Complexity-reduction by first-order approximation of non-linear kinetics

Ecological, toxicological, and pharmacological research is often concerned with the answer to the question of how a substance is processed within a biological system. The exact knowledge of the corresponding kinetic pattern forms the basis for a useful answer. In order to identify non-linear kinetics, a first-order approximation method is proposed for complexity-reduction. A simulation study is presented to investigate the error of the approximation in case of a simple Michaelis-Menten kinetic process. The proposed method shows to give useful results which allow to characterize the underlying kinetic pattern. Furthermore it could be shown that in simulating kinetic processes the applied numerical methods may perform with considerable numerical instabilities

Complexity-reduction by first-order approximation of non-linear kinetics

Ecological, toxicological, and pharmacological research is often concerned with the answer to the question of how a substance is processed within a biological system. The exact knowledge of the corresponding kinetic pattern forms the basis for a useful answer. In order to identify non-linear kinetics, a first-order approximation method is proposed for complexity-reduction. A simulation study is presented to investigate the error of the approximation in case of a simple Michaelis-Menten kinetic process. The proposed method shows to give useful results which allow to characterize the underlying kinetic pattern. Furthermore it could be shown that in simulating kinetic processes the applied numerical methods may perform with considerable numerical instabilities

Naproxen Has No Relevant Effect on the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor.

Abstract BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. BAY 59-7939 compared favourably with enoxaparin in recent clinical trials of the prevention of venous thromboembolism following major orthopaedic surgery. Possible concomitant medications in patients receiving BAY 59-7939 for either the prevention or treatment of venous thromboembolism include non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. This randomized, two-way crossover study was performed to investigate the influence of naproxen on the safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939 in 11 healthy male subjects. The study included a run-in period with naproxen. Treatments were: naproxen 500 mg on 2 consecutive days (run-in), followed by a 14-day washout period, and then randomization either to BAY 59-7939 15 mg; or to naproxen 500 mg on the first day, and naproxen 500 mg and BAY 59-7939 15 mg on the second day. There was a 14-day washout period between crossovers. BAY 59-7939, naproxen, and the combination were well tolerated. Adverse events (eight in total) were reported by three subjects, and all were mild in intensity; there were no drug-related, treatment-emergent adverse events. BAY 59-7939 significantly inhibited Factor Xa activity by 35%, and prolonged prothrombin time (by 1.4 times baseline [tb]), activated partial thromboplastin time (1.3 tb), and HepTest (1.9 tb), with no influence from naproxen. No interaction was observed with respect to collagen-stimulated platelet aggregation. BAY 59-7939 and naproxen together significantly increased bleeding time compared with BAY 59-7939 alone; however, this difference was small compared with naproxen alone for all but one subject. This indicates that some subjects may be more sensitive to the combined effect of naproxen and BAY 59-7939. However, analysis of patients’ data from clinical trials after major orthopaedic surgery showed similar bleeding risks in patients with and without co-medication with NSAIDs at BAY 59-7939 doses up to 10 mg twice daily. The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for BAY 59-7939 both increased by approximately 10% following co-administration of naproxen; however, this small increase in BAY 59-7939 bioavailability was not considered clinically relevant. In conclusion, there is no relevant interaction between BAY 59-7939 and naproxen, although some individuals may be more sensitive to a combination of these drugs. Initial analysis of data from phase II clinical trials of BAY 59-7939 has shown a similar bleeding risk in patients using NSAIDs concomitantly compared with BAY 59-7939 alone. This will be further substantiated in phase III trials. Parameter Naproxen BAY 59-7939 BAY 59-7939 + naproxen aGeometric mean/geometric coefficient of variation; bMedian relative change from baseline; N=11 for all data Bleeding time (tb)a 1.46/0.583 1.20/0.613 2.17/0.576 Platelet aggregationb 0.052 1.02 0.086 AUC (μg.h/L)a - 1250/28.56 1396/26.30 Cmax (μ g/L)a - 152.9/31.51 165.3/27.69</jats:p

Effects of Single-Dose BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor - in Subjects with Extreme Body Weight.

Abstract Currently, agents used for the prevention of venous thromboembolism, such as low molecular weight heparins and pentasaccharides, require dose adjustments for patients in extreme weight categories. BAY 59-7939 is a novel, oral, direct Factor Xa (FXa) inhibitor currently undergoing clinical development for the prevention and treatment of thromboembolic disorders. In this single-center, randomized, single-blind, placebo-controlled, parallel-group study, the influence of extremely low and high body weight on the safety, tolerability, pharmacodynamics and pharmacokinetics of a single 10 mg dose of BAY 59-7939 administered with food was investigated. In total, 48 healthy male and female subjects aged 20–54 years and in three different weight groups (≤ 50, 70–80, and &gt;120 kg) were evaluated; 12 received placebo and 36 received BAY 59-7939. The 70–80 kg and &gt;120 kg groups were gender-balanced (six men and six women in each group); the ≤ 50 kg group comprised of 12 women. Overall, BAY 59-7939 was well tolerated. No serious adverse events were reported; all events were of mild to moderate intensity and resolved 7 days after drug administration. The occurrence of adverse events was similar among the weight groups. No adverse events were reported in the placebo group. FXa was inhibited by BAY 59-7939 in all three weight groups, with a maximum inhibition (Emax) of 46.8%, 45.8%, and 41.7% in the ≤ 50, 70–80, and &gt;120 kg groups, respectively; maximum inhibition was observed about 2–3 hours after BAY 59-7939 administration in all three weight groups. AUC for inhibition of Factor Xa activity was comparable for all volunteer groups regardless of the body weight. BAY 59-7939 prolonged prothrombin time (PT), which was less pronounced in the higher weight groups: 1.7 times baseline (tb), 1.6 tb, and 1.5 tb in subjects ≤ 50, 70–80, and &gt;120 kg, respectively. The pharmacodynamic parameters have returned to baseline within 24 hours in all weight groups. Placebo treatment had no effect on PT. The clotting tests activated partial thromboplastin time and HepTest were also distinctly prolonged after drug administration in all weight groups; the prolongation was slightly more pronounced in subjects in the ≤ 50 kg group than in the other weight groups. The bioavailability of BAY 59-7939 as a 10 mg single dose, in terms of AUC of plasma concentrations, was similar in all three weight groups (P=0.205). However, peak plasma concentrations (Cmax) were 24% higher in subjects with ≤ 50 kg body weight compared with normal-weight subjects. For subjects &gt;120 kg, Cmax was similar to normal-weight subjects. No pharmacokinetic differences between men and women were detected in the normal-weight and &gt;120 kg groups. In conclusion, these data demonstrate that only small influences of body weight on pharmacodynamic or pharmacokinetic parameters are observed which require no dose adjustment of BAY 59-7936 in subjects with extreme body weight.</jats:p