Prediction of human pharmacokinetic properties of BAL4815, a new azole antifungal, from animal data

Abstract number: 1134_02_313

Schmitt-Hoffmann A.H., Spickermann J.

Objective:

To predict the pharmacokinetic properties of BAL4815 a new azole antifungal, in humans.

Methods: BAL8557 (the water-soluble pro-drug of BAL4815) was incubated at 10 mg/mL in pooled heparinized rat, cynomolgus monkey and human plasma for 5 minutes at 37°C. BAL4815 was incubated at 1,10 and 100 mg/mL equivalent BAL4815 with rat, cynomolgus monkey and human liver microsomes for 120 min at 37°C in the presence of 1 mg/mL proteins. 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-BAL4815. Rats received a single oral dose of 10 mg/kg equivalent BAL4815 and a single intravenous dose of 5 mg/kg equivalent BAL4815 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 is 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 is metabolized during a 120 min period. BAL4815 is 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 is converted to BAL4815 within minutes. BAL4815 has 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 is slowly eliminated with half-lives of 5 h in rat and 10 h in cynomolgus monkey. After oral administration of the pro-drug, BAL4815 reaches 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 pro-drug BAL4815 is 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 human (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 suggest a good oral bioavailability as is confirmed in humans.