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- Cullberg, M., et al.
(författare)
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Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis
- 2005
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Ingår i: Clin Pharmacol Ther. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 77:4, s. 279-90
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis. METHODS: A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models. RESULTS: The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat. CONCLUSIONS: The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.
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- Eriksson, Henry, 1946, et al.
(författare)
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Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran
- 2005
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Ingår i: Thromb Haemost. - 0340-6245. ; 94:3, s. 522-7
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Tidskriftsartikel (refereegranskat)abstract
- The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.
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- Hellgren, Margareta, 1947, et al.
(författare)
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The oral direct thrombin inhibitor, ximelagatran, an alternative for anticoagulant treatment during the puerperium and lactation
- 2005
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Ingår i: Bjog. - : Wiley. ; 112:5, s. 579-83
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the excretion of the oral direct thrombin inhibitor (oral DTI), ximelagatran, and its active form, melagatran, in human milk, and to thus evaluate the potential exposure of breastfed infants to melagatran. DESIGN: An open, single dose, single centre study. SETTING: Department of Antenatal Care, Primary Health Care South Bohuslan and Institute for the Health of Women and Children, Goteborg University, Sweden. SAMPLE: Seven healthy Caucasian breastfeeding women who were at least two months postpartum were studied. METHODS: The concentrations of ximelagatran, its two intermediates, and melagatran were determined using liquid chromatography-mass spectrometry, with the limit of quantification of 2 nmol L(-1) for human milk and 10 nmol L(-1) for plasma concentrations. MAIN OUTCOME MEASURES: Concentrations of ximelagatran, its intermediates and melagatran were measured in breast milk over 72 hours, and in plasma over 12 hours, after a single oral 36 mg dose of ximelagatran. RESULTS: Neither ximelagatran nor its intermediates were detected in human breast milk. Only trace amounts of melagatran were detected. The mean cumulative amount of melagatran excreted into breast milk over the 72-hour period after dosing with oral ximelagatran was 0.00091% of the administered dose of ximelagatran. Ximelagatran was well tolerated, with no clinically relevant changes in laboratory variables or vital signs. CONCLUSIONS: Trace levels of melagatran are excreted in human breast milk following administration of the oral DTI ximelagatran. The exposure of breastfed infants to melagatran appears to be low and is therefore unlikely to be of clinical concern.
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- Karlsson, Cecilia, 1968, et al.
(författare)
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Development of Human Target Validation Classification that Predicts Future Clinical Efficacy
- 2019
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 368:2, s. 255-261
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Tidskriftsartikel (refereegranskat)abstract
- Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late-phase development have been identified as a common cause of this decline. Improved ways to ensure early selection of the right drug targets when it comes to efficacy is therefore a highly desirable goal. The aim of this work was to develop a strategy to facilitate selection of novel targets already in the discovery phase that later on in clinical development would demonstrate efficacy. A cross-functional team at AstraZeneca with extensive experience in drug discovery and development participated in several workshops to identify the critical elements that contribute to building human target validation [(HTV); the relevance of the target from a human perspective]. The elements were consolidated into a 10-point HTV classification system that was ranked from lowest to highest in terms of perceived impact on future clinical efficacy. Using 50 years of legacy research and development data, the ability of the 10-point HTV classification to predict future clinical efficacy was evaluated. Drug targets were classified as having low, medium, or high HTV at the time of candidate drug selection. Comparing this HTV classification with later clinical development efficacy data showed that HTV classification was highly predictive of future clinical efficacy success. This new strategy for HTV assessment provides a novel approach to early prediction of clinical efficacy and a better understanding of portfolio risk.
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