Pharmacokinetic scaling of epirubicin using allometric and species-invariant time methods

The pharmacokinetics of epirubicin, an anthracycline, were investigated after intravenous bolus administration (5 mg/kg) in mice, rats, rabbits and dogs. Based on animal data, we predicted the following human pharmacokinetic parameters using allometric scaling: 120 and 35.2 L/h for total body clearance (CL t ) using simple and maximum life-span potential (MLP)-corrected allometry, respectively; 702 L for steady-state volume of distribution (V dss ). The scaled V dss value was twofold lower than the corresponding values in humans. However, the scaled CL t values were consistent with those clinically observed in humans (35.6–133.4 L/h). We also predicted human parameters using species-invariant time transformations (equivalent time, kallynochrons, apolysichrons and dienetichrons). The mean V dss (854 L) obtained using kallynochrons and that derived from simple allometry were comparable. The lowest CL t (121 L/h) derived using kallynochrons was comparable to that obtained using simple allometry. The results of this study also indicated that the predicted human CL t generated using MLP-corrected allometry can be used for the selection of a safe dose for studies in healthy adult human volunteers. These results suggest that such approaches may be useful in designing pharmacokinetic studies for novel anthracyclines.