Multiple Ascending Dose Pharmacokinetics of the new Antifungal BAL4815 after Intravenous and Oral Administration of its Prodrug BAL8557

A. SCHMITT-HOFFMANN 1, B. ROOS 1, J. SPICKERMANN 1, E. WEIDEKAMM 1, M. ROEHRLE 2;

Author address: 

1Basilea Pharmaceutica Ltd, Basel, Switzerland, 2AAI, Neu-Ulm, Germany.

Abstract: 

Revised Abstract


Background: BAL8557 is a water soluble pro-drug converted in plasma to the drug BAL4815. BAL4815 showed in vitro broad-spectrum antifungal activity against all major opportunistic fungi and true pathogenic fungi, including fluconazole-resistant strains. The pro-drug is particularly suited for intravenous (iv) and oral (po) administration. The objective of this study was to assess po and iv pharmacokinetics of the pro-drug and drug in humans, following repeated ascending doses.


Methods: In this double-blind, placebo controlled MAD study, we randomly assigned 32 healthy males into 4 cohorts (C) to receive either BAL8557 doses as BAL4815 equivalents (n=6/Cohort) or placebo (n=2/Cohort). Cohort 1 (C1) received an oral loading dose (LD) of 100 mg followed by once-daily maintenance doses (MD) of 50 mg up to Study Day 21. Cohort 2 (C2) an oral LD of 200 mg and MD of 100 mg. Cohort 3 (C3) received a 1 h-iv infusion LD of 100 mg followed by MD of 50 mg and Cohort 4 (C4) a 1 h-iv infusion LD of 200 mg and MD of 100 mg. Blood samples were collected up to 24 h after administration on selected study days and up to 480
h after the last administration. Pharmacokinetics were estimated by noncompartmental analysis.

 

Results: After po administration, 24-h AUC-values of BAL4815 reached 8.75 (C1) and 18.5 (C2) μg.h/mL and 21.6 (C1) and 40.3 (C2) μg.h/mL , on Study Days 1 and 21, respectively. After i.v infusion, 24-h AUC-values of BAL4815 were 7.31 (C3) and 12.9 (C4) μg.h/mL and 14.3 (C3) and 33.6 (C4) μg.h/mL, on Study Days 1 and 14, respectively. After both iv and po administrations a 4- to 5-fold accumulation of BAL4815 was observed in line with its elimination half-life (85 to 117 h). At steadystate, the systemic clearance was 2.4 to 4.1 L/h and the volume of distribution was 308 to 542 L. 24 h-urinary ratios of «6-β-hydroxycortisol/cortisol» were dose-, time- and treatmentindependent.

 

Conclusion: After repeated po and iv administrations, the plasma levels of BAL4815 were dose proportional, as anticipated from single dose studies. There was no indication of inhibition or induction. Absolute bioavailability of the po formulation appeared excellent.

    • ICAAC 44th