Micafunginの高用量での薬物動態試験

The pharmacokinetics of micafungin (MCFG) were examined using 30 healthy male volunteers both in single and repeated administration studies. In the single administration studies, 25, 50, 75 and 150mg of MCFG were given intravenously using a continuous infusion pump. In the single administration studies, plasma concentrations of unchanged drug declined in a bi-exponential way after cessation of infusion. There were no differences between dosage groups in elimination half-life (t_1/2), volume of distribution at steady state (Vd_ss), total clearance (CL_t) and other pharmacokinetic parameters. The meantS.D. of t_1/2, Vd_ss, and CL_t were 13.9±1.0 h, 0.228±0.016L/kg and 0.197±0.018ml/min/kg, respectively. The area under the plasma concentration-time curve from time zero to infinity (AUC_0-∞) of unchanged drug increased proportionally to the dose of MCFG in a linear fashion. Urinary recovery of MCFG was less than 1% of the administered dose, showing virtually no urinary excretion. In the repeated administration studies, 75mg of MCFG was given intravenously with continuous infusion pump once daily for 7 days. C_max of unchanged drug during repeated administration reached a steady state by day 4. The t_1/2 and AUC_0-24h during repeated administration were about the same as those obtained in the single administration studies. Unchanged drug was minimally excreted into the urine, showing a urinary recovery of less than 1% of the administered dose. The percent of unchanged drug bound to plasma protein did not differ between day 1 (99.83±0.01%) and day 7 (99.82±0.01%). The drug was thus concluded to exhibit linear pharmacokinetics during repeated administration as well. Metabolite M 1 (catechol form) and M 2 (methoxy form), which are found in rats and dogs, were also studied. In the single administration studies, M 1 was detected in plasma at dose levels of 50mg or more. On the other hand, M 1 was detected from day 2 in plasma, and its concentration reached a constant level on day 7, at 0.297±0.039 to 0.307±0.042μg/ml, during repeated administration at a dose level of 75mg. Although metabolite M 1 was detected in plasma in the repeated administration studies, its concentration was less than 1/5 of the trough concentration of unchanged drug. In addition, M 1 showed very little urinary excretion, with a urinary recovery of only 0.15±0.02% of the administered dose. The amount of metabolite M 2 was less than the quantifiable limit in plasma and urine in most cases.