scholarly journals The Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban-An Oral, Direct Factor Xa Inhibitor

2013 ◽  
Vol 53 (3) ◽  
pp. 249-255 ◽  
Author(s):  
Dagmar Kubitza ◽  
Michael Becka ◽  
Angelika Roth ◽  
Wolfgang Mueck
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Age And Gender ◽  
And Gender

Safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of R1663, an oral factor Xa inhibitor, in healthy young subjects coupled with exploration of influence of gender and age

2012 ◽  
Vol 108 (07) ◽  
pp. 54-64 ◽  
Author(s):  
Anne Charoin-Pannier ◽  
Christine McIntyre ◽  
Hagen Zandt ◽  
Cornelia Ciorciaro ◽  
Katie Winters ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Factor Xa ◽  
Peak Height ◽  
Factor Xa Inhibitor ◽  
Dependent Manner ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Age And Gender ◽  
Gender And Age ◽  
And Gender ◽  
Oral Doses

SummaryThis study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3–5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC50 = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.

The Effect of Extreme Age, and Gender, on the Pharmacology and Tolerability of Rivaroxaban - An Oral, Direct Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 905-905 ◽  
Author(s):  
Dagmar Kubitza ◽  
Michael Becka ◽  
Wolfgang Mueck ◽  
Michael Zuehlsdorf
Keyword(s):  
Plasma Concentration ◽  
Dose Adjustment ◽  
Factor Xa ◽  
Phase Iii ◽  
Elderly Subjects ◽  
Direct Factor ◽  
Age And Gender ◽  
Young Males ◽  
Elderly Males ◽  
And Gender

Abstract Anticoagulants, such as warfarin, are indicated for a variety of medical conditions, some of which are strongly age dependent. In younger people, the prevalence of many cardiovascular diseases is typically higher in males; however, with increasing age, this difference often resolves. Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This randomized, single-blind study was performed to investigate the influences of age and gender on the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of rivaroxaban in healthy subjects. Four subject groups (young males or females, aged 18–45 years, and elderly males or females, aged >75 years) received a single dose of rivaroxaban 10 mg or placebo (N=34). Gender had no effect on the area under the plasma concentration-time curve (AUC), or maximum plasma concentration (Cmax) of rivaroxaban (Table); however, elderly subjects had higher AUC values than young subjects (least-squares mean ratio [LS-mean] 1.41, 90% confidence interval [CI] 1.20–1.66). The Cmax of rivaroxaban was unaffected by age (LS-mean 1.08, 90% CI 0.96–1.25). Total and renal clearance of rivaroxaban correlated positively with creatinine clearance (CrCL), and inversely with age. The patterns of inhibition of FXa activity by rivaroxaban for all groups were mirrored by those of prolongation of prothrombin time (PT); the maximum effect (Emax) of both consistently occurred 2–4 hours after administration and was unaffected by age or gender. In parallel with the PK results, the AUC of the PD effect, from administration of rivaroxaban to the final time point (AUC0-tn), was increased in elderly subjects (inhibition of FXa activity, LS-mean 1.58, 90% Cl 1.32–1.89; prolongation of PT, LS-mean 1.46, 90% Cl 1.29–1.66); however, all values returned to within 10% of baseline 24 hours after administration of rivaroxaban. The AUC0-tn values correlated inversely with CrCL. Rivaroxaban was well tolerated by all groups; the incidence and intensity of adverse events was similar to placebo. In conclusion, these results demonstrate that the observed effect of age on the PK and PD of this rivaroxaban dose - increased AUC in elderly subjects - was largely due to reduced renal function. Gender had virtually no effect on the PK and PD of rivaroxaban, and neither age nor gender affected tolerability. These findings suggest that rivaroxaban, at similar doses, may not require dose adjustment in elderly patients, or for gender. Phase II studies of rivaroxaban for the prevention of venous thromboembolism also suggested that dose adjustment may not be required for age or gender in this indication. However, this will require confirmation in large-scale phase III studies. PK and PD parameters in subjects receiving rivaroxaban 10 mg (n=6 in each group) Young males Young females Elderly males Elderly females Values are geometric means/geometric coefficients of variation (%) AUC (μg·h/L) 1477/29.97 1210/12.69 1839/28.24 1941/16.15 Cmax (μg/L) 227.57/18.25 209.73/23.95 228.80/23.79 245.01/18.23 Inhibition of FXa Emax (%) 50.86/16.84 53.99/12.44 56.30/6.39 60.16/9.01 AUC0-tn (%/h) 432.76/38.75 343.14/24.61 613.94/11.09 596.48/23.20 Prolongation of PT Emax (x-fold) 1.62/9.06 1.69/8.49 1.66/5.67 1.75/4.63 AUC0-tn (x-fold/h) 22.69/28.09 15.98/10.41 29.77/3.15 26.06/17.52

Pharmacokinetics, Biotransformation, and Mass Balance of Edoxaban, a Selective, Direct Factor Xa Inhibitor, in Humans

2012 ◽  
Vol 40 (12) ◽  
pp. 2250-2255 ◽  
Author(s):  
Mohinder S. Bathala ◽  
Hiroshi Masumoto ◽  
Toshihiro Oguma ◽  
Ling He ◽  
Chris Lowrie ◽  
...  
Keyword(s):  
Mass Balance ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor
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