Abstract
Bendamustine, an alkylating anticancer agent, is used to treat chronic lymphocytic
leukemia by intravenous infusion alone or in combination. The work aimed to develop
a method to predict time vs. concentration profile for humans based on preclinical
pharmacokinetics using the assumption of superimposability of normalized time course
profiles of animals and humans. Standard allometric equations with/without correction
factors (CF) were also used in prediction. The Vss was predicted by simple allometry
of 0.312W0.871 (r2=0.987), where W is body weight; predicted Vss (19.71 L) was similar to the reported
value (20.10 L). However, CL prediction involved both simple and CF allometry. Best
proximity CL (543 vs. 598 mL/min) was obtained with maximum life span correction (MLP)
[2.46W1.215 (r2=0.988)]. Normalized curves were obtained by normalizing the time (with mean residence
time) vs. concentration (with dose/Vss) in animal species. The concentration vs. time
profile in humans after intravenous infusion was then simulated using normalized curve
for each animal species and the values of CL and Vss were predicted for humans. In
summary the findings indicate that normalized time course approach could predict the
bendamustine human pharmacokinetics and such an approach could be prospectively applied
for analog drugs of this class.
Key words
Bendamustine - preclinical pharmacokinetics - clinical pharmacokinetics - interspecies
scaling - simulations - normalized curve