2.2.1 Determination of the EH dose escalation range
According to the ”Guidelines for
Estimating the Maximum Recommended Starting Dose of Drugs for the First
Clinical Trial of Healthy Adult Volunteers” promulgated by the CENTER
FOR DRUG EVALUATION and the No Observed Adverse Effect Level (NOAEL)
calculation results of preclinical animal trials, it was known that the
most suitable NOAEL of EH for long-term toxicity testing of cynomolgus
monkeys was 1.3 mg/kg. The recommended clinical dose of
REFLUDAN,20a similar drug from Bayer, approved by the FDA on March 6, 1998, for the
treatment of HIT (Heparin-Induced Thrombocytopenia) was 0.4 mg/kg
intravenous bolus first, and then 0.15 mg/kg/h of continuous intravenous
drip for 2-7 days. Preclinical studies of EH showed that 0.4mg/kg of
hirudin was equivalent to 0.416mg/kg EH, and the pharmacodynamic dose
range of EH animal test was about 0.06~2.13mg/kg. The
preclinical mouse and cynomolgus acute toxicity test of this drug showed
that its Maximum Tolerated Dose (MTD) was much higher than the planned
clinical effective dose. It was safe and reasonable to initially
consider 0.2~2.0mg/kg as the dose increase range of this
clinical trial.