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Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases

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An Erratum to this article was published on 19 March 2016

Abstract

Purpose

Cancer patients with predominantly hepatic metastases have poor outcomes and limited options. Hepatic arterial infusion (HAI) of a therapeutic agent may be an appropriate option for producing increased drug concentrations at the tumor sites while reducing systemic adverse effects in normal tissues.

Methods

Patients with predominantly hepatic metastases (n = 48) were placed in 6 groups according to nanoparticle albumin-bound paclitaxel (nab-paclitaxel) dose level using a 3 + 3 design plus dose expansion for responsive tumor types. We evaluated the toxicity, antitumor activity, and pharmacokinetics of nab-paclitaxel delivered via HAI.

Results

Thirty-eight and ten patients underwent HAI over 1 and 4 h, respectively, at doses of up to 300 mg/m2. The treatment was safe and exhibited antitumor activity. Pharmacokinetic analyses revealed that HAI of nab-paclitaxel over 4 h resulted in markedly lower peak drug concentrations (C max) and longer times to peak concentration (T max) than that over 1 h. The self-control pharmacokinetic studies showed that HAI of nab-paclitaxel led to much lower C max and areas under the curve (AUC), compared with intravenous infusion.

Conclusions

HAI of nab-paclitaxel at up to 300 mg/m2 over 4 h was well tolerated. Pharmacokinetic evaluation of C max, T max, and AUC implied that 4-h HAI enhanced hepatic extraction of nab-paclitaxel. Further preclinical and clinical studies are required to develop reliable methods of evaluation of hepatic extraction (clinicaltrials.gov registration number NCT00732836, first registered on August 8, 2008, and last updated on October 27, 2014).

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Acknowledgments

The authors thank Vivianne Velez-Bravo in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center for coordinating the study, Sha Huang and Lisa Norberg in the Department of Experimental Therapeutics at MD Anderson Cancer Center for pharmacokinetic studies, and Donald R Norwood in the Department of Scientific Publications at MD Anderson for editing the manuscript. This study was approved and funded by a grant from the National Comprehensive Cancer Network (NCCN CS2008-00022710JW) via general research support provided by Abraxis BioScience through the NCCN Oncology Research Program.

Authors’ Contributions

SF and RK contributed to trial conception and design. SF, KSC, and MMH acquired the data and drafted the manuscript, and all other co-authors critically revised the manuscript. SF, DSH, GSF, AN, and FJ observed the patients and collected the data. KSC, ALM, and YPZ conducted pharmacokinetic studies. All authors have approved the final version of the manuscript.

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Authors and Affiliations

  1. Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Fu Siqing, Gerald S. Falchook, David S. Hong, Aung Naing, Filip Janku & Ming-Mo Hou

  2. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Kirk S. Culotta

  3. Department of Pharmacy Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Alan L. Myers & Yan-Ping Zhang

  4. Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

    Ming-Mo Hou

  5. UC San Diego Moores Cancer Center, La Jolla, CA, USA

    Razelle Kurzrock

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  1. Fu Siqing
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Correspondence to Fu Siqing.

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Siqing, F., Culotta, K.S., Falchook, G.S. et al. Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases. Cancer Chemother Pharmacol 77, 357–364 (2016). https://doi.org/10.1007/s00280-015-2946-x

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