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...