41 results on '"Täubel J"'
Search Results
2. LANTHANUM CARBONATE (FOSRENOL™) DOES NOT HAVE A CLINICALLY SIGNIFICANT EFFECT ON THE PHARMACOKINETICS OF DIGOXIN, WARFARIN OR METOPROLOL
- Author
-
Fiddler, G., Täubel, J., Webster, I., and Gill, M.
- Published
- 2003
3. A comparison of simplified lansoprazole suspension administered nasogastrically and pantoprazole administered intravenously: effects on 24-h intragastric pH
- Author
-
Täubel, J. J., Sharma, V. K., Chiu, Y. L., Lukasik, N. L., Pilmer, B. L., and Pan, W. J.
- Published
- 2001
4. Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects
- Author
-
Täubel, J, Ferber, G, Fox, G, Fernandes, S, Lorch, U, and Camm, AJ
- Abstract
AIM: The D2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT). METHODS: This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period. RESULTS: The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5). CONCLUSIONS: Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose.
- Published
- 2017
5. Cardiac Safety of Rupatadine in a Single-Ascending-Dose and Multiple-Ascending-Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments-Comparison With the Previous White Caucasian Thorough QT Study
- Author
-
Täubel, J., primary, Ferber, G., additional, Fernandes, S., additional, Santamaría, E., additional, and Izquierdo, I., additional
- Published
- 2017
- Full Text
- View/download PDF
6. Time of the Day and Magnitude of the Effect of a Drug on the QTc Interval
- Author
-
Täubel, J, primary, Fernandes, S, additional, and Ferber, G, additional
- Published
- 2017
- Full Text
- View/download PDF
7. Cizolirtine Citrate (E-4018) in the Treatment of Chronic Neuropathic Pain
- Author
-
Shembalkar, P., primary, Täubel, J., additional, Abadias, M., additional, Arezina, R., additional, Hammond, K., additional, and Anand, P., additional
- Published
- 2001
- Full Text
- View/download PDF
8. Cizolirtine Citrate (E-4018) in the Treatment of Chronic Neuropathic Pain
- Author
-
Täubel, J., Abadias, M., Arezina, R., Hammond, K., and Anand, P.
- Abstract
SummaryThis study was performed to determine the efficacy and safety of oral cizolirtine citrate, a novel agent, in the treatment of chronic neuropathic pain. Cizolirtine was tested in a double-blind, placebo-controlled, two-way crossover study, having previously been shown to have significant analgesic and anti-hyperalgesic action in neuropathic pain models and preliminary human studies.Twenty-five patients with neuropathic pain, which was persistent for at least three months, and scored >30 mm on a 100 mm visual analogue scale (VAS), were included. A subgroup of five patients had primary skin allodynia, i.e. pain evoked by non-noxious stimuli in the territory of the injured nerve. Cizolirtine 200 mg or placebo was administered twice daily for a treatment period of 21 days, each separated by a washout interval of 7 days. Assessments of skin allodynia were performed using the graded monofilaments (von Frey hairs) on days 1 (predose), 14 and 21 (90 min postdose). All patients were instructed to maintain a daily pain diary throughout the study. Results showed that the differences in VAS and allodynia scores between cizolirtine and placebo treatments were not significant in the overall analysis (p > 0.05); cizolirtine was well tolerated. In a subgroup of five patients with primary allodynia, a 53 reduction in VAS score from baseline at rest (p 0.007) and 55 on movement (p 0.0002) at day 21 was observed with cizolirtine, as compared to 8 at rest (p 0.5215) and 13 on movement (p 0.4187) with placebo. Similarly, allodynia improved with cizolirtine (p 0.03) but not with placebo (p 0.9) in this subgroup. Cizolirtine may be effective in primary allodynia after peripheral nerve injury, and a further trial in a larger number of such subjects is warranted.
- Published
- 2001
- Full Text
- View/download PDF
9. C286, an orally available retinoic acid receptor β agonist drug, regulates multiple pathways to achieve spinal cord injury repair.
- Author
-
Goncalves MB, Wu Y, Clarke E, Grist J, Moehlin J, Mendoza-Parra MA, Hobbs C, Kalindjian B, Fok H, Mander AP, Hassanin H, Bendel D, Täubel J, Mant T, Carlstedt T, Jack J, and Corcoran JPT
- Abstract
Retinoic acid receptor β2 (RARβ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARβ agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve-injured rats. We also found that other clinically available retinoids, that are not RARβ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARβ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARβ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions., Competing Interests: MG and JC have a matter of composition patent for KCL-286. JT was employed by Richmond Pharmacology Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Goncalves, Wu, Clarke, Grist, Moehlin, Mendoza-Parra, Hobbs, Kalindjian, Fok, Mander, Hassanin, Bendel, Täubel, Mant, Carlstedt, Jack and Corcoran.)
- Published
- 2024
- Full Text
- View/download PDF
10. Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL-286, a novel retinoic acid receptor-β agonist for treatment of spinal cord injury, in male healthy participants.
- Author
-
Goncalves MB, Mant T, Täubel J, Clarke E, Hassanin H, Bendel D, Fok H, Posner J, Holmes J, Mander AP, and Corcoran JPT
- Subjects
- Humans, Male, Healthy Volunteers, Dose-Response Relationship, Drug, Area Under Curve, Double-Blind Method, Receptors, Retinoic Acid, Drugs, Investigational
- Abstract
Aims: KCL-286 is an orally available agonist that activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL-286 in male healthy volunteers to establish dosing to be used in the SCI patient population., Methods: The design was a double blind, randomized, placebo-controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells., Results: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration-time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells., Conclusion: KCL-286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL-286 as a novel oral treatment for SCI., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Published
- 2023
- Full Text
- View/download PDF
11. Both osmolality-dependent and independent mechanisms are associated with acute hyperglycemia-induced cardiovascular adverse reactions: Analysis of the mutual interactions leading to cardiovascular phenotypes in dogs.
- Author
-
Kambayashi R, Izumi-Nakaseko H, Goto A, Takei Y, Matsumoto A, Lorch U, Täubel J, and Sugiyama A
- Subjects
- Dogs, Animals, Glucose, Mannitol, Phenotype, Cardiovascular System, Hyperglycemia
- Abstract
Acute hyperglycemia causes various cardiovascular responses; however, the underlying pathophysiology in vivo is myriad and complex, of which mutual interactions remain poorly understood. We analyzed the cardiovascular effects of acute hyperglycemia in comparison with those of hyperosmolality alone. Three g/kg of D-glucose (n = 4) or D-mannitol (n = 4) was intravenously infused to isoflurane-anesthetized intact dogs. Glucose infusion increased plasma glucose level and osmolality, whereas mannitol infusion similarly changed osmolality to glucose infusion but decreased glucose level. Glucose infusion decreased total peripheral vascular resistance, but increased heart rate, left ventricular contraction, left ventricular preload and cardiac output without altering mean blood pressure. Mannitol infusion likewise changed them, but its positive chronotropic and inotropic effects were less potent than those of glucose infusion. Glucose infusion prolonged PR interval, QRS width and QTcV. Mannitol infusion similarly changed them, but its QTcV prolongation was smaller than that of glucose infusion. Glucose infusion-induced cardiovascular responses would be basically attributed to osmolality-dependent mechanisms, whereas its positive chronotropic and inotropic effects along with repolarization delay may be enhanced by osmolality-independent mechanisms, including hyperglycemia by itself and insulin release.
- Published
- 2023
- Full Text
- View/download PDF
12. Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.
- Author
-
Täubel J, Lorch U, Ferber G, Spencer CS, Freier A, Coates S, El Gaaloul M, Donini C, Chughlay MF, and Chalon S
- Subjects
- Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Electrocardiography, Healthy Volunteers, Heart Rate, Humans, Male, Antimalarials adverse effects, Malaria drug therapy
- Abstract
Aims: Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety., Methods: This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals., Results: Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal., Conclusion: Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Published
- 2022
- Full Text
- View/download PDF
13. Kinetics of anti-SARS-CoV-2 IgG antibody levels and potential influential factors in subjects with COVID-19: A 11-month follow-up study.
- Author
-
Luo H, Camilleri D, Garitaonandia I, Djumanov D, Chen T, Lorch U, Täubel J, and Wang D
- Subjects
- Adult, Aged, Antibodies, Viral, COVID-19 immunology, COVID-19 virology, Female, Follow-Up Studies, Humans, Kinetics, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Time Factors, Young Adult, COVID-19 blood, Immunoglobulin G blood, SARS-CoV-2 immunology
- Abstract
We aim to study kinetics of anti-SARS-CoV-2 IgG antibody levels in subjects with COVID-19 for up to 11 months and the potential influential factors. The study was a prospective longitudinal study. The analyses were based on 77 serum/plasma samples with a mean of 4 samples per participant (range 1 - 18) in 20 participants with at least one positive Polymerase Chain Reaction testing result from 19 March 2020 up to 10 February 2021. Among the subjects (median age 34.5 years, 65% male), IgG level declined with the follow-up time (per month; geometric mean ratio [GMR] 0.73; 95% CI, 0.72 - 0.74). In a small sample of subjects from the general population with COVID-19, IgG levels declined non-linearly from month 2 to 11 with individual heterogeneity in quantity and changing speed and may be associated with gender, race and the loss of smell and taste., Competing Interests: Declaration of competing interests The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
14. Ethnic Sensitivity Study of the Extrafine, Single-Inhaler, Triple Therapy Beclomethasone Dipropionate, Formoterol Fumarate, and Glycopyrronium Bromide Pressurized Metered Dose Inhaler in Japanese and Caucasian Healthy Individuals: A Randomized, Double-Blind, Single-Dose Crossover Study.
- Author
-
Cella M, Täubel J, Delestre-Levai I, Tulard A, Vele A, and Georges G
- Subjects
- Administration, Inhalation, Beclomethasone therapeutic use, Bronchodilator Agents therapeutic use, Cross-Over Studies, Double-Blind Method, Drug Combinations, Ethnicity, Female, Formoterol Fumarate therapeutic use, Humans, Japan, Male, Metered Dose Inhalers, Nebulizers and Vaporizers, Glycopyrrolate, Pulmonary Disease, Chronic Obstructive drug therapy
- Abstract
Purpose: A number of single-inhaler, fixed-dose, triple combinations are available for the management of chronic obstructive pulmonary disease and/or asthma. One of these is the extrafine formulation beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB). Given that differences in ethnicity can result in differences in systemic exposure, we evaluated the relative pharmacokinetic (PK) profiles of BDP/FF/GB in Japanese vs Caucasian healthy volunteers to assess the need for dose adjustment., Methods: This randomized, double-blind, single-dose, 4-way crossover study recruited healthy men and women 20 to 55 years of age; for each Japanese person a Caucasian was enrolled who matched in terms of sex, age, and weight. Study treatments included BDP/FF/GB 200/12/25 and 400/12/25 μg (therapeutic), 800/48/100 μg (supratherapeutic), and placebo. PK blood samples were taken up to 24 hours for evaluation of BDP, beclomethasone 17-monopropionate (B17MP, an active metabolite of BDP), and formoterol and up to 48 h for GB. The primary objective was to characterize the PK profiles of BDP, FF, and GB after administration of a single dose of BDP/FF/GB in Caucasian and Japanese healthy volunteers in terms of the AUC
0-t and Cmax of B17MP, formoterol, and GB., Findings: Of the 32 recruited participants (16 Japanese and 16 Caucasian ), 30 completed the study. A clear plasma exposure dose-response relationship was found for all 4 molecules. B17MP Cmax geometric mean ratios for Japanese vs Caucasian participants for the 3 study treatments ranged from 1.17 to 1.26, and AUC0-t ratios ranged from 1.16 to 1.22; thus, the findings were comparable between the ethnicities. Formoterol exposure was higher in Japanese than Caucasian participants (Cmax , 1.22-1.53; AUC0-t , 1.23-1.40). The GB Cmax with BDP/FF/GB 400/12/25 μg (1.09) and AUC0-t values for all three doses (0.98-1.17) were comparable in the 2 populations, but Cmax with 200/12/25 and 800/48/100 μg were higher in Japanese participants (1.32 and 1.42, respectively). Pharmacodynamic (cortisol, potassium, glucose, blood pressure, heart rate, and QT interval with the Fridericia correction) and safety profile results were similar in the 2 ethnicities, with most patients not experiencing any adverse events., Implications: Exposure to BDP/FF/GB pressurized metered dose inhaler at therapeutic and supratherapeutic doses was associated with higher plasma levels in Japanese versus Caucasian healthy volunteers. These PK differences did not translate into meaningful differences in the safety or pharmacodynamic parameters assessed in this study and were consistent with the results of other long-term (52-week) published studies. Dose adjustments in Japanese people are not deemed necessary. CLINICALTRIALS., Gov Identifier: NCT03859414., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
15. Comparing the consistency of electrocardiogram interval measurements by resting ECG versus 12-lead Holter.
- Author
-
Mendzelevski B, Spencer CS, Freier A, Camilleri D, Graff C, and Täubel J
- Subjects
- Cross-Over Studies, Double-Blind Method, Female, Heart Rate, Humans, Male, Electrocardiography, Electrocardiography, Ambulatory
- Abstract
In clinical trials, traditionally only a limited number of 12-lead resting electrocardiograms (ECGs) can be recorded and, thus, long intervals may elapse between assessment timepoints and valuable information may be missed during times when patients' cardiac electrical activity is not being monitored. These limitations have led to the increasing use of Holter recorders which provide continuous data registrations while reducing the burden on patients and freeing up time for clinical trial staff to perform other tasks. However, there is a shortage of data comparing the two approaches. In this study, data from a randomized, double-blind, four-period, crossover thorough QT study in 40 healthy subjects were used to compare continuous 12-lead Holter recordings to standard 12-lead resting ECGs which were recorded in parallel. Heart rate and QT interval data were estimated by averaging three consecutive heartbeats. Values exceeding the sample average by more than 5% were tagged as outliers and excluded from the analysis. Visual comparisons of the ECG waveforms of the Holter signal showed a good correlation with resting ECGs at matching timepoints. Resting ECG data revealed sex differences that Holter data did not show. Specifically, women were found to have a longer QTcF of 20 ms, while men had a lower heart rate. We found that continuous recordings provided a more accurate reflection of changes in cardiac electrical activity over 24 hr. However, manual adjudication is still required to ensure the quality and accuracy of ECG data, and that only artifacts are removed thereby avoiding loss of true signals., (© 2021 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
16. A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.
- Author
-
Täubel J, Mazzetti A, Ferber G, Burch W, Fernandes S, Patel A, Spencer CS, Freier A, Graff C, Kanters JK, and Camm J
- Subjects
- Administration, Cutaneous, Adolescent, Adult, Androgen Antagonists adverse effects, Androgen Antagonists pharmacokinetics, Cortodoxone administration & dosage, Cortodoxone adverse effects, Cortodoxone pharmacokinetics, Double-Blind Method, Electrocardiography, Female, Humans, Male, Propionates adverse effects, Propionates pharmacokinetics, Young Adult, Androgen Antagonists administration & dosage, Cortodoxone analogs & derivatives, Food-Drug Interactions, Propionates administration & dosage
- Abstract
Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested., (© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Published
- 2021
- Full Text
- View/download PDF
17. Confirmation of the cardiac safety of nolasiban in a randomised cohort of healthy female volunteers.
- Author
-
Täubel J, Lorch U, Spencer CS, Freier A, Camilleri D, Djumanov D, Ferber G, Marchand L, Gotteland JP, and Pohl O
- Subjects
- Adult, Cohort Studies, Dose-Response Relationship, Drug, Electrocardiography, Female, Healthy Volunteers, Heart diagnostic imaging, Heart Rate drug effects, Humans, Oximes adverse effects, Pyrrolidines adverse effects, Receptors, Oxytocin antagonists & inhibitors, Young Adult, Heart drug effects, Oximes administration & dosage, Pyrrolidines administration & dosage, Receptors, Oxytocin genetics, Reproductive Techniques, Assisted adverse effects
- Abstract
Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch served 4.5 h post-dose. Concentration-effect modelling was used to assess the effect of two dosages of nolasiban (900 mg and 1800 mg) on QTc following single-dose administration. We found no significant change in QTc at all tested dosages. Two-sided 90% confidence intervals of geometric mean C
max for estimated QTc effects of nolasiban were below the threshold of regulatory concern. The sensitivity of the assay to detect small changes in QTc was confirmed by a significant shortening of QTc between 2 and 4 h after consumption of a meal, which served to validate the model. Independent of the nolasiban assessment, this study also explored the effects of sex hormones on ECG parameters, especially QT subintervals. We found a significant relationship between JTpc and oestradiol. Heart rate was negatively correlated with progesterone. This study confirms the cardiovascular safety of nolasiban and describes relationships of sex hormones and ECG parameters.- Published
- 2021
- Full Text
- View/download PDF
18. Safety, Tolerability, and Dose Proportionality of a Novel Transdermal Fentanyl Matrix Patch and Bioequivalence With a Matrix Fentanyl Patch: Two Phase 1 Single-Center Open-Label, Randomized Crossover Studies in Healthy Japanese Volunteers.
- Author
-
Lorch U, Pierscionek T, Freier A, Spencer CS, and Täubel J
- Subjects
- Administration, Cutaneous, Adult, Analgesics, Opioid administration & dosage, Analgesics, Opioid adverse effects, Area Under Curve, Biological Availability, Cross-Over Studies, Dose-Response Relationship, Drug, Drug Compounding methods, Drug Delivery Systems, Fentanyl administration & dosage, Fentanyl adverse effects, Healthy Volunteers statistics & numerical data, Humans, Japan epidemiology, Naltrexone administration & dosage, Narcotic Antagonists administration & dosage, Reproducibility of Results, Safety, Therapeutic Equivalency, Transdermal Patch adverse effects, Analgesics, Opioid pharmacokinetics, Drug Tolerance ethnology, Fentanyl pharmacokinetics
- Abstract
Two open-label, single-dose, randomized crossover studies were conducted in healthy Japanesemen to (1) assess dose proportionality of 5 doses (1.38, 2.75, 5.5, 8.25, and 11.0 mg) of Lafenta, a novel matrix-type transdermal fentanyl patch with a rate-controlling membrane; and (2) compare patch bioequivalence (11.0 mg) with a commercially available reference patch (Durotep MT Patch [16.8 mg]). Pharmacokinetics, adhesion performance, residual fentanyl, and safety parameters were assessed. Increases in mean AUC
0-t and Cmax after application of the test patch were dose proportional. The test patch (11.0 mg) was bioequivalent to the 16.8-mg reference patch in terms of mean AUC0-inf , AUC0-t , and Cmax . Residual fentanyl levels 72 hours postapplication were lower in the test than in the reference patch. Differences in adhesion performance between the test and the reference patch did not affect delivery efficacy and reliability of the novel matrix patch. Safety findings were in line with previous experiences with fentanyl. Both studies showed low variation in fentanyl exposure and delivery via the test patch. The test patch provided equivalent fentanyl exposure at a lower dose than the reference patch formulation with lower variability and the potential to lower medicinal waste., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2021
- Full Text
- View/download PDF
19. Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study.
- Author
-
Täubel J, Hauke W, Rump S, Viereck J, Batkai S, Poetzsch J, Rode L, Weigt H, Genschel C, Lorch U, Theek C, Levin AA, Bauersachs J, Solomon SD, and Thum T
- Subjects
- Double-Blind Method, Humans, Natriuretic Peptide, Brain, Peptide Fragments, Stroke Volume, Treatment Outcome, Ventricular Function, Left, Heart Failure drug therapy, MicroRNAs
- Abstract
Aims: Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study (NCT04045405)., Methods and Results: Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed a median 23.3% NT-proBNP reduction, vs. a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraging positive trends for relevant cardiac fibrosis biomarkers., Conclusion: This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. Although this study is limited by the small patient numbers, the indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2021
- Full Text
- View/download PDF
20. Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data From Multiple Phase I Trials.
- Author
-
Coates S, Wang D, Pierscionek T, Fernandes S, Djumanov D, Lorch U, and Täubel J
- Abstract
Most UK hospitals, laboratories, and research institutions use uniform reference intervals (RI) that do not take into account known diurnal and racial variation in total white blood cells (WBC) count and its constituent parameters. These risks of excluding potentially suitable ethnic minority volunteers from participating in phase I clinical trials could call into question the validity of a trial's findings or limit its scientific applications and ability to accurately observe drug effects upon WBC parameters. This study pools data from multiple phase I trials, assesses the effects of race and time of day on WBC count, and compares it to the existing literature to establish race and time-specific RIs. A total 13,332 venous blood samples obtained from 7,157 healthy male and female volunteers at the time of screening or admission (predosing) who took part in 35 phase I trials over a period of seven years were pooled and the data were analyzed using generalised estimating equation models. Adjusted RI of total WBC count and its individual parameters were then calculated according to time of day (morning vs. evening) for both black and nonblack populations. This study indicates that black individuals on average had lower total WBC, neutrophil, monocyte, eosinophil, and basophil counts than individuals from nonblack racial groups. Black volunteers had higher mean lymphocyte counts relative to their nonblack counterparts. These differences were deemed statistically significant. Statistically significant increases in total WBC, neutrophil, lymphocyte, and monocyte counts were also observed over the course of daily sampling. Eosinophil counts decreased during this time period, but this finding was only statistically significant in the nonblack population. Despite an observed mild diurnal increase in basophil count in both populations, this was not considered statistically significant. This high-powered study adds significant weight to the known evidence for diurnal and racial variation in WBC parameters. Importantly, it proposes specific RIs that more precisely reflect race and time of day. These could ensure increased participation of black volunteers in clinical trials for improved population representation. Furthermore, the proposed RIs allow for more accurate postdose safety monitoring and reporting, and ensure improved monitoring of postdose WBC count changes., (Copyright © 2020 Coates, Wang, Pierscionek, Fernandes, Djumanov, Lorch and Täubel.)
- Published
- 2020
- Full Text
- View/download PDF
21. Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.
- Author
-
Täubel J, Prasad K, Rosano G, Ferber G, Wibberley H, Cole ST, Van Langenhoven L, Fernandes S, Djumanov D, and Sugiyama A
- Subjects
- Action Potentials drug effects, Adult, Algorithms, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents blood, Calcium Channels metabolism, Cross-Over Studies, Double-Blind Method, Electrocardiography drug effects, Female, Gonadal Steroid Hormones metabolism, Healthy Volunteers, Heart drug effects, Humans, Levofloxacin administration & dosage, Levofloxacin blood, Male, Moxifloxacin administration & dosage, Moxifloxacin blood, Potassium Channels metabolism, Retrospective Studies, Sex Characteristics, Anti-Bacterial Agents adverse effects, Levofloxacin adverse effects, Long QT Syndrome chemically induced, Moxifloxacin adverse effects
- Abstract
Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-T
peak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs., (© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)- Published
- 2020
- Full Text
- View/download PDF
22. Efficient Design of Integrated and Adaptively Interlinked Protocols for Early-Phase Drug Development Programs.
- Author
-
Coates S, Pohl O, Gotteland JP, Täubel J, and Lorch U
- Subjects
- Humans, Receptors, Prostaglandin antagonists & inhibitors, Retrospective Studies, Adaptive Clinical Trials as Topic, Drug Development, Research Design
- Abstract
Background: Adaptive trial designs have the potential to address common challenges in drug development; they decrease timelines and costs of early drug development and efficiently create data that support future trials in target populations. While allowing for flexibility and evolution, adaptive strategies introduce some complexity to the design and implementation of trial protocols. Previously published work by the authors include a retrospective analysis of time savings using adaptive design and a systematic, 3- step methodology for writing early-phase adaptive integrated protocols., Methods: This article builds on the authors' published work demonstrating the practical implementation of the adaptive protocol writing methodology and discussing the challenges and efficiencies. It describes the integration of an early development program of OBE022, a novel, oral, selective prostaglandin F2a receptor antagonist, intended as a treatment for preterm labor, using 2 interdependent, adaptive trial protocols. The program consisted of first-in-human single and multiple ascending dose parts with assessments of food effect, cardiac safety, proof of concept, and interactions of OBE022 with 4 standard of care medicines., Results: The manuscript shows how the trials were tailored to OBE022's pharmacokinetic and pharmacodynamic characteristics and its therapeutic indication. The use of 2 large interdependent, adaptive protocols was facilitated by the United Kingdom's (UK's) regulatory environment and its acceptance of a rules-guided progression through the program. Changes to the planned trial conduct could be made without impacting on timelines, because they used predefined adaptive options within their authorized boundaries, and could therefore be made as nonsubstantial amendments. The program was successful and achieved its objectives. It was efficient and fast: it required a small number of participants (n=83) and completed from start of protocol writing to first draft of the clinical study report in just 11 months., Conclusions: This program included all key elements of early drug development in 2 interlinked protocols: the assessment of single and multiple ascending doses, food effect, cardiac safety and proof of concept. The approach described in this article demonstrates how early-phase programs can be designed to be performed, analyzed and reported time- and cost-efficiently.
- Published
- 2020
- Full Text
- View/download PDF
23. Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone.
- Author
-
Pohl O, Marchand L, Gotteland JP, Coates S, Täubel J, and Lorch U
- Subjects
- Adolescent, Adult, Area Under Curve, Betamethasone administration & dosage, Betamethasone pharmacology, Cross-Over Studies, Drug Interactions, Esters adverse effects, Esters pharmacokinetics, Female, Humans, Magnesium Sulfate administration & dosage, Magnesium Sulfate pharmacology, Middle Aged, Nifedipine administration & dosage, Nifedipine pharmacology, Receptors, Prostaglandin antagonists & inhibitors, Sulfones adverse effects, Sulfones pharmacokinetics, Thiazolidines adverse effects, Thiazolidines pharmacokinetics, Tocolytic Agents adverse effects, Tocolytic Agents pharmacokinetics, Vasotocin administration & dosage, Vasotocin analogs & derivatives, Vasotocin pharmacology, Young Adult, Esters administration & dosage, Sulfones administration & dosage, Thiazolidines administration & dosage, Tocolytic Agents administration & dosage
- Abstract
Aims: To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development., Methods: Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO
4 . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13)., Results: OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO4 . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [Cmax ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (Cmax + 18%, AUC +27%) and OBE002 exposure (Cmax + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (Cmax + 29%, AUC +24%) and markedly increased nifedipine exposure (Cmax by 2-fold and AUC by 2-fold), which may be clinically significant., Conclusions: The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022., (© 2019 The British Pharmacological Society.)- Published
- 2019
- Full Text
- View/download PDF
24. The Cardiovascular Effects of a Meal: J-T peak and T peak -T end Assessment and Further Insights Into the Physiological Effects.
- Author
-
Täubel J, Ferber G, Van Langenhoven L, Del Bianco T, Fernandes S, Djumanov D, Kanters JK, Graff C, and Camm AJ
- Subjects
- Calcium, Cardiovascular System, Electrocardiography, Female, Healthy Volunteers, Heart physiology, Humans, Male, Meals, Retrospective Studies, Eating physiology, Heart Rate physiology
- Abstract
Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown. This shortening of the myocardial action potential caused by the ingestion of food was further investigated in the present study by measuring the QRS, J-T
peak , and Tpeak -Tend intervals in search of further clues to better understand the underlying mechanisms. A retrospective analysis was conducted based on data collected in a formal thorough QT/QTc study in which 32 subjects received a carbohydrate-rich "continental" breakfast, moxifloxacin without food, and moxifloxacin with food. We assessed the effect of food on T-wave morphology using validated algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Our findings demonstrate that a standardized meal significantly shortened J-Tpeak for 4 hours after a meal and to a much lesser extent and shorter duration (up to 1 hour) prolonged the Tpeak -Tend and QRS intervals. This suggests that the QTc shortening occurs mainly during phase 2 of the cardiac action potential. As there was no corresponding effect on Tpeak -Tend beyond the first hour, we conclude that a meal does not interfere with the outward correcting potassium channels but possibly with Ca2+ currents. An effect on mainly Ca2+ aligns well with our understanding of physiology whereby an increase in stroke volume, as observed after a meal, is associated with changes in Ca2+ cycling in and out of the sarcoplasmic reticulum during cardiac myocyte contraction., (© 2019, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)- Published
- 2019
- Full Text
- View/download PDF
25. Practical risk management in early phase clinical trials.
- Author
-
Coates S, Täubel J, and Lorch U
- Subjects
- Clinical Trials, Phase I as Topic methods, Clinical Trials, Phase I as Topic standards, Cohort Studies, Decision Making, Drug-Related Side Effects and Adverse Reactions etiology, Drug-Related Side Effects and Adverse Reactions prevention & control, Drugs, Investigational administration & dosage, Humans, Clinical Trials as Topic methods, Clinical Trials as Topic standards, Drugs, Investigational adverse effects, Risk Management methods, Risk Management standards
- Abstract
Purpose: Stopping rules are an essential part of risk management in early phase clinical trials. As well as being necessary for ensuring the safety of participants on clinical trials, they are also a requirement under the revision to the European Medicine Agency's first-in-human and early clinical trial guideline. The increasing complexity and size of modern trial designs (e.g. integrated trials) raise potential issues with risk management, which, if also too complex, presents challenges for both regulators and investigators to implement. Therefore, there is a clear need for a standard, template, or algorithm-based approach to risk management, in particular rules concerning adverse reactions. The purpose of this manuscript is to present template stopping (or adverse reaction, AR) rules that fulfil regulatory requirements and that can be adapted, taking into account trial design, nature of the investigational medicinal product, and anticipated effects., Methods: The template AR rules that use a systematic, objective and consistent process were developed, taking into account severity (using an objective grading system), seriousness, frequency and reversibility of ARs. These rules control decisions relating to individual trial participants, dosing regimens and dose escalation and/or progression to successive trial parts. For ease of use, the template rules consist of a single, one-page table., Results: The template AR rules have been successfully applied to many early phase adaptive integrated trials that received regulatory authorisation and were performed in the UK. This manuscript presents the template rule table and case studies of some trial-specific adaptations., Conclusions: This work demonstrates how a systematic, objective and consistent approach to risk management of large integrated trials can be simple yet robust, facilitating effective decision making and trial progression whilst safeguarding participant safety.
- Published
- 2019
- Full Text
- View/download PDF
26. Diurnal Profile of the QTc Interval Following Moxifloxacin Administration.
- Author
-
Täubel J, Ferber G, Fernandes S, and Camm AJ
- Subjects
- Adult, Circadian Rhythm, Cross-Over Studies, Double-Blind Method, Female, Humans, Male, Young Adult, Anti-Bacterial Agents pharmacology, Electrocardiography drug effects, Heart Rate drug effects, Moxifloxacin pharmacology
- Abstract
Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects., (© 2018, The American College of Clinical Pharmacology.)
- Published
- 2019
- Full Text
- View/download PDF
27. Confirmation of the Cardiac Safety of PGF 2α Receptor Antagonist OBE022 in a First-in-Human Study in Healthy Subjects, Using Intensive ECG Assessments.
- Author
-
Täubel J, Lorch U, Coates S, Fernandes S, Foley P, Ferber G, Gotteland JP, and Pohl O
- Subjects
- Dose-Response Relationship, Drug, Esters blood, Esters pharmacokinetics, Female, Healthy Volunteers, Humans, Middle Aged, Sulfones blood, Sulfones pharmacokinetics, Thiazolidines blood, Thiazolidines pharmacokinetics, Electrocardiography drug effects, Esters adverse effects, Sulfones adverse effects, Thiazolidines adverse effects
- Abstract
OBE022, a new orally active prostaglandin F
2α receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration-effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration-response analysis showed the absence of QTc prolongation at all doses tested. Two-sided 90% confidence intervals of the geometric mean Cmax for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method., (© 2018, The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)- Published
- 2018
- Full Text
- View/download PDF
28. Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2α receptor antagonist tocolytic: A first-in-human trial in healthy postmenopausal women.
- Author
-
Pohl O, Marchand L, Gotteland JP, Coates S, Täubel J, and Lorch U
- Subjects
- Administration, Oral, Area Under Curve, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Esters adverse effects, Esters pharmacokinetics, Female, Food-Drug Interactions, Healthy Volunteers, Humans, Middle Aged, Postmenopause, Pregnancy, Prodrugs adverse effects, Prodrugs pharmacokinetics, Prospective Studies, Sulfones adverse effects, Sulfones pharmacokinetics, Thiazolidines adverse effects, Thiazolidines pharmacokinetics, Tocolytic Agents adverse effects, Tocolytic Agents pharmacokinetics, Esters administration & dosage, Obstetric Labor, Premature prevention & control, Prodrugs administration & dosage, Receptors, Prostaglandin antagonists & inhibitors, Sulfones administration & dosage, Thiazolidines administration & dosage, Tocolytic Agents administration & dosage
- Abstract
Aims: Preterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F
2α receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F2α receptor antagonists under development for treating preterm labour., Methods: We performed a prospective, first in human, Phase I, dose escalation, placebo-controlled, randomized trial at a clinical trial site in the UK. Placebo, single ascending doses of 10, 30, 100, 300, 1000 or 1300 mg, and multiple ascending doses over 7 days of 100, 300 or 1000 mg day-1 ; were administered to postmenopausal female volunteers. Food interaction was additionally evaluated., Results: Subjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events. Observations showed that prodrug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses, reaching exposure levels that were anticipated to be clinically relevant within 1 h following administration. There was no clinically significant food interaction, with peak exposures reduced to 80% and area under the curve staying bioequivalent. The mean half-life of OBE002 ranged between 8 and 11 h following administration of a single dose and 22-29 h after multiple doses., Conclusions: Administration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients., (© 2018 The British Pharmacological Society.)- Published
- 2018
- Full Text
- View/download PDF
29. Estimation of the Power of the Food Effect on QTc to Show Assay Sensitivity.
- Author
-
Ferber G, Fernandes S, and Täubel J
- Subjects
- Biological Assay methods, Cross-Over Studies, Double-Blind Method, Healthy Volunteers, Humans, Long QT Syndrome blood, Pharmaceutical Preparations blood, Sensitivity and Specificity, Electrocardiography drug effects, Food adverse effects, Food-Drug Interactions physiology, Long QT Syndrome metabolism, Meals physiology
- Abstract
The most recent International Conference on Harmonisation E14 Q&A document states that a separate positive control would not be necessary provided sufficiently high exposures are achieved in the early-phase studies. Realistically, a phase 1 study is unlikely to include a pharmacological positive control, and in cases in which plasma levels of the drug exceeding therapeutic levels are not achieved, the lack of a positive control can constitute a limitation when excluding an effect of regulatory concern. It has been proposed to use the effect of a standardized meal on the estimate of the diurnal time course of QTc to show assay sensitivity. We conducted simulations by subsampling subjects from a 3 different studies and could show that the effect on food on QTc can be reliably prove assay sensitivity for sample sizes as low as 3 × 6 subjects with a power greater than 80%., (© 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)
- Published
- 2018
- Full Text
- View/download PDF
30. Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects.
- Author
-
Täubel J, Ferber G, Fox G, Fernandes S, Lorch U, and Camm AJ
- Subjects
- Administration, Intravenous, Adult, Amisulpride, Asian People, Cross-Over Studies, Dopamine Antagonists adverse effects, Dopamine Antagonists pharmacokinetics, Dose-Response Relationship, Drug, Double-Blind Method, Electrocardiography, Female, Fluoroquinolones administration & dosage, Humans, Male, Middle Aged, Moxifloxacin, Sulpiride administration & dosage, Sulpiride adverse effects, Sulpiride pharmacokinetics, White People, Young Adult, Dopamine Antagonists administration & dosage, Fluoroquinolones adverse effects, Long QT Syndrome chemically induced, Sulpiride analogs & derivatives
- Abstract
Aim: The D
2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT)., Methods: This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period., Results: The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5)., Conclusions: Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose., (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2017
- Full Text
- View/download PDF
31. Stability of the Effect of a Standardized Meal on QTc.
- Author
-
Täubel J, Fernandes S, and Ferber G
- Subjects
- Amisulpride, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Healthy Volunteers, Heart Rate drug effects, Humans, Postprandial Period physiology, Randomized Controlled Trials as Topic, Reproducibility of Results, Research Design, Sensitivity and Specificity, Sulpiride pharmacology, Antipsychotic Agents pharmacology, Eating physiology, Electrocardiography drug effects, Heart Conduction System drug effects, Morpholines pharmacology, Pyrazoles pharmacology, Sulpiride analogs & derivatives
- Abstract
Background: The assessment of QTc changes after the intake of a standardized meal has been proposed as an alternative approach to prove assay sensitivity when the proarrhythimic potential of a drug is to be excluded in either TQT or intensive Phase I QT studies., Methods: In this article, an analysis of the food effect at baseline across periods in two different studies is presented to support the robustness of the method., Results: The results show that the time-effect attributed to food is stable over different study periods demonstrating consistency of the physiological response triggered by food., Conclusions: Stability and reproducibility of the effect is comparable with moxifloxacin., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
32. Comparison of Digital 12-Lead ECG and Digital 12-Lead Holter ECG Recordings in Healthy Male Subjects: Results from a Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.
- Author
-
Wang D, Bakhai A, Arezina R, and Täubel J
- Subjects
- Adult, Double-Blind Method, Electrocardiography, Ambulatory, Healthy Volunteers, Humans, Male, Benzimidazoles pharmacology, Bridged Bicyclo Compounds pharmacology, Electrocardiography methods
- Abstract
Background: Electrocardiogram (ECG) variability is greatly affected by the ECG recording method. This study aims to compare Holter and standard ECG recording methods in terms of central locations and variations of ECG data., Methods: We used the ECG data from a double-blinded, placebo-controlled, randomized clinical trial and used a mixed model approach to assess the agreement between two methods in central locations and variations of eight ECG parameters (Heart Rate, PR, QRS, QT, RR, QTcB, QTcF, and QTcI intervals)., Results: A total of 34 heathy male subjects with mean age of 25.7 ± 4.78 years were randomized to receive either active drug or placebo. Digital 12-lead ECG and digital 12-lead Holter ECG recordings were performed to assess ECG variability. There are no significant differences in least square mean between the Holter and the standard method for all ECG parameters. The total variance is consistently higher for the Holter method than the standard method for all ECG parameters except for QRS. The intraclass correlation coefficient (ICC) values for the Holter method are consistently lower than those for the standard method for all ECG parameters except for QRS, in particular, the ICC for QTcF is reduced from 0.86 for the standard method to 0.67 for the Holter method., Conclusions: This study suggests that Holter ECGs recorded in a controlled environment are not significantly different but more variable than those from the standard method., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
33. Pharmacokinetics, Safety and Cognitive Function Profile of Rupatadine 10, 20 and 40 mg in Healthy Japanese Subjects: A Randomised Placebo-Controlled Trial.
- Author
-
Täubel J, Ferber G, Fernandes S, Lorch U, Santamaría E, and Izquierdo I
- Subjects
- Adult, Area Under Curve, Cyproheptadine administration & dosage, Cyproheptadine adverse effects, Cyproheptadine pharmacokinetics, Dose-Response Relationship, Drug, Double-Blind Method, Female, Healthy Volunteers, Histamine Antagonists adverse effects, Histamine Antagonists pharmacokinetics, Humans, Japan, Male, Placebos, Platelet Activating Factor antagonists & inhibitors, Cognition drug effects, Cyproheptadine analogs & derivatives, Histamine Antagonists administration & dosage
- Abstract
Introduction: Rupatadine is a marketed second generation antihistamine, with anti-PAF activity, indicated for symptomatic treatment of allergic rhinitis and urticaria. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of rupatadine in healthy Japanese subjects after single and multiple oral doses., Methods: In this randomised, double-blind, placebo-controlled study, 27 male and female healthy Japanese subjects were administered single and multiple escalating rupatadine dose of 10, 20 and 40 mg or placebo. Blood samples were collected at different time points for PK measurements and subjects were assessed for safety and tolerability. The effect of rupatadine on cognitive functioning was evaluated by means of computerized cognitive tests: rapid visual information processing (RVP), reaction time (RT), spatial working memory (SWM) and visual analogue scales (VAS)., Results: Exposure to rupatadine as measured by Cmax and AUC was found to increase in a dose dependent manner over the dose range of 10-40 mg for both single and multiple dose administration. The safety assessments showed that all treatment related side effects were of mild intensity and there were no serious adverse events (SAEs) or withdrawals due to treatment-emergent adverse events (TEAEs) in this study. The therapeutic dose of rupatadine did not show any CNS impairment in any of the cognitive tests., Conclusions: This study demonstrated that rupatadine is safe and well tolerated by Japanese healthy subjects. The PK-PD profile confirmed previous experience with rupatadine., Competing Interests: Competing Interests: ES and II are employees of J. Uriach y Compañía, S.A, the founder of this study. JT, SF and UL are employees of Richmond Pharmacology Ltd. GF is an employee of Statistik Georg Ferber GmbH that received funding from Richmond Pharmacology to carry out the statistical analysis of this study. There are no patents to declare. This commercial affiliation, funding and involvement of Uriach does not alter our adherence to all the PLOS ONE policies on sharing data and materials.
- Published
- 2016
- Full Text
- View/download PDF
34. Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.
- Author
-
Täubel J, Ferber G, Lorch U, Wang D, Sust M, and Camm AJ
- Subjects
- Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Morpholines blood, Morpholines pharmacokinetics, Pyrazoles blood, Pyrazoles pharmacokinetics, Retrospective Studies, Young Adult, Electrocardiography drug effects, Heart Rate drug effects, Morpholines pharmacology, Pyrazoles pharmacology, Receptors, sigma antagonists & inhibitors
- Abstract
Background: E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects., Methods: Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day)., Results: In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis., Conclusion: The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal., Trial Registration: EU Clinical Trials Register EudraCT 2010 020343 13.
- Published
- 2015
- Full Text
- View/download PDF
35. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Rising TAK-438 (Vonoprazan) Doses in Healthy Male Japanese/non-Japanese Subjects.
- Author
-
Sakurai Y, Nishimura A, Kennedy G, Hibberd M, Jenkins R, Okamoto H, Yoneyama T, Jenkins H, Ashida K, Irie S, and Täubel J
- Abstract
Objectives: To evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-438 (vonoprazan, a potassium-competitive acid blocker) in healthy male subjects., Methods: In two phase I, randomized, double-blind, placebo-controlled, single rising-dose studies, healthy male subjects (Japan N=84; UK N=63) received a single TAK-438 dose (1-120 mg in Japan and 1-40 mg in the UK). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (intragastric pH)., Results: Plasma concentration-time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax up to 2 h). Estimated mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional. No clear difference in TAK-438 pharmacokinetics was observed between Japanese and non-Japanese subjects. Acid suppression was dose dependent and similar in both studies. The 24-h intragastric pH ≥4 holding time ratio with 40 mg TAK-438 was 92% in Japan and 87% in the UK. TAK-438 was well tolerated, with no adverse events reported in Japanese subjects; 10 of 63 UK subjects experienced 12 treatment-emergent adverse events (non-serious). Increases in serum gastrin and pepsinogen I and II concentrations were observed at doses ≥10 mg, but there were no changes in alanine aminotransferase concentrations., Conclusions: Single oral doses of TAK-438 20-120 mg caused rapid, profound, and 24-h suppression of gastric acid secretion in healthy male subjects, regardless of geographical region, and TAK-438 was well tolerated at all doses studied, making it a potential alternative to proton pump inhibitors for the treatment of acid-related disorders.
- Published
- 2015
- Full Text
- View/download PDF
36. The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study.
- Author
-
Ferber G, Lorch U, and Täubel J
- Subjects
- Computer Simulation, Cross-Over Studies, Data Collection, Data Interpretation, Statistical, Electrocardiography, False Negative Reactions, False Positive Reactions, Fluoroquinolones blood, Fluoroquinolones pharmacokinetics, Healthy Volunteers, Humans, Moxifloxacin, Randomized Controlled Trials as Topic, Time Factors, Clinical Trials, Phase I as Topic, Long QT Syndrome diagnosis, Long QT Syndrome therapy
- Abstract
Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around t max are missed.
- Published
- 2015
- Full Text
- View/download PDF
37. Concentration-effect modeling based on change from baseline to assess the prolonging effect of drugs on QTc together with an estimate of the circadian time course.
- Author
-
Ferber G, Wang D, and Täubel J
- Subjects
- Analgesics blood, Analgesics pharmacokinetics, Analgesics pharmacology, Anti-Bacterial Agents adverse effects, Anti-Bacterial Agents blood, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents pharmacology, Cross-Over Studies, Dose-Response Relationship, Drug, Fluoroquinolones adverse effects, Fluoroquinolones blood, Fluoroquinolones pharmacokinetics, Fluoroquinolones pharmacology, Food-Drug Interactions, Humans, Morpholines blood, Morpholines pharmacokinetics, Morpholines pharmacology, Moxifloxacin, Pyrazoles blood, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Long QT Syndrome chemically induced, Long QT Syndrome metabolism, Models, Biological
- Abstract
As ICH E14 was adopted by the US FDA and the EU CPMC in 2005, thorough QT studies have routinely been analyzed by looking at the time-matched difference between (baseline corrected) QTcF or QTcI under the supra-therapeutic dose and placebo. A study is considered negative, if the two-sided 90% confidence interval for this difference is below 10 ms for all investigated time points. ICH E14 suggests including a positive control, such as moxifloxacin, for assay sensitivity. Concentration-response analysis has been considered a more powerful alternative, but its application to parallel group studies was hampered as a double difference of QTcF per subject cannot be calculated. Recently, a new model based on change from baseline with fixed time and concentration effects has been proposed. It allows for a placebo-corrected prediction of the drug effect with an unbiased standard error, and the estimate of a time effect can be used for assay sensitivity. We demonstrate this approach, utilizing 2 studies reported elsewhere with a crossover design. We compare the results from a conventional concentration-response analysis based on the difference to placebo with results from the novel analysis based on the change from average baseline that includes a fixed time effect., (© 2014, The American College of Clinical Pharmacology.)
- Published
- 2014
- Full Text
- View/download PDF
38. Analyzing the relationship of QT interval and exposure to nitazoxanide, a prospective candidate for influenza antiviral therapy--A formal TQT study.
- Author
-
Täubel J, Lorch U, Rossignol JF, Ferber G, and Camm AJ
- Subjects
- Adolescent, Adult, Antiviral Agents adverse effects, Antiviral Agents blood, Antiviral Agents pharmacokinetics, Cross-Over Studies, Double-Blind Method, Electrocardiography drug effects, Female, Humans, Influenza, Human drug therapy, Male, Middle Aged, Nitro Compounds, Thiazoles adverse effects, Thiazoles blood, Thiazoles pharmacokinetics, Young Adult, Antiviral Agents pharmacology, Heart Rate drug effects, Thiazoles pharmacology
- Abstract
In this randomized, double-blind, placebo controlled study, the safety of therapeutic (675 mg) and supra-therapeutic (2,700 mg) doses of nitazoxanide was evaluated in accordance with the ICH E14 guidelines. Fifty six (56) subjects participated in four treatment periods and received single doses of nitazoxanide 675 mg, nitazoxanide 2,700 mg, moxifloxacin 400 mg, or placebo. For 675 mg nitazoxanide, the largest change in QTcF from baseline was observed at 12 hours post-dose with a peak value of 1.6 ms (two-sided 90% CI: -0.3, 3.6 ms). The largest negative change in QTcF was observed at 1 hour post-dose (-2.7 ms with two-sided 90% CI: -4.5, -0.8 ms). The largest change in QTcF from baseline for 2,700 mg nitazoxanide was observed at 24 hours post-dose with a peak value of 3.4 ms (two-sided CI: 1.4, 5.4 ms). These findings demonstrate that neither a single dose of 675 mg nor 2,700 mg nitazoxanide prolonged the QT interval in healthy male and female volunteers. The safety results also demonstrate that all four treatments were well-tolerated and the most frequently reported adverse events in the nitazoxanide and moxifloxacin treatment groups were gastrointestinal disorders which were as expected according to the reference safety information., (© 2014, The American College of Clinical Pharmacology.)
- Published
- 2014
- Full Text
- View/download PDF
39. Tolerability and pharmacokinetics of ACT-280778, a novel nondihydropyridine dual L/T-type calcium channel blocker: early clinical studies in healthy male subjects using adaptive designs.
- Author
-
Mueller MS, Shakeri-Nejad K, Gutierrez MM, Krause A, Täubel J, Sanderson B, and Dingemanse J
- Subjects
- Administration, Oral, Adult, Area Under Curve, Benzimidazoles adverse effects, Benzimidazoles pharmacokinetics, Bridged Bicyclo Compounds adverse effects, Bridged Bicyclo Compounds pharmacokinetics, Calcium Channel Blockers adverse effects, Calcium Channel Blockers pharmacokinetics, Dose-Response Relationship, Drug, Double-Blind Method, Food-Drug Interactions, Humans, Male, Prospective Studies, Young Adult, Benzimidazoles administration & dosage, Bridged Bicyclo Compounds administration & dosage, Calcium Channel Blockers administration & dosage, Calcium Channels, L-Type drug effects, Calcium Channels, T-Type drug effects
- Abstract
ACT-280778 is a novel nondihydropyridine dual L/T-type calcium channel blocker. Two clinical studies (AC-067-101 and AC-067-102) were conducted to characterize its safety, tolerability, and pharmacokinetics in healthy male subjects after oral administration of single and multiple doses. Both trials were single-center, randomized, double-blind, placebo-controlled, adaptive design, ascending-dose studies, in which ACT-280778 was administrated as single doses of 2, 5, 15, or 40 mg, or as once-daily doses of 5 or 15 mg for 7 days. Single and multiple doses up to and including 15 mg were well tolerated, and no serious or severe adverse event was reported in either study. A single dose of 40 mg was associated with abnormal electrocardiogram findings resulting in the discontinuation of further treatment at this dose or higher doses. ACT-280778 was rapidly absorbed, and larger than dose-proportional increases of the maximum plasma concentration and area under the plasma concentration-time curve were observed. Food intake delayed the time to maximum plasma concentration and doubled exposure. Urinary excretion of unchanged ACT-280778 was negligible, and accumulation at steady state was modest. Overall, pharmacokinetic and tolerability profiles of ACT-280778 observed in these 2 studies warranted further evaluation of ACT-280778 in a proof-of-concept study in patients with hypertension.
- Published
- 2014
- Full Text
- View/download PDF
40. Comparison of the effects of single and repeated oral doses of lansoprazole and rabeprazole on ambulatory 24-hour intragastric pH in healthy volunteers.
- Author
-
Tolman KG, Täubel J, Warrington S, Chiu YL, Pilmer BL, and Pan WJ
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles administration & dosage, 2-Pyridinylmethylsulfinylbenzimidazoles pharmacokinetics, Administration, Oral, Adult, Area Under Curve, Cross-Over Studies, Female, Gastric Acidity Determination, Humans, Lansoprazole, Male, Rabeprazole, 2-Pyridinylmethylsulfinylbenzimidazoles pharmacology, Anti-Ulcer Agents pharmacology, Enzyme Inhibitors pharmacology
- Abstract
Background: As the comparative pharmacokinetics and pharmacodynamics of lansoprazole and rabeprazole have not previously been studied, we set out in this study to compare the pharmacokinetics and pharmacodynamics of single and repeated daily doses of lansoprazole 15 mg and 30 mg with those of rabeprazole 10 mg and 20 mg., Methods: This was an open-label, randomised, crossover, two-centre study in 72 healthy volunteers. Each subject received each of the four treatments for 5 days, with 2-week washout periods. Continuous 24-hour intragastric pH and pharmacokinetics were studied on days 1 and 5., Results: Mean 24-hour pH and percentage time for pH > 4 were not significantly different between lansoprazole 30 mg and rabeprazole 20 mg. Mean 24-hour pH and percentage time for pH > 4 were significantly greater after lansoprazole 30 mg and rabeprazole 20 mg than after lansoprazole 15 mg and rabeprazole 10 mg, respectively. Lansoprazole resulted in greater acid suppression during hours 0-5 on days 1 and 5, whereas rabeprazole had greater suppression during hours 11-24 on day 5. Time to maximum plasma concentration was significantly shorter for lansoprazole on both days., Conclusion: Lansoprazole had a consistently faster onset of action, whereas rabeprazole had a greater effect during the evening hours after 5 days of administration.
- Published
- 2006
- Full Text
- View/download PDF
41. Effects on 24-hour intragastric pH: a comparison of lansoprazole administered nasogastrically in apple juice and pantoprazole administered intravenously.
- Author
-
Freston J, Chiu YL, Pan WJ, Lukasik N, and Täubel J
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles, Adolescent, Adult, Anti-Ulcer Agents administration & dosage, Anti-Ulcer Agents pharmacokinetics, Benzimidazoles administration & dosage, Benzimidazoles pharmacokinetics, Cross-Over Studies, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Female, Humans, Hydrogen-Ion Concentration, Injections, Intravenous, Intubation, Gastrointestinal, Kinetics, Lansoprazole, Male, Omeprazole administration & dosage, Omeprazole analogs & derivatives, Omeprazole pharmacokinetics, Pantoprazole, Proton Pump Inhibitors, Random Allocation, Rosales, Sulfoxides administration & dosage, Sulfoxides pharmacokinetics, Anti-Ulcer Agents pharmacology, Benzimidazoles pharmacology, Enzyme Inhibitors pharmacology, Omeprazole pharmacology, Stomach chemistry, Sulfoxides pharmacology
- Abstract
Objective: To compare the 24-h intragastric pH effects of lansoprazole, 30 mg administered nasogastrically, with pantoprazole, 40 mg administered i.v., Methods: Healthy adults were enrolled in an open label, two-way crossover, single-center study. Thirty milligrams of lansoprazole (administered nasogastrically in apple juice) or pantoprazole (i.v.) were administered once daily at 8:00 AM for 5 consecutive days with at least a 2-wk washout period between the regimens. Ambulatory 24-h intragastric pH was monitored at baseline and on days 1 and 5 of each treatment period. Blood specimens were collected on days I and 5 for pharmacokinetic parameter determinations., Results: Thirty-three adults completed both crossover periods, with the exception of one patient with a zero lansoprazole plasma concentration on day 1 of period 2. Lansoprazole, 30 mg per nasogastric tube, produced significantly higher mean 24-h intragastric pH values relative to pantoprazole, 40 mg i.v., on both day 1 (3.05 vs 2.76, p < 0.002) and day 5 (3.65 vs 3.45, p = 0.024). Lansoprazole sustained the intragastric pH above 3 (days 1 and 5), 4, and 5 (day 1) significantly longer relative to pantoprazole. Lansoprazole's time to the maximum observed concentration and area under the plasma concentration-time curve over the 24-h time interval increased significantly from day I to day 5 (1.7 h vs 2.0 h and 1865 ng x h/ml vs 2091 ng x h/ml, respectively), and a significant increase in half-life relative to day 1 (0.96 h) was observed on day 5 (1.03 h) during pantoprazole treatment., Conclusion: Lansoprazole, 30 mg administered nasogastrically, effectively controls intragastric pH and is an alternative to i.v. pantoprazole in patients who are unable to swallow solid dosage formulations.
- Published
- 2001
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.