BAY 59--7939 was well tolerated with predictable pharmacodynamics and pharmacokinetics across a wide range of doses in healthy male subjects. BAY 59--7939 was shown to be an effective and specific factor Xa inhibitor.

BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.

Paediatric clinical trial development could greatly benefit from clearance scaling, particularly in guiding dosing regimens. Furthermore, since the proportion of clearance via different elimination pathways is age-dependent, information could be gained on the developmental extent of drug-drug interactions.

No abstract

In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10-to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t 1/2 ) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t 1/2 , its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t 1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.Artemisinin and its derivatives, artesunate, artemether, and dihydroartemisinin, are the most potent and rapidly acting antimalarial drugs available today (1, 33). They have very high parasite kill rates with a broad stage specificity of antimalarial action and produce a faster clinical and parasitological response than any other class of antimalarial drug (24,32,33). However, a therapeutic drawback of the artemisinins is the high recrudescence rates associated with monotherapy (6). For artemisinins to be effective when given alone, they must be administered for 7 days, but adherence to 7-day regimens may be poor in patients (34).The latest therapeutic approach to combat both malaria infections and the development of drug resistance has been the use of artemisinin-based combination therapy (ACT) administered over 3 days (1,23,24,34). However, 3-day regimens with the rapidly eliminated artemisinins are usually not curative unless they are given in combination with a slowly eliminated drug, such as mefloquine (34). Although the artemisinins have become the drug of choice for the treatment of multidrug-resistant Plasmodium falciparum malari...

Rivaroxaban, an oral, direct factor Xa inhibitor, is currently used in clinical practice for the prevention and treatment of thromboembolic disorders. This single-center, three-way crossover study was designed to investigate the pharmacodynamic effects of rivaroxaban (10 mg) and enoxaparin (40 mg) alone and in combination as well as the influence of enoxaparin on the pharmacokinetics of rivaroxaban in healthy male subjects. When given alone, both drugs exhibited similar, rapid anti-factor Xa activity. Combined administration resulted in an increase of $50% in anti-factor Xa activity and a lesser increase in activated partial thromboplastin time, compared with either drug alone. Enoxaparin had no additional effect on prolongation of the prothrombin time induced by rivaroxaban and did not affect the pharmacokinetic parameters of rivaroxaban. The results showed that rivaroxaban (10 mg) and enoxaparin (40 mg) had a similar and rapid onset of action, as indicated by the similar anti-factor Xa activity-time curves, suggesting that both drugs have a similar duration of pharmacological activity at the factor X site. Co-administration of rivaroxaban and enoxaparin is associated with enhanced pharmacodynamic effects.

AimsThe pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose-effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p. ]-angiotensin II). Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose-effect curves were fitted according to an E max model and dose ratios (DR) calculated from the antagonist induced rightward shifts. Results Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t 1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6-9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4-7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent K i -doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible. Conclusions A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off-rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.

The investigations of bioavailability and bioequivalence can be classified according to three separate areas of information. Firstly, estimation of bioavailability judged on a drug substance's in vivo characteristics taking into account solubility, polymorphism, stability (especially under the conditions of the GI tract), gut wall permeability and first pass metabolism. Secondly, evaluation of formulation properties including dissolution profile in the GI tract and its contribution to exposure variability with respect to the desired absorption characteristics. Finally, maintaining quality during the market phase with respect to equivalence to the clinical trial formulations. While in the first two areas, the range of the estimated mean values and the intra- and inter-subject variabilities contain the desired information for proper medical decisions, in the third area the mean values and their confidence limits describe the quality with regard to the formulations of proven efficacy. Guidelines should clearly distinguish between the different areas in their recommendations regarding the intended information, e.g. mean values and/or ranges and confidence intervals. New approaches of granting limited waivers for BE studies (e.g. Biopharmaceutical Classification System (BCS)) should be expanded to consideration of pharmacokinetic properties of drugs (e.g. gastrointestinal metabolism, evidence for an absorption window, magnitude of first-pass effect, half-life) as already partly implemented in the German waiver concept, and further (scientifically) validated to achieve world-wide harmonisation (e.g. via ICH).