Pharmacokinetics of BAL4815, a New Azole Antifungal, after Administration of Single Ascending Oral Doses of its Pro-Drug BAL8557

A. SCHMITT-HOFFMANN, B. ROOS, M. HEEP, M. SCHLEIMER, 1C. BEGLINGER and E. WEIDEKAMM

Author address: 

Basilea Pharmaceutica Ltd, Basel, Switzerland; 1Dept. of Gastroenterology, University of Basel, Switzerland

Abstract: 

Revised Abstract

Background: BAL8557 is the water-soluble pro-drug of the active azole BAL4815, which has broad-spectrum activity in vitro and in vivo against opportunistic and pathogenic fungi, including fluconazole-resistant strains, and is specifically suited for intravenous and oral administration. In toxicity studies, BAL8557 showed a favorable safety profile in various animal species. In humans, the minimum effective concentrations of the active drug BAL4815 predicted to be required for treatment of systemic candidiasis and aspergillosis ranged from 125 to 350 ng/mL during a 24-hour dosing interval.


Methods: In this double-blind, placebo controlled study, 15 healthy male subjects were randomly assigned to
receive single ascending oral doses of 100 mg, 200 mg, or 400 mg equivalents of BAL4815 in the form of prodrug
BAL8557. Based on blood samples obtained up to 504 hours after drug intake, pharmacokinetic parameters
were estimated using non-compartmental analysis.


Results: All doses were well tolerated with no serious or severe adverse events. Two to three hours after oral administration of 100, 200, or 400 mg equivalents of BAL4815, Cmax-values of the active drug BAL4815 reached 1.45, 2.59, and 5.57 µg/mL, respectively. The corresponding AUCinf -values were 37.0, 78.4, and 215 µg.h/mL. Thus, concentrations of BAL4815 seem to increase fairly proportionally to the administered doses. Mean elimination half-lives in the three dose groups were particularly long (63, 77, and 56 hours, respectively) and appeared to be independent of the dose. The volume of distribution (VZ/F) amounted to 153 to 293 L and systemic clearance (CLS/F) reached 1.9 to 2.8 L/h.


Conclusion: After oral administration, BAL8557 was rapidly absorbed and converted to its active form BAL4815. High plasma concentrations of the active drug BAL4815 were present in the systemic circulation for prolonged times. Based on pharmacokinetic modelling, once-weekly dosing with 400 mg or daily doses of 50 mg should be adequate to treat systemic candidiasis and aspergillosis. All doses of BAL8557 were well tolerated.

    • ICAAC 43rd