Oeckl P.,Boehringer Ingelheim |
Oeckl P.,Nuvisan GmbH |
Lattke M.,University of Ulm |
Wirth T.,University of Ulm |
And 2 more authors.
Neurobiology of Disease | Year: 2012
A key regulator of inflammatory gene expression is the transcription factor NF-κB that is controlled by the IκB proteins. We used a transgenic mouse model expressing a constitutively active IκB-kinase-2 (IKK2-CA) in astrocytes under control of the human glial fibrillary acidic protein promotor (IKK2-mice) to investigate neuroinflammation, proinflammatory cytokine expression, microglial activation and a potential enhanced susceptibility to the neurotoxin MPTP (4 × 10 mg/kg). Readouts included the determination of cytokines, striatal dopamine (DA), nigral tyrosine hydroxylase (TH) positive neurons, microglial activation and motor activity. IKK2-CA expression in astrocytes conditionally induced by the tet-off system resulted in a widespread neuroinflammation indicated by the increased expression of inflammatory cytokines and the presence of activated microglia and astrogliosis. Additionally, striatal DA concentrations but not nigral TH-positive neurons were reduced in IKK2-mice by 20%. Motor activity of IKK2-mice was not affected. Surprisingly, there was a similar reduction in striatal DA concentrations and the number of nigral TH-positive neurons in IKK2 and control mice after MPTP treatment. In conclusion, although naïve IKK2-mice showed reduced striatal DA concentrations and an increase in inflammatory markers in the brain, a higher susceptibility to MPTP was not observed. This finding argues against a prominent role of astrocyte specific, IKK2-mediated neuroinflammation in MPTP-induced neurodegeneration. © 2012 Elsevier Inc.
Undre N.,Astellas Pharma Europe Ltd. |
Dickinson J.,NUVISAN GmbH |
Dickinson J.,Fujisawa GmbH
BMJ Open | Year: 2017
ObjectiveTacrolimus, an immunosuppressant widely used in solid organ transplantation, is available as a prolonged-release capsule for once-daily oral administration. In the immediate postsurgical period, if patients cannot take intact capsules orally, tacrolimus therapy is often initiated as a suspension of the capsule contents, delivered orally or via a nasogastric tube. This study evaluated the relative bioavailability of prolonged-release tacrolimus suspension versus intact capsules in healthy participants. DesignA phase 1, open-label, single-dose, cross-over study. SettingA single clinical research unit. ParticipantsIn total, 20 male participants, 18-55 years old, entered and completed the study. InterventionsAll participants received nasogastric administration of tacrolimus 10 mg suspension in treatment period 1, with randomisation to oral administration of suspension or intact capsules in periods 2 and 3. Blood concentration-time profile over 144 hours was used to estimate pharmacokinetic parameters. Primary and secondary outcome measuresPrimary end point: relative bioavailability of prolonged-release intact capsule versus oral or nasogastric administration of prolonged-release tacrolimus suspension (area under the concentration-time curve (AUC) from time 0 to infinity post-tacrolimus dose (AUC0-a); AUC measured until the last quantifiable concentration (AUC0-tz); maximum observed concentration (Cmax); time to Cmax (Tmax)). Tolerability was assessed throughout the study. ResultsRelative bioavailability of prolonged-release tacrolimus suspension administered orally was similar to intact capsules, with a ratio of least-square means for AUC0-tz and AUC0-a of 1.05 (90% CI 0.96 to 1.14). Bioavailability was lower with suspension administered via a nasogastric tube versus intact capsules (17%; ratio 0.83; CI 0.76 to 0.92). Cmax was higher for oral and nasogastric suspension (30% and 28%, respectively), and median Tmax was shorter (difference 1.0 and 1.5 hours postdose, respectively) versus intact capsules (2.0 hours). Single 10 mg doses of tacrolimus were well tolerated. ConclusionsCompared with intact capsules, the rate of absorption of prolonged-release tacrolimus from suspension was faster, leading to higher peak blood concentrations and shorter time to peak; relative bioavailability was similar with suspension administered orally. © 2017 Published by the BMJ Publishing Group Limited.
Lissy M.,Nuvisan GmbH |
Ode M.,Hexal AG |
Roth K.,Hexal AG
Drugs in R and D | Year: 2011
Background: HX575, licensed under the brand names Binocrit®, Epoetin Alfa Hexal®, and Abseamed®, was approved in 2007 as the first biosimilar recombinant human erythropoietin alfa (epoetin alfa) in the EU using Erypo®/ Eprex® as reference product. Objectives: The aim of this study was to investigate the bioequivalence and potency of registered epoetin alfa products that have not been compared before in a randomized controlled clinical study. Methods: The study was conducted in two parts: part A compared the European-marketed HX575 and the US-marketed Epogen®; part B compared the European-marketed Erypo®/Eprex® and HX575 manufactured at two different drug substance production sites (HX575-TT denoting the already-approved technology-transfer product from an additional manufacturing site). In analyses across both study parts, Epogen® was exploratorily compared with Erypo®/Eprex®. A dense-sampling 48-hour pharmacokinetic profile was recorded at steady state after 11 doses of 100 IU epoetin alfa per kg of bodyweight. The hemoglobin response over 4 weeks of study medication administration was analyzed as the primary efficacy surrogate parameter using an ANCOVA model with the baseline value as co-variate. The per-protocol population comprised a total of 268 subjects, 76 in part A (equally randomized to HX575 or Epogen®) and 192 in part B (equally randomized to HX575, HX575-TT, or Erypo ®/Eprex®). Pairs of study arms were compared in terms of the ratio of the mean epoetin alfa area under the curve (AUC) and the ratio of the mean hemoglobin area under the effect curve (AUEC). Results: Bioequivalence was shown in all pair-wise comparisons with the 90% confidence intervals of theAUC ratios falling within the standard bioequivalence limits of 80125%. Moreover, an equivalent pharmacodynamic response was achieved with all compared epoetin alfa products, as confirmed by the hemoglobin AUEC ratios 90% CI falling within the predefined acceptance margins of 96.8103.2%. Thus, bioequivalence and equivalent potency was demonstrated for HX575 and Epogen ® in part A of the study, as well as for HX575, HX575-TT and Erypo®/Eprex® in part B of the study. Pair-wise comparison across study parts indicated similar pharmacokinetic and pharmacodynamic profiles of Epogen® and Erypo®/ Eprex®. All compared epoetin alfa products were well tolerated and had a similar safety profile. No subject developed anti-erythropoietin antibodies upon administration of study medication. Conclusion: The results show, for the first time in a prospective randomized clinical study, equivalent bioavailability at steady state and similar potency of the US-marketed Epogen® and the European-marketed Binocrit®. Differences in the formulation between the epoetin alfa products had no apparent clinical impact. The high degree of similarity between Epogen® and Erypo®/ Eprex® provides justification for linking and comparing results from clinical studies that were conducted using either US- or European-marketed epoetin alfa products. © 2011 Niazi et al., publisher and licensee Adis Data Information BV.
Cawello W.,UCB Pharma |
Rosenkranz B.,Stellenbosch University |
Schmid B.,NUVISAN GmbH
Epilepsia | Year: 2013
Summary Purpose To determine whether the antiepileptic drug lacosamide affects the pharmacokinetics or pharmacodynamics of a combined oral contraceptive (OC; ethinylestradiol 0.03 mg plus levonorgestrel 0.15 mg). Methods This was an open-label trial in healthy female volunteers. Eligible women entered cycle 1 of the trial on the first day of menstruation. Cycle 1 was a medication-free, run-in phase of approximately 28 days to confirm that normal ovulation occurred. Volunteers with confirmed ovulation entered the subsequent cycle and started taking OCs. After establishing ovulation suppression (defined as progesterone serum concentration <5.1 nm on day 21 of the menstrual cycle) in volunteers taking the OCs in cycle 2, lacosamide 400 mg/day was administered concomitantly in the subsequent cycle (cycle 3). The pharmacokinetic parameters of area under the concentration-time curve (AUC), maximum steady-state plasma drug concentration (Cmax), and time to maximum concentration (t max) were measured for the OC components and lacosamide. Key Findings A total of 37 volunteers completed cycle 1, and 32 completed cycle 2. In each of the 31 volunteers who completed the trial (through cycle 3), pharmacodynamic assessment showed progesterone serum concentration was <5.1 nm on day 21 of cycle 2, when the OC was administered alone, and on day 21 of cycle 3, when lacosamide was administered concomitantly. The AUC of ethinylestradiol alone versus together with lacosamide was 1,067 ± 404 versus 1,173 ± 330 pg h/ml. Corresponding values of Cmax were 116.9 ± 48.8 versus 135.7 ± 28.6 pg/ml. For levonorgestrel, the AUC alone was 74.2 ± 21.4 versus 80.9 ± 18.5 ng h/ml with lacosamide. Corresponding values of Cmax were 6.7 ± 1.9 versus 7.4 ± 1.5 ng/ml. The AUC and Cmax point estimates and almost all 90% confidence intervals (except for Cmax of ethinylestradiol) for ethinylestradiol and levonorgestrel (with and without lacosamide) were within the conventional bioequivalence range, and no relevant changes in tmax were observed for ethinylestradiol (1.5 ± 0.6 h alone vs. 1.4 ± 0.7 h with lacosamide) or for levonorgestrel (1.5 ± 1.0 h alone vs. 1.1 ± 0.6 h with lacosamide). Lacosamide pharmacokinetics were consistent with those observed in previous studies of lacosamide alone, with values for AUC of 113.5 ± 20.7 μg h/ml, Cmax of 13.8 ± 2.2 μg/ml, and tmax of 1.1 ± 0.4 h. Significance Lacosamide and an OC containing ethinylestradiol and levonorgestrel have low potential for drug-drug interaction; therefore, coadministration of the two drugs is unlikely to result in contraceptive failure or loss of seizure control. © Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.
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 | Year: 2015
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.
De Vries R.,Janssen R and D NV |
Barfield M.,Glaxosmithkline |
Van De Merbel N.,PRA |
Schmid B.,Nuvisan GmbH |
And 7 more authors.
Bioanalysis | Year: 2013
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.
Jongen P.J.,MS4 Research Institute |
Lehnick D.,STATPROC |
Sanders E.,Amphia Hospital |
Seeldrayers P.,Hospital Civil Of Charleroi |
And 3 more authors.
Health and Quality of Life Outcomes | Year: 2010
Glatiramer acetate (GA) and interferon-beta (INFb) are first-line disease modifying drugs for relapsing remitting multiple sclerosis (RRMS). Treatment with INFb is associated with a significant increase in health-related quality of life (HR-QoL) in the first 12 months. It is not known whether HR-QoL increases during treatment with GA.Methods: 197 RRMS patients, 106 without and 91 with prior immunomodulation/immunosuppression, were studied for HR-QoL (Leeds Multiple Sclerosis-QoL [LMS-QoL] scale, score range 0 - 32), fatigue (Fatigue Impact Scale [FIS]) and depressed mood (Beck Depression Inventory-Short Form [BDI-SF]) at baseline and 6 and 12 months after start of GA treatment.Results: At 6 and 12 months mean LMS-QoL scores were significantly increased in the treatment-naive patient group (p < 0.001), not in the pre-treated group. At month 12 43% of treatment-naïve patients had improved HR-QoL (increase LMS-QoL score 3 or more points) (p < 0.001). Likewise, mean FIS scores were decreased at months 6 and 12 in the treatment-naïve group (p < 0.01), not in the pre-treated group. In both groups mean BDI-SF scores did not change. No demographic or clinical baseline factor was predictive of HR-QoL increase. HR-QoL changes were zero to negative for patients who had discontinued GA before month 12 (28.4% of patients).Conclusions: In RRMS patients without prior immunomodulation/immunosuppression treatment with GA was associated with an increase in HR-QoL in the first 6 months, that was sustained at 12 months. In 4 out of 10 patients HR-QoL improved. Increase in HR-QoL was associated with decrease in fatigue. © 2010 Jongen et al; licensee BioMed Central Ltd.
Du D.,GSK Consumer Healthcare |
Targett D.,GSK Consumer Healthcare |
Stolberg E.,Nuvisan GmbH |
Canali A.,GSK Consumer Healthcare
European Journal of Drug Metabolism and Pharmacokinetics | Year: 2014
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.
PubMed | Biokinetic Europe Ltd, Nuvisan GmbH and Bayer AG
Type: Journal Article | Journal: Human reproduction (Oxford, England) | Year: 2016
Does administration of vilaprisan (VPR) to healthy women for 12 weeks reduce menstrual bleeding?In this 12-week proof-of-concept phase 1 trial, most women (30/33, 90%) who received VPR at daily doses of 1-5 mg reported the absence of menstrual bleeding.Vilaprisan (BAY 1002670) is a novel, highly potent selective progesterone receptor modulator that markedly reduces the growth of human leiomyoma tissue in a preclinical model of uterine fibroids (UFs).In this double-blind, parallel-group study, of the 163 healthy women enrolled 73 were randomized to daily VPR 0.1 mg (n = 12), 0.5 mg (n = 12), 1 mg (n = 13), 2 mg (n = 12), 5 mg (n = 12) or placebo tablets (n = 12) for 12 weeks. Participants were followed up until the start of the second menstrual bleeding after the end of treatment. Trial simulations were used to determine the minimum sample size required to estimate the non-bleeding rate (i.e. self-assessed bleeding intensity of none or spotting) using Bayesian dose-response estimation with incorporated prior information. It was estimated that 48 participants in the per-protocol analysis population would be sufficient.Women aged 18-45 years who had been sterilized by tubal ligation were enrolled between November 2011 and May 2012. Participants kept a daily diary of bleeding intensity. Blood and urine samples were taken, and transvaginal ultrasound was performed before treatment, during treatment and follow-up. Endometrial biopsies were obtained during the pretreatment cycle, at the end of the treatment period and during the follow-up phase. The primary outcome was the estimated dose-response curve of the observed non-bleeding rate during Days 10-84 of treatment, excluding the endometrial biopsy day and 2 days after biopsy. Secondary outcomes included return of bleeding during follow-up, size of follicle-like structures and serum hormone levels. Safety assessments included adverse events (AEs), endometrial thickness and histology, laboratory parameters, vital signs and 12-lead electrocardiography.All 73 randomized participants received at least one dose of study medication and were included in safety analyses; six participants were excluded from the per-protocol analyses. A total of 69 completed the study. Observed non-bleeding rates increased with VPR dose: 0.1 mg (0%; 90% confidence interval [CI]: 0-23.8), 0.5 mg (27.3%; 90% CI: 7.9-56.4), 1 mg (80.0%; 90% CI: 49.3-96.3), 2 mg (100%; 90% CI: 77.9-100), 5 mg (90.9%; 90% CI: 63.6-99.5), compared with 0% (90% CI: 0-22.1) in the placebo group. Maximal non-bleeding rates were reached at doses of 2 mg and higher. Return of menstrual bleeding was observed in all women 52 days after VPR discontinuation. No treatment-emergent critical endometrial findings occurred. Follicular growth was not suppressed and minimum average estradiol levels remained above 40 pg/ml. No serious treatment-emergent AEs or study discontinuations due to AEs were reported. Clinically relevant changes in laboratory parameters or vital signs were not evident.The results of this small proof-of-concept study will need to be confirmed in larger trials in patients with UFs to establish the potential therapeutic benefits and safety of VPR.The high rates of non-bleeding (80-100% at VPR doses of 1-5 mg) support further evaluation of VPR in patients with UFs and heavy menstrual bleeding.This study was funded by Bayer Pharma AG. B.S., A.K., M.-H.S.M., C.S. and B.R. are employees of Bayer Pharma AG. B.S., A.K. and M.-H.S.M. are listed as inventors of an issued patent related to this work, and received payment for this from Bayer Pharma AG. D.B. is the founder of Biokinetic Europe Ltd, UK, which received funding for this study from Bayer Pharma AG. M.K. is an employee of Nuvisan GmbH, Germany, which received funding for this study from Bayer Pharma AG.Clinicaltrials.gov identifier: NCT01816815.20 March 2013.28 November 2011.
PubMed | Merck KGaA and Nuvisan GmbH
Type: Journal Article | Journal: Clinical pharmacology in drug development | Year: 2016
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 50mg 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 30minutes. Treatments were separated by wash-out intervals of at least 17 days. Serial blood samples were collected for 240hours postdosing to evaluate safinamide parent drug and metabolite concentrations for the determination of PK parameters. The absolute BA of safinamide 50mg 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 50mg single-dose administrations were generally well tolerated.