Pharmacokinetics and partial thromboplastin time after intravenous recombinant hirudin variant-2 in rhesus monkeys.
OBJECTIVE
To study the pharmacokinetics (PK) and changes of kaolin partial thromboplastin time (KPTT) following single or multiple (7 d) dosing of a novel recombinant hirudin variant-2 (rHV-2) via the route of iv bolus injection (50 % of the total dose) plus infusion (the remained 50 % of the dose) in rhesus monkeys.


METHODS
A crossover design was applied to research the PK and KPTT profiles of rHV-2 after single (with total dose at 1, 3, and 6 mg/kg, respectively) and multiple dosing (3 mg/kg). An enzyme-linked immunosorbent assay (ELISA) method was utilized to determine the level of rHV-2 in plasma.


RESULTS
The concentration profiles of rHV-2 during or after administration were dependent both on the loading dose and the infusion rate. Mean Cmax after bolus in three single dose groups were 2.90, 9.78, and 15.68 mg/L, respectively. Infusions at rate of 8.35, 25, and 50   g/kg/h in 1 h resulted in steady-state levels of 0.73-0.86, 1.94-2.04, and 5.41-5.59 mg/L, respectively. The plasma rHV-2 levels during or after administration among doses were significantly different at most of the time points. Area under concentration-time curve (AUC) increased linearly with dose but systemic clearances were similar among different groups. KPTT was significantly prolonged (compared with baseline) at all dose levels, and trended to increase with dose.


CONCLUSIONS
Both the loading dose and the infusion rate are very important for controlling the rHV-2 level, and the data may be helpful for optimizing dosage-regimen in clinical trials.
Liu
Xiu-Wen
XW
Beijing Institute of Radiation Medicine, Beijing 100850, China. liuxw@nic.bmi.ac.cn
Song
Hai-Feng
HF
Tang
Zhong-Ming
ZM
Zhao
Kai
K
Zhu
Bao-Zhen
BZ
Wang
Li-Ping
LP
Zhang
Yang
Y
D000818:Animals; D019540:Area Under Curve; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006629:Hirudins / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D010314:Partial Thromboplastin Time; D011994:Recombinant Proteins / Q000493:pharmacokinetics
D006629:Hirudins; D011994:Recombinant Proteins