Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach.

We have attempted to predict the human pharmacokinetics of troglitazone after oral administration based on animal data. Troglitazone is a new antidiabetic agent that exhibits a high-metabolic clearance and is metabolized mainly in the liver to sulfate and glucuronide conjugates. The prediction of the area under the plasma concentration-time curve (AUCp.o.) and bio-availability (F) in humans after oral administration was initially attempted by use of allometric equations involving the oral plasma clearance of total (CLp.o.) or unbound drug (CLp.o.,fu), or the hepatic intrinsic clearance of unbound drug (CLuint) and animal body weight. The exponents in the allometric equations between the clearances and body weights were 0.63 to 0.82 with high correlation coefficients (r > .98), and there was no marked difference in predictability by the three methods. Next, the prediction of the range of plasma profiles after oral administration to humans was attempted by the following series of steps: (1) calculation of the exponent and coefficients in the allometric relationships between body weight and parameters, such as total body plasma clearance (CLi.v.) and various distribution volumes (Vss, V beta and Vc) based on animal data; (2) estimation of the absorption rate constant (ka) from allometric relationship to body weight, and estimation of F value from the predicted AUCp.o. (3) description of the plasma concentration-time profiles after oral administration by an equation involving the allometric exponents and coefficients, ka, F and body weight. The observed and simulated plasma profiles were similar and the predicted AUCp.o. values were 60 to 120% of those observed. These methodologies will be useful for predicting the human pharmacokinetics after oral dosing from animal data.