Back to Journals » Clinical Pharmacology: Advances and Applications » Volume 10

Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans

Authors Li YF, Zhang C, Zhou S, He M, Zhang H, Chen N, Li F, Luan X, Pai M, Yuan H, Sun D, Li Y

Received 27 August 2018

Accepted for publication 5 October 2018

Published 8 November 2018 Volume 2018:10 Pages 165—174

DOI https://doi.org/10.2147/CPAA.S185449

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Professor Arthur Frankel


Ying Fei Li,1 Chengyue Zhang,1 Simon Zhou,1 Miao He,2 Huixia Zhang,2 Nianhang Chen,1 Feng Li,2 Xin Luan,2 Manjunath Pai,3 Hebao Yuan,2 Duxin Sun,2 Yan Li1

1
Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ 07901, USA; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; 3Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA

Background: Paclitaxel (PTX) products currently approved by the Food and Drug Administration include Kolliphor EL-paclitaxel micelles (KoEL-paclitaxel, Taxol) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane). Despite containing the same cytotoxic agent, different PTX formulations have distinct pharmacological responses and indications in patients with cancer. Several novel PTX delivery vehicles that have shown superior efficacy to Taxol in animal models failed to demonstrate efficacy in Phase II/III human clinical trials.
Materials and methods: A 10 mg/kg IV dose of KoEL-paclitaxel or nab-paclitaxel was administered to mice, and the pharmacokinetics (PK) profile of PTX in mice was then compared with the human PK profile from clinical studies. Population PK model and simulation was used to delineate the distribution and elimination characteristics in each species. In addition, tumor shrinkage was measured after weekly administration of both formulations in mouse xenograft model.
Results: Our pharmacokinetic modeling results suggested that elimination predominates over distribution in driving PTX disposition in mice, hence restricting the PTX tissue accumulation. Moreover, the rapid elimination of PTX in mice minimized the different formulation effects on PTX tissue distribution, which is believed to link to the superior efficacy of nab-paclitaxel over KoEL-paclitaxel seen in human. In contrast to mice, PTX distribution predominates over elimination in human, and the decline in plasma PTX concentration reflected the deeper tissue distribution by nab-paclitaxel.
Conclusion: This species difference in PTX distribution and elimination hinders a simple direct extrapolation from animals to humans. Therefore, species difference in drug distribution and elimination should be carefully assessed during translational drug development.

Keywords: paclitaxel, pharmacokinetics, tissue distribution, drug elimination, disposition, species difference
 

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]