment group were rated as severe. Results of in vitro experiments suggest that teneligliptin-mediated inhibition of organic cation transporter-2 does not increase metformin exposure. Implications Coadministration of teneligliptin and metformin was well tolerated by these healthy subjects during the 8-day treatment period. Coadministration with metformin did not affect the pharmacokinetics of teneligliptin. Although coadministration with teneligliptin increased exposure to metformin, this change is unlikely to be clinically relevant. European Clinical Trials Database identifier: 2007-001511-29. © 2015 Elsevier HS Journals, Inc. Source

Nakamaru Y.,Mitsubishi Group | Hayashi Y.,Mitsubishi Group | Sekine M.,Mitsubishi Group | Kinoshita S.,Clinical Data | And 6 more authors.
Clinical Therapeutics

Objective The aim of this study was to examine the effect of ketoconazole, a potent cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, on teneligliptin pharmacokinetics and to evaluate the safety of combined administration of teneligliptin with ketoconazole. Methods This open-label, fixed-sequence study was conducted in 16 healthy adult volunteers in Germany. On day 1, under fasting conditions, 20 mg of teneligliptin was administered to evaluate the pharmacokinetics of teneligliptin alone. For 3 days (days 8-10), 400 mg of ketoconazole was administered once daily. On day 11, teneligliptin 20 mg and ketoconazole 400 mg were concurrently administered, and for 2 days (days 12 and 13), ketoconazole was administered once daily. The pharmacokinetic parameters (Cmax, Tmax, AUC, terminal t, apparent total plasma clearance, and Vd during the terminal phase) of teneligliptin on days 1 and 11 were calculated. The safety profile was evaluated based on adverse events and clinical findings. To investigate the role of human P-gp in membrane permeation of teneligliptin, an in vitro study was performed to measure the transcellular transport of teneligliptin across monolayers of human P-gp-expressing cells and control cells. Results For Cmax and AUC, the geometric least squares mean ratios (90% CIs) of teneligliptin with ketoconazole to teneligliptin alone were 1.37 (1.25-1.50) and 1.49 (1.39-1.60), respectively. There was no change in t of the terminal elimination phase. In addition, the tolerability of teneligliptin coadministered with ketoconazole was acceptable. The in vitro study revealed corrected efflux ratios for teneligliptin of 6.81 and 5.27 at teneligliptin concentrations of 1 and 10 μM, respectively. Conclusions Because the exposure to teneligliptin in combined administration with ketoconazole, a potent CYP3A4 and P-gp inhibitor, was less than twice that of administration of teneligliptin alone, it is suggested that combined administration of teneligliptin with drugs and foods that inhibit CYP3A4 should not cause a marked increase in exposure. The results of our in vitro study suggest that teneligliptin is a substrate of P-gp. Clinical Trial Registration: EudraCT No. 2009-016652-51. © 2014 Elsevier HS Journals, Inc. Source

Du D.,Medical Affairs | Targett D.,GSK Consumer Healthcare | Stolberg E.,Nuvisan GmbH | Canali A.,GSK Consumer Healthcare
European Journal of Drug Metabolism and Pharmacokinetics

Azelastine hydrochloride is a potent second-generation antihistamine, available in Europe and the USA as a nasal spray formulation for the treatment of allergic rhinitis symptoms. GlaxoSmithKline (GSK) Consumer Healthcare has developed a new nasal formulation of azelastine hydrochloride. The present study was aimed at comparing the clinical pharmacokinetic profiles and assessing the bioequivalence of the new formulation of azelastine hydrochloride with a marketed reference nasal spray product. This was a randomized, two-way crossover, two-stage, single-dose pharmacokinetic study with 2 weeks washout between the two treatment periods. A dosage of 0.28 mg of the test and reference products was administered as a single dose to healthy volunteers according to the crossover design. Twenty-three subjects (15 subjects from stage 1 and 8 subjects from stage 2) were enrolled in the study. Adjusted mean values for AUC0-t were 1,526.8 h pg/mL for the test drug and 1,441.5 h pg/mL for the reference drug; for Cmax the values were 61.59 pg/mL for the test drug and 58.21 pg/mL for the reference drug. The 94.12 % CI of geometric mean ratios (test/reference) were 0.99-1.13 and 0.95-1.18 for AUC0-t and Cmax. This met the predefined criteria for bioequivalence between test and reference drugs. Secondary pharmacokinetic parameters for azelastine and for the metabolite desmethyl azelastine, AUC(0-∞) and tmax, were numerically similar between the two study treatments. Both test and reference azelastine hydrochloride formulations were well tolerated at single dose. This study demonstrated the bioequivalence between the new azelastine hydrochloride nasal spray formulation and the marketed reference Allergodil® after single-dose administration. © 2013 Springer-Verlag. Source

De Vries R.,Janssen R and D NV | Barfield M.,Glaxosmithkline | Van De Merbel N.,PRA | Schmid B.,Nuvisan GmbH | And 7 more authors.

Background: The European Bioanalysis Forum dried blood spots (DBS)/microsampling consortium is reporting back from the experiments they performed on further documenting the potential hurdles of the DBS technology. This paper is focused on the impact of hematocrit changes on DBS analyses. Results: The hematocrit can have an effect on the size of the blood spot, on spot homogeneity and on extraction recovery in a compound-dependent manner. The extraction recovery can change upon aging in an hematocrit-dependent way. Different card materials can give different outcomes. Conclusions: The results from the conducted experiments show that the issues of DBS in regulated bioanalysis are real and that the technology will need improvements to be ready for use as a general tool for regulated bioanalysis. © 2013 Future Science Ltd. Source

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