The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5'-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues.

BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.

BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by oncedaily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (C max ) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study, C max values of 2.56 and 2.55 g/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-␤-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50-or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.The frequency of severe systemic mycoses has steadily increased during the last years, and resistance to currently prescribed antifungals is growing rapidly (8,10,17). Therefore, there is an urgent need for new potent and safe antifungals which can be administered orally as well as intravenously (6, 9, 18).The water-soluble triazole prodrug BAL8557 (for chemical structure, see reference 15) is suitable for oral and intravenous administration. In plasma, it is rapidly and almost quantitatively (Ͼ99%) converted by esterases to BAL8728 (prodrug cleavage product) and to BAL4815 (active drug) (2). Area under the concentration-time curve (AUC) values of BAL8728 were low and amounted to approximately 1% of the corresponding AUCs of BAL4815 (15). BAL4815 is a potent inhibitor of ergosterol biosynthesis and shows in vitro broad-spectrum activity against all major opportunistic fungi and the true pathogenic fungi. In rat and murine models, BAL4815 was highly effective against systemic candidiasis and aspergillosis First pharmacokinetic data of BAL4815 in human were obtained in a single-ascen...

BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. We investigated the safety and pharmacokinetics of BAL5788 in a double-blind, single-ascending-dose study with 40 healthy male subjects. The subjects were randomized to receive placebo (n ‫؍‬ 2 subjects per dose) or BAL5788 (n ‫؍‬ 6 subjects per dose) as a 200-ml intravenous infusion over 30 min. The BAL5788 doses used were 125, 250, 500, 750, and 1,000 mg (BAL9141 equivalents). All doses were well tolerated, with no severe or serious adverse events (AEs). The most frequent AE was taste disturbance. No electrocardiographic abnormalities and no trends or clinically significant changes in laboratory parameters or vital signs were observed. The maximum concentration of drug in serum and the area under the concentrationtime curve for BAL9141 were dose proportional over the dosing range. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment, and the rate of renal clearance of free drug corresponded to the normal glomerular filtration rate for adults. More than 70% of the administered dose was excreted as BAL9141 in the urine, and almost no prodrug was detected. After the infusion of 750 mg, the mean plasma BAL9141 concentrations exceeded the MIC at which 100% of MRSA isolates are inhibited (4 g/ml) for approximately 7 h, or 58% of a 12-h dosing interval. These results indicate that infusions of 750 mg twice a day should be adequate for the treatment of infections caused by MRSA.

BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. Safety and pharmacokinetic data from a multiple-dose study with 16 healthy male volunteers are reported. Subjects were randomized to receive BAL5788 at 500 or 750 mg (as BAL9141 equivalents; n ‫؍‬ 6 subjects per dose) or placebo (n ‫؍‬ 2 subjects per dose). The doses were given as 200-ml infusions over 30 min once daily on days 1 and 8 and twice daily on days 2 to 7. BAL5788 was well tolerated, with no severe or serious adverse events (AEs) or dosing-related changes in laboratory parameters, electrocardiographic findings, or vital signs. Drug accumulation in plasma was negligible during the dosing period. The results of pharmacokinetic analyses agreed well with data reported from a previous single-ascending-dose study. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment. BAL9141 was predominantly eliminated in urine, and renal clearance of the free drug corresponded to the normal glomerular filtration rate in adults. After multiple infusions of 750 mg, the mean concentrations of BAL9141 in plasma exceeded the MIC at which 100% of MRSA isolates are inhibited (4 g/ml) for approximately 7 to 9 h, corresponding to 58 to 75% of a 12-h dosing interval.