Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 13 de 13
Filter
Add more filters










Publication year range
1.
Pulm Pharmacol Ther ; 44: 1-6, 2017 06.
Article in English | MEDLINE | ID: mdl-28232118

ABSTRACT

BACKGROUND/OBJECTIVE: To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler® devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma. METHODS: In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV1 ≥80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler® M2 or Turbuhaler® M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had a PC20 methacholine <8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV1 at all visits (90-110% of enrolment value). RESULTS: 60 patients (mean age 31.1 years [range:18-64]; mean FEV1 92.1% predicted normal [78.4-120.6%]) were randomised to treatment; all completed the study. There was a clear dose-response for both devices. The within-device ratios (1.5 mg:0.5 mg) were 1.79 and 1.87 for Turbuhaler® M3 and M2, respectively (both p < 0.001). The between-device ratios (M3:M2) were 0.92 (95% CI: 0.75-1.13) for 0.5 mg and 0.88 (95% CI 0.72-1.08) for 1.5 mg. Both confidence intervals lie inside the interval 0.67-1.50, which was the pre-specified condition for equivalent effect. CONCLUSIONS: Bronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate therapeutic equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler® to the other without adjustment of therapy. Moreover, they show the robustness and utility of this study design and its suitability for investigating therapeutic equivalence. EUDRACT NUMBER: 2014-001457-16. CLINICALTRIALS. GOV IDENTIFIER: NCT02322788.


Subject(s)
Asthma/drug therapy , Bronchodilator Agents/administration & dosage , Terbutaline/administration & dosage , Administration, Inhalation , Adolescent , Adult , Bronchial Provocation Tests , Bronchoconstriction/drug effects , Bronchoconstrictor Agents/administration & dosage , Bronchoconstrictor Agents/pharmacology , Bronchodilator Agents/pharmacology , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Equipment Design , Female , Forced Expiratory Volume , Humans , Male , Methacholine Chloride/administration & dosage , Methacholine Chloride/pharmacology , Middle Aged , Nebulizers and Vaporizers , Terbutaline/pharmacology , Young Adult
2.
Mol Pharm ; 10(11): 4252-62, 2013 Nov 04.
Article in English | MEDLINE | ID: mdl-24079718

ABSTRACT

Two clinical trials and a large set of in vitro transporter experiments were performed to investigate if the hepatobiliary disposition of the direct thrombin inhibitor prodrug AZD0837 is the mechanism for the drug-drug interaction with ketoconazole observed in a previous clinical study. In Study 1, [(3)H]AZD0837 was administered to healthy male volunteers (n = 8) to quantify and identify the metabolites excreted in bile. Bile was sampled directly from the jejunum by duodenal aspiration via an oro-enteric tube. In Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics of AZD0837, the intermediate metabolite (AR-H069927), and the active form (AR-H067637) was investigated (n = 17). Co-administration with ketoconazole elevated the plasma exposure to AZD0837 and the active form approximately 2-fold compared to placebo, which may be explained by inhibited CYP3A4 metabolism and reduced biliary clearance, respectively. High concentrations of the active form was measured in bile with a bile-to-plasma AUC ratio of approximately 75, indicating involvement of transporter-mediated excretion of the compound. AZD0837 and its metabolites were further investigated as substrates of hepatic uptake and efflux transporters in vitro. Studies in MDCK-MDR1 cell monolayers and P-glycoprotein (P-gp) expressing membrane vesicles identified AZD0837, the intermediate, and the active form as substrates of P-gp. The active form was also identified as a substrate of the multidrug and toxin extrusion 1 (MATE1) transporter and the organic cation transporter 1 (OCT1), in HEK cells transfected with the respective transporter. Ketoconazole was shown to inhibit all of these three transporters; in particular, inhibition of P-gp and MATE1 occurred in a clinically relevant concentration range. In conclusion, the hepatobiliary transport pathways of AZD0837 and its metabolites were identified in vitro and in vivo. Inhibition of the canalicular transporters P-gp and MATE1 may lead to enhanced plasma exposure to the active form, which could, at least in part, explain the clinical interaction with ketoconazole.


Subject(s)
Ketoconazole/metabolism , Liver/metabolism , Adult , Amidines/metabolism , Azetidines/metabolism , Bile/metabolism , Drug Interactions , Humans , Male , Young Adult
3.
Thromb Res ; 129(4): e83-91, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21925716

ABSTRACT

INTRODUCTION: AZD0837 and ximelagatran are oral direct thrombin inhibitors that are rapidly absorbed and bioconverted to their active forms, AR-H067637 and melagatran, respectively. This study investigated the antithrombotic effect of AZD0837, compared to ximelagatran and the vitamin K antagonist (VKA) phenprocoumon (Marcoumar), in a disease model of thrombosis in patients with non-valvular atrial fibrillation (NVAF). METHODS: Open, parallel-group studies were performed in NVAF patients treated with VKA, which was stopped aiming for an international normalized ratio (INR) of ≤ 2 before randomization. Study I: 38 patients randomized to AZD0837 (150,250 or 350 mg) or ximelagatran 36 mg twice daily for 10-14 days. Study II: 27 patients randomized to AZD0837 250 mg twice daily or VKA titrated to an INR of 2-3 for 10-14 days. A control group of 20 healthy elderly subjects without NVAF or anticoagulant treatment was also studied. Size of thrombus formed on pig aorta strips was measured after a 5-minute perfusion at low shear rate with blood from the patient/control subject. RESULTS: Thrombus formation was inhibited by AZD0837 and ximelagatran. Relative to untreated patients, a 50% reduction of thrombus size was estimated at plasma concentrations of 0.6 and 0.2 µmol/L for AR-H067637 and melagatran, respectively. For patients receiving VKA treatment, the thrombus size was about 15% lower compared with healthy elderly controls. CONCLUSIONS: Effects of AZD0837 and ximelagatran on thrombus formation were similar or greater than for VKA therapy and correlated with plasma concentrations of their active forms.


Subject(s)
Amidines/administration & dosage , Anticoagulants/administration & dosage , Atrial Fibrillation/drug therapy , Azetidines/administration & dosage , Benzylamines/administration & dosage , Thrombosis/prevention & control , Vitamin K/antagonists & inhibitors , Administration, Oral , Aged , Animals , Antithrombins/administration & dosage , Atrial Fibrillation/complications , Atrial Fibrillation/diagnosis , Female , Humans , In Vitro Techniques , Male , Middle Aged , Swine , Thrombosis/complications , Thrombosis/diagnosis , Treatment Outcome
4.
Eur J Clin Pharmacol ; 66(9): 903-10, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20535457

ABSTRACT

PURPOSE: Reversible mean increases in serum creatinine (approx. 10%) have been observed during clinical investigations of the oral direct thrombin inhibitor AZD0837. The aim of this study was to evaluate whether the increase in s-creatinine is due to a decrease in renal glomerular filtration rate (GFR) or an inhibition of the tubular secretion of creatinine. METHODS: Thirty healthy subjects aged 60-71 years were enrolled in an open-label, randomised, placebo-controlled, two-way crossover study (D1250C00033) in which they received AZD0837 450 mg extended-release formulation once daily for 8 days. Cimetidine was co-administered on Days 6-8 during both treatment periods. Blood and urine samples were collected for assessment of s-creatinine, s-cystatin C, endogenous creatinine clearance (CrCl) and urinary markers of renal damage. GFR was measured by the plasma clearance of iohexol. RESULTS: A 6% increase in mean s-creatinine, but no increase in s-cystatin C, was observed during treatment with AZD0837. Co-administration of cimetidine resulted in a 21% increase in s-creatinine. A significant decrease in CrCl was found during AZD0837 treatment compared with placebo [-5.73 ml/min; 95% confidence interval (CI) -11.3 to -0.12]. No significant difference in GFR (-1.6 ml/min/1.73 m(2); 90% CI -3.7 to 0.5) was seen during treatment with AZD0837 versus placebo. No changes in renal damage markers were found during the treatment periods. CONCLUSIONS: An increase in s-creatinine and a decrease in CrCl, but no decrease in GFR, were found during treatment with AZD0837. These findings suggest that inhibition of the renal tubular secretion of creatinine is the likely cause of the observed increase in s-creatinine.


Subject(s)
Amidines/pharmacology , Azetidines/pharmacology , Creatinine/blood , Fibrinolytic Agents/pharmacology , Glomerular Filtration Rate/drug effects , Kidney Tubules/drug effects , Thrombin/antagonists & inhibitors , Aged , Amidines/pharmacokinetics , Anti-Ulcer Agents/pharmacology , Area Under Curve , Azetidines/pharmacokinetics , Biomarkers/blood , Cimetidine/pharmacology , Cross-Over Studies , Female , Fibrinolytic Agents/pharmacokinetics , Humans , Kidney Function Tests , Kidney Tubules/metabolism , Male , Middle Aged , Stroke/etiology , Stroke/prevention & control
5.
Eur J Clin Pharmacol ; 63(6): 571-81, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17387462

ABSTRACT

OBJECTIVE: To study the effects of amoxicillin, doxycycline, ciprofloxacin, azithromycin, and cefuroxime on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, which is a substrate for the P-glycoprotein pump (P-gp) transporter but is not metabolized by the cytochrome P450 (CYP450) enzyme system. METHODS: Five parallel groups of 16 healthy volunteers received two sequential treatments. The first treatment was a single 36-mg dose of ximelagatran. During the second treatment period, one of the above antibiotics was given on days 1-5 after a washout of at least 2 days. A single 36-mg oral dose of ximelagatran was given on the mornings of days 1 and 5 of the second treatment period. RESULTS: No pharmacokinetic interactions were detected between ximelagatran and amoxicillin, doxycycline, or ciprofloxacin as the least-squares geometric mean treatment ratio of ximelagatran with-to-without antibiotic fell within the intervals of 0.80-1.25 for the area under the curve (AUC) and 0.7-1.43 for C(max). After co-administration with azithromycin, the least square mean ratio with-to-without antibiotic for AUC of melagatran was 1.60 (90% CI, 1.40-1.82) on day 1 and 1.41 (90% CI, 1.24-1.61) on day 5. For melagatran C(max), the corresponding ratios were 1.63 (90% CI, 1.38-1.92) and 1.40 (90% CI, 1.18-1.66). After co-administration with cefuroxime, the ratios were 1.23 (90% CI, 1.07-1.42) and 1.16 (90% CI, 0.972-1.38) for AUC and 1.33 (90% CI, 1.07-1.66) and 1.19 (90%CI, 0.888-1.58) for C(max) of melagatran. Co-administration with the antibiotics did not change mean time to C(max), half-life, or renal clearance of melagatran. The melagatran plasma concentration-response relationship for activated partial thromboplastin time (APTT) prolongation was not altered by any of the studied antibiotics, but the increased plasma concentrations of melagatran after co-administration of ximelagatran with azithromycin resulted in a minor increase in the mean maximum APTT of about 15%. CONCLUSION: The pharmacokinetics of ximelagatran were not affected by amoxicillin, doxycycline, or ciprofloxacin. Melagatran exposure was increased when ximelagatran was co-administered with azithromycin and, to a lesser extent, with cefuroxime. APTT was not significantly altered by any of the antibiotics.


Subject(s)
Anti-Bacterial Agents/pharmacology , Anticoagulants/pharmacology , Azetidines/pharmacology , Benzylamines/pharmacology , Thrombin/antagonists & inhibitors , Adult , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Anticoagulants/administration & dosage , Anticoagulants/pharmacokinetics , Azetidines/administration & dosage , Azetidines/pharmacokinetics , Benzylamines/administration & dosage , Benzylamines/pharmacokinetics , Drug Interactions , Female , Humans , Male
6.
Drug Metab Dispos ; 34(5): 775-82, 2006 May.
Article in English | MEDLINE | ID: mdl-16455803

ABSTRACT

A pharmacokinetic interaction between erythromycin and ximelagatran, an oral direct thrombin inhibitor, was demonstrated in this study in healthy volunteers. To investigate possible interaction mechanisms, the effects of erythromycin on active transport mediated by P-glycoprotein (P-gp) in vitro in Caco-2 and P-gp-over-expressing Madin-Darby canine kidney-human multidrug resistance-1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (seven males and nine females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg t.i.d. on days 2 to 5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on day 6, the least-squares mean estimates (90% confidence intervals) for the ratio of ximelagatran with erythromycin to ximelagatran given alone were 1.82 (1.64-2.01) for the area under the concentration-time curve and 1.74 (1.52-2.00) for the maximum plasma concentration of melagatran, the active form of ximelagatran. Neither the slope nor the intercept of the melagatran plasma concentration-effect relationship for activated partial thromboplastin time statistically significantly differed as a function of whether or not erythromycin was administered with ximelagatran. Ximelagatran was well tolerated regardless of whether it was administered with erythromycin. Erythromycin inhibited P-gp-mediated transport of both ximelagatran and melagatran in vitro and decreased the biliary excretion of melagatran in the rat. These results indicate that the mechanism of the pharmacokinetic interaction between oral ximelagatran and erythromycin may involve inhibition of transport proteins, possibly P-gp, resulting in decreased melagatran biliary excretion and increased bioavailability of melagatran.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Anti-Bacterial Agents/pharmacology , Azetidines/pharmacokinetics , Benzylamines/pharmacokinetics , Erythromycin/pharmacology , Adult , Animals , Anti-Bacterial Agents/adverse effects , Antimalarials/pharmacology , Azetidines/adverse effects , Benzylamines/adverse effects , Bile/metabolism , Biological Transport, Active , Caco-2 Cells , Calcium Channel Blockers/pharmacology , Cell Line , Dogs , Dose-Response Relationship, Drug , Drug Interactions , Erythromycin/adverse effects , Female , Humans , In Vitro Techniques , Male , Partial Thromboplastin Time , Quinidine/pharmacology , Rats , Rats, Sprague-Dawley , Verapamil/pharmacology
7.
Clin Drug Investig ; 25(7): 425-33, 2005.
Article in English | MEDLINE | ID: mdl-17532684

ABSTRACT

OBJECTIVE: To assess the potential effects of food on the pharmacokinetics and tolerability/safety of ximelagatran, an oral direct thrombin inhibitor developed for the prevention and treatment of thromboembolic disease that is rapidly bioconverted to its active form, melagatran. DESIGN AND STUDY PARTICIPANTS: In two open-label, randomised, crossover studies, healthy male and female volunteers received oral ximelagatran as a single 24mg tablet (study 1, n = 30) or a single 36mg tablet (study 2, n = 50). Potential effects of food on the pharmacodynamics (activated partial thromboplastin time; APTT) of the 36mg tablet were also investigated in study 2. RESULTS: For the 24mg tablet, the 90% confidence intervals (CIs) and least-squares mean estimates for the ratio of the tablet with food to the tablet without food fell within the predefined bounds demonstrating no effect on area under the melagatran concentration-time curve (AUC ratio = 0.94 [90% CI 0.90, 0.99]) or maximum plasma concentration (C(max) ratio = 0.88 [90% CI 0.82, 0.95]). The same result was observed for the 36mg tablet (AUC ratio = 1.07 [90% CI 1.03, 1.12]; C(max) ratio = 1.05 [90% CI 0.98, 1.12]). Melagatran AUC normalised for differences in bodyweight was comparable between women and men administered the 24mg or 36mg tablet without food. In addition, food did not clinically significantly alter the melagatran-induced prolongation of the APTT of the 36mg tablet. Ximelagatran was well tolerated with or without food. CONCLUSION: The pharmacokinetics (AUC, C(max)), pharmacodynamics (APTT) and tolerability of melagatran after administration of oral ximelagatran tablets were not affected by food.

8.
J Clin Pharmacol ; 44(9): 1063-71, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15317834

ABSTRACT

The oral direct thrombin inhibitor ximelagatran is being developed for the prevention and treatment of thromboembolism. This single-blind, randomized, placebo-controlled, parallel-group study investigated the potential for the interaction of ximelagatran (36 mg every 12 hours for 8 days, measured as its active form melagatran in blood) and amiodarone (single 600-mg oral dose on day 4) in healthy male subjects (n = 26). For amiodarone + ximelagatran versus amiodarone + placebo, geometric mean ratios (90% confidence intervals for amiodarone AUC(0-120) and C(max) were 0.87 (0.69-1.08) and 0.86 (0.66-1.11), respectively. For desethylamiodarone, the principal metabolite of amiodarone, the corresponding ratios were 1.00 (0.89-1.12) for AUC(0-120) and 0.92 (0.77-1.09) for C(max). The geometric mean ratios (90% confidence intervals) for ximelagatran + amiodarone versus ximelagatran were 1.21 (1.17-1.25) for melagatran AUC(0-12) and 1.23 (1.18-1.28) for melagatran C(max). These confidence intervals were within or only slightly outside the interval, suggesting no interaction (0.8-1.25 for the effect of amiodarone on melagatran and 0.7-1.43 for the effect of melagatran on amiodarone or desethylamiodarone). Amiodarone did not affect the concentration-effect relationship of melagatran on activated partial thromboplastin time. Ximelagatran was well tolerated when coadministered with a single dose of amiodarone. Evaluation of the safety of the combination is needed to confirm that the relatively small pharmacokinetic changes in this study are of no clinical significance.


Subject(s)
Amiodarone/analogs & derivatives , Amiodarone/pharmacokinetics , Anti-Arrhythmia Agents/pharmacokinetics , Anticoagulants/pharmacokinetics , Azetidines/pharmacokinetics , Thrombin/antagonists & inhibitors , Adolescent , Adult , Amiodarone/administration & dosage , Amiodarone/blood , Anti-Arrhythmia Agents/administration & dosage , Anticoagulants/administration & dosage , Area Under Curve , Azetidines/administration & dosage , Azetidines/pharmacology , Benzylamines , Drug Interactions , Half-Life , Humans , Male , Middle Aged , Partial Thromboplastin Time , Regression Analysis , Single-Blind Method , Thrombin/administration & dosage , Thrombin/pharmacology
9.
J Clin Pharmacol ; 44(8): 928-34, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15286097

ABSTRACT

In this randomized, 2-way crossover study, the potential for interaction was investigated between atorvastatin and ximelagatran, an oral direct thrombin inhibitor. Healthy female and male volunteers (n = 16) received atorvastatin 40 mg as a single oral dose and, in a separate study period, ximelagatran 36 mg twice daily for 5 days plus a 40-mg oral dose of atorvastatin on the morning of day 4. In the 15 subjects completing the study, no pharmacokinetic interaction was detected between atorvastatin and ximelagatran for all parameters investigated, including melagatran (the active form of ximelagatran) area under the plasma concentration versus time curve (AUC) and maximum plasma concentration, atorvastatin acid AUC, and AUC of active 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors. Atorvastatin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between atorvastatin and ximelagatran was observed in this study.


Subject(s)
Anticoagulants/pharmacology , Anticoagulants/pharmacokinetics , Azetidines/pharmacology , Azetidines/pharmacokinetics , Glycine/analogs & derivatives , Heptanoic Acids/pharmacology , Heptanoic Acids/pharmacokinetics , Prodrugs/pharmacology , Prodrugs/pharmacokinetics , Pyrroles/pharmacology , Pyrroles/pharmacokinetics , Administration, Oral , Adult , Anticholesteremic Agents/pharmacokinetics , Anticholesteremic Agents/pharmacology , Area Under Curve , Atorvastatin , Benzylamines , Cross-Over Studies , Drug Combinations , Drug Interactions , Female , Glycine/blood , Half-Life , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Male , Partial Thromboplastin Time
10.
J Clin Pharmacol ; 44(8): 935-41, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15286098

ABSTRACT

The interaction potential of digoxin and ximelagatran, an oral direct thrombin inhibitor being developed for the prevention and treatment of thromboembolic disease, was investigated in this randomized, double-blind, 2-way crossover study. On 2 separate occasions, healthy female and male volunteers (n = 16) received ximelagatran 36 mg or placebo twice daily for 8 days separated by a 4- to 14-day washout period. All volunteers received a single oral dose of digoxin 0.5 mg on day 4 of both study periods. No interaction between ximelagatran and digoxin was detected in the pharmaco-kinetic parameters (using a 90% confidence interval [CI] of least squares mean estimate ratios), including melagatran (the active form of ximelagatran) AUC(tau) and C(max) and digoxin AUC(t) and C(max). Digoxin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between digoxin and ximelagatran was observed in this study.


Subject(s)
Anticoagulants/pharmacology , Anticoagulants/pharmacokinetics , Azetidines/pharmacology , Azetidines/pharmacokinetics , Digoxin/pharmacology , Digoxin/pharmacokinetics , Glycine/analogs & derivatives , Administration, Oral , Adult , Anti-Arrhythmia Agents/pharmacokinetics , Anti-Arrhythmia Agents/pharmacology , Area Under Curve , Benzylamines , Cross-Over Studies , Double-Blind Method , Drug Interactions , Female , Glycine/blood , Glycine/urine , Half-Life , Humans , Male , Partial Thromboplastin Time , Prodrugs/pharmacokinetics , Prodrugs/pharmacology
11.
J Clin Pharmacol ; 44(4): 388-93, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15051746

ABSTRACT

Ximelagatran-a direct thrombin inhibitor rapidly converted to its active form, melagatran, after oral administration-is being developed for the prevention and treatment of thromboembolic disease. The pharmacokinetics, pharmacodynamics, and tolerability/safety of ximelagatran following a single 36-mg oral dose of ximelagatran +/- a single oral dose of alcohol (0.5 and 0.6 g ethanol/kg to women and men, respectively) were assessed in a randomized, open-label, two-way crossover study (n = 26). The 90% confidence intervals (CIs) and least squares mean estimates for the ratio of ximelagatran plus alcohol to ximelagatran alone for melagatran AUC (1.04 [90% CI = 1.00-1.08]) and C(max) (1.08 [90% CI = 1.03-1.14]) fell within the bounds demonstrating no interaction. Alcohol did not alter the melagatran-induced prolongation of the activated partial thromboplastin time or the good tolerability/safety profile of ximelagatran. In conclusion, the pharmacokinetics, pharmacodynamics, and tolerability/safety of oral ximelagatran were not affected by alcohol.


Subject(s)
Azetidines/pharmacokinetics , Ethanol/pharmacology , Prodrugs/pharmacokinetics , Thrombin/antagonists & inhibitors , Adult , Area Under Curve , Azetidines/adverse effects , Azetidines/pharmacology , Benzylamines , Drug Interactions , Ethanol/administration & dosage , Female , Humans , Male , Partial Thromboplastin Time , Prodrugs/adverse effects , Prodrugs/pharmacology
12.
Curr Med Res Opin ; 20(3): 325-31, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15025841

ABSTRACT

OBJECTIVE: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders. RESEARCH DESIGN AND METHODS: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20-33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube. RESULTS: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6 micromol.h/L (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (C(max)) was 0.3 micromol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t(1/2)) was 2.8 h for all treatments. The time to C(max) (t(max)) was 2.2h for the whole tablet and approximately 0.5 h earlier when the tablet was crushed or dissolved (1.7-1.8 h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported. CONCLUSION: The present study showed that the pharmacokinetics (AUC and C(max)) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.


Subject(s)
Azetidines/administration & dosage , Azetidines/pharmacokinetics , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/pharmacokinetics , Adult , Benzylamines , Cross-Over Studies , Dosage Forms , Female , Humans , Male
13.
Pacing Clin Electrophysiol ; 26(1P2): 361-6, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12687846

ABSTRACT

The ECG may vary during the day (intra-day), and between days (interday), for the same subject. Variability in ECG characteristic measurements between different investigators is well documented and is often large. During days 1-6 of each placebo period of a two-way crossover Phase I study, digital ECGs were recorded at about 8 and 12 AM in 16 healthy volunteers (8 men, 8 women). Two observers independently analyzed leads V2 and V6 using EClysis software. The durations and amplitudes of major ECG waves and the intervals between major electrocardiographic events were analyzed in a mixed model ANOVA, in which subject, observer, time, and day were treated as random factors. The influence of various corrections for heart rate on the variability of QT intervals was investigated. The difference among subjects explained between 44-81% of the total variability in ECG intervals and amplitudes. Overall, inter- and intraday variability was not statistically significant for any variable. The individualized exponential correction of the QT interval for heart rate eliminated the QT interval dependence on the RR interval in all subjects. Changes in T wave morphology and shortening of the QT interval from morning to noon were observed in ten subjects. The interobserver variability was close to zero (SD < 0.005 ms) for all variables except the PQ interval (SD 1.4 ms). The various sources of variability in determinations of ECG wave characteristics should be considered in the design of clinical studies. The use of EClysis software for ECG measurements is this study made the results highly observer independent.


Subject(s)
Circadian Rhythm , Electrocardiography , Adult , Cross-Over Studies , Female , Heart Rate , Humans , Male , Reference Values , Reproducibility of Results , Signal Processing, Computer-Assisted
SELECTION OF CITATIONS
SEARCH DETAIL
...