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Background Although the quality-adjusted life-years (QALY) model is standard in health technology assessment, quantitative methods are less frequent but increasingly used for benefit-risk assessment (BRA) at earlier stages of drug development. A frequent challenge when implementing metrics for BRA is to weigh the importance of effects on a chronic condition against the risk of severe events during the trial. The lifetime component of the QALY model has a counterpart in the BRA context, namely, the risk of dying during the study. Methods A new concept is presented, the hazard of death function that a subject is willing to accept instead of the baseline hazard to improve his or her chronic health status, which we have called the quality-of-life-adjusted hazard of death. Results It has been proven that if assumptions of the linear QALY model hold, the excess mortality rate tolerated by a subject for a chronic health improvement is inversely proportional to the mean residual life. Conclusions This result leads to a new representation of the linear QALY model in terms of hazard rate functions and allows utilities obtained by using standard methods involving trade-offs of life duration to be translated into thresholds of tolerated mortality risk during a short period of time, thereby avoiding direct trade-offs using small probabilities of events during the study, which is known to lead to bias and variability. © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. Source

Eriksson B.I.,Sahlgrenska University Hospital | Agnelli G.,University of Perugia | Gallus A.S.,Flinders Medical Center | Lassen M.R.,Copenhagen University | And 5 more authors.
Thrombosis and Haemostasis

This double-blind, double-dummy, randomised, phase IIb study (NCT00902928) evaluated different dosing regimens of darexaban compared with enoxaparin (randomised 1:1:1:1:1 to 15 mg twice daily [bid], 30 mg once daily [qd], 30 mg bid or 60 mg qd or enoxapa-rin 40 mg qd) in patients undergoing elective total hip arthroplasty. Patients, investigators, pharmacists and sponsor were all blinded to treatment allocation. Darexaban administration started 6-10 hours (h) post-surgery. Enoxaparin 40 mg qd administration started 12 ± 2 h before surgery. Treatment continued for 35 days. Bilateral venography was performed on Day 10 ± 2. The primary efficacy outcome was total VTEs (composite of proximal/distal deep-vein thrombosis, pulmonary embolism) or death, at Day 12. Total VTE rates were similar across all groups. There was no apparent difference in efficacy between once-and twice-daily darexaban (odds ratio [OR] 1.00; 95% confidence in-terval [CI] 0.71-1.42; p=0.988), or total daily dose (30 mg/day vs 60 mg/day; OR 0.81; 95% CI 0.57-1.15; p=0.244). There was no significant difference in major and/or clinically relevant non-major bleeding between darexaban qd or bid, or between total daily doses of 30 mg or 60 mg, and also for any dosing regimen of darexaban vs enoxapa-rin. Darexaban was well tolerated, without signs of liver toxicity. In conclusion, darexaban, administered qd or bid, and at total daily doses of 30 mg or 60 mg, appears to be effective for VTE prevention and was well tolerated. Data suggest no significant differences between a once- or twice-daily dosing regimen. © Schattauer 2014. Source

Kadokura T.,Astellas Pharma Inc. | Akiyama N.,Astellas Pharma Inc. | Kashiwagi A.,Shiga University of Medical Science | Utsuno A.,Astellas Pharma Inc. | And 5 more authors.
Diabetes Research and Clinical Practice

Aims: Ipragliflozin is a novel and highly selective sodium-glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM. Methods: In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50mg or 100mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days -1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0-3h (AUC0-3h) and 0-24h (AUC0-24h). Pharmacokinetic characteristics included AUC0-24h, maximum ipragliflozin concentration (Cmax), and time to maximum plasma ipragliflozin concentration (tmax). Results: Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC0-3h and AUC0-24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC0-24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0-24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group. Conclusions: Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM. © 2014 Elsevier Ireland Ltd. Source

Kadokura T.,Astellas Pharma Inc. | Groenendaal D.,Astellas Pharma Global Development Europe | Heeringa M.,Astellas Pharma Global Development Europe | Mol R.,Astellas Pharma Global Development Europe | And 3 more authors.
European Journal of Drug Metabolism and Pharmacokinetics

To investigate the impact of the direct Factor Xa inhibitor darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double-blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6-7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin Cmax,ss and AUC0-24h, ss with and without darexaban-MR co-administration were within 0.80-1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for Cmax,ss and AUC0-24h,ss of digoxin plus darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94-1.12) and 1.11 (90 % CI: 1.05-1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80-1.25, indicating a lack of drug-drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co-administration of darexaban-MR did not impact the steady-state PK profile of digoxin. © 2013 Springer-Verlag. Source

Groenendaal D.,Astellas Pharma Global Development Europe | Strabach G.,Life Science Services Clinical Research | Garcia-Hernandez A.,Astellas Pharma Global Development Europe | Kadokura T.,Astellas Pharma Inc. | And 4 more authors.
British Journal of Clinical Pharmacology

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT •Darexaban is an oral direct factorXa inhibitor developed as an antithrombotic for several indications. Several other new oral anticoagulants are metabolized via CYP3A4 and transported by P-glycoprotein, displaying clinically relevant drug interactions with rifampicin and ketoconazole. •Darexaban is almost entirely metabolized to darexaban glucuronide, which is the main active moiety. In vitro, CYP3A4 metabolism is not involved in the formation or metabolism of darexaban glucuronide; and darexaban, but not darexaban glucuronide, is a P-glycoprotein substrate in vitro. WHAT THIS STUDY ADDS •The study shows that rifampicin does not affect the pharmacokinetic profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug-drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low. •This study was carried out to confirm the susceptibility of darexaban/darexaban glucuronide to CYP3A4 and P-glycoprotein induction in vivo in humans. AIMS We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factorXa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect. METHODS In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60mg on day 1 and oral rifampicin 600mg once daily on days 4-14. On day 11, a second dose of darexaban 60mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1-14. The maximal plasma drug concentration (Cmax) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUClast) or AUClast extrapolated to infinity (AUC∞)] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and Cmax ratios were predefined as 80-125%. RESULTS Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUClast with/without rifampicin was 1.08 (1.00, 1.16). The Cmax of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated. CONCLUSIONS Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug-drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low. © 2012 The British Pharmacological Society. Source

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