Interspecies scaling of a camptothecin analogue: Human predictions for intravenous topotecan using animal data

Abstract

As a class, camptothecin analogues via market entry of topotecan and irinotecan, have shown promise for the treatment of various solid tumours. Topotecan, in particular, was chosen as the substrate for allometric scaling and prediction of human parameter values for both total clearance (CL) and volume of distribution (V_ss). The availability of published data in mouse, rat, dog, and monkey paved the way for interspecies scaling via allometry. Although it appeared that at a minimum mouse, rat, and dog would reasonably fit in a three-species allometry scale-up, the inclusion of monkey data enabled a better prediction of the human parameter values for total topotecan–e.g., CL: allometric equation: 1.5234W^0.7865; predicted value = 43.04 l h⁻¹: observed CL = 24–53 l h⁻¹; V_ss: allometric equation: 1.1939W^1.0208; predicted value = 91.29 litres: observed V_ss = 66–146 litres. The proximity of the allometric exponent values of CL (0.7885) and V_ss (1.0208) to the suggested values of 0.75 and 1.00 was not only encouraging, but also confirmed the applicability of interspecies scaling approach for topotecan. The data suggest that allometric scaling approaches with suitable correction factors could potentially be used to predict the human pharmacokinetics of novel CPT analogues prospectively.

Keywords: :

• Allometry
• pharmacokinetics
• topotecan
• camptothecin
• clearance
• volume of distribution