Prediction of Human Pharmacokinetic Properties of BAL4815, a New Azole Antifungal, from Animal Data

A. Schmitt-Hoffmann, J. Spickermann


Objective: To predict the pharmacokinetic properties in man of BAL4815, a new azole antifungal.
Methods: BAL8557 (the water-soluble pro-drug of BAL4815) was incubated at a concentration of 10g/mL in heparinized rat, cynomolgus monkey and human plasma for 5 minutes at 37 degrees C. BAL8557 BAL4815 with rat, cynomolgus monkey and human liver microsomes for 120 min at 37 degrees C in the presence of 1 mg/mL protein. The extent of plasma protein binding of BAL4815 in rat, cynomolgus and human plasma was measured using the red blood cell partitioning method and 14C-labeled BAL4815. Rats received a single oral dose of 10 mg/kg and a single intravenous dose of 5 mg/kg as BAL8557. Cynomolgus monkeys received single oral and intravenous doses of 3 mg/kg as BAL8557. Serial blood samples were obtained. Plasma concentrations of BAL4815 and BAL8557 were quantified using an HPLC/fluorescence method or a LC-MS/MS assay.
Results: In plasma BAL8557 was converted within minutes to BAL4815 in all species investigated. In the presence of rat, cynomolgus monkey and human liver microsomes, less than 10% of BAL4815 were metabolized during a 120 min period. BAL4815 was bound to plasma proteins with a free fraction of 3.5%, 3.6% and 2.2% in rat, cynomolgus monkey and human, respectively. After intravenous administration, the pro-drug BAL8557 was converted to BAL4815 within minutes. BAL4815 had a large volume of distribution with values greater than the total body water: 15 L/kg and 5 L/kg in rat and cynomolgus monkey, respectively. BAL4815 was slowly eliminated with half-lives of 5 h in rat and 10 h in cynomolgus monkey. After oral administration of the pro-drug BAL4815 reached Cmax-values between 2.0 to 3.5 hours. We observed high bioavailability of BAL4815: 62% in rat and 87% in cynomolgus monkey.
Conclusions: Based on these in vitro results and animal data, we predict that the prodrug BAL4815 will be very rapidly converted to BAL4815 in man. Due to the protein binding and in vitro metabolic stability, BAL4815 is expected to behave as a low intrinsic clearance drug in man (clearance < 10 % of liver blood flow). This combined with a large volume of distribution explains the long half-life > 30 hours observed in man. Animal data suggested a good oral bioavailability as is confirmed in man.


abstract No: 

    • ECCMID 15th (2005)