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Xenobiotica
the fate of foreign compounds in biological systems
Volume 38, 2008 - Issue 11
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Research Article

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

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Pages 1377-1385 | Received 11 Jun 2008, Accepted 18 Sep 2008, Published online: 04 Nov 2008
 

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 (Vss). 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: 1.5234W0.7865; predicted value = 43.04 l h−1: observed CL = 24–53 l h−1; Vss: allometric equation: 1.1939W1.0208; predicted value = 91.29 litres: observed Vss = 66–146 litres. The proximity of the allometric exponent values of CL (0.7885) and Vss (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.

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