Summary
Introduction Pazopanib exhibits wide inter-patient pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological responses than total concentrations. Thus it is desirable to evaluate pazopanib binding on plasma proteins and different factors potentially affecting this process. Methods An equilibrium dialysis method coupled with UPLC-MS/MS assay has been optimized and validated for the determination of pazopanib unbound fraction (fu%) in human plasma. Pazopanib binding in the plasma of healthy volunteers and in isolated protein solutions was investigated. The unbound fraction was determined for 24 cancer patients treated daily with pazopanib. Results We found that pazopanib was extensively bound in human plasma (>99.9 %) with a mean fu% value of 0.0106 ± 0.0013 % at 40 μg/mL. Protein binding was concentration independent over a clinically relevant range of concentrations. In isolated protein solutions, pazopanib at 40 μg/mL was mainly bound to albumin (40 g/L) and to a lesser extent to α1-acid glycoprotein (1 g/L) and low density lipoproteins (1.2 g/L), with a mean fu% of 0.0073 ± 0.0022 %, 0.992 ± 0.44 % and 7.4 ± 1.7 % respectively. Inter-patient variability (CV%) of fu% in cancer patients was limited (27.2 %). A correlation was observed between individual unbound fraction values and albuminemia. Conclusions Pazopanib exhibits extensive binding to plasma proteins in human plasma. Variable albumin concentrations, frequently observed in cancer patients, may affect pazopanib unbound fraction with implications for inter-patient variability in drug efficacy and toxicity.
Similar content being viewed by others
References
Hurwitz HI, Dowlati A, Saini S, Savage S, Suttle AB, Gibson DM, Hodge JP, Merkle EM, Pandite L (2009) Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 15(12):4220–4227
Craveiro RB, Ehrhardt M, Holst MI, Pietsch T, Dilloo D (2014) In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy. Oncotarget 5(16):7149–7161
Davidson BA, Secord AA (2014) Profile of pazopanib and its potential in the treatment of epithelial ovarian cancer. Int J Womens Health 6:289–300
Nieto M, Borregaard J, Ersboll J, ten Bosch GJ, van Zwieten-Boot B, Abadie E, Schellens JH, Pignatti F (2011) The European Medicines Agency review of pazopanib for the treatment of advanced renal cell carcinoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Clin Cancer Res 17(21):6608–6614
Sonpavde G, Hutson TE, Sternberg CN (2009) Pazopanib for the treatment of renal cell carcinoma and other malignancies. Drugs Today (Barc) 45(9):651–661
Verweij J, Sleijfer S (2013) Pazopanib, a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother 14(7):929–935
Deng Y, Sychterz C, Suttle AB, Dar MM, Bershas D, Negash K, Qian Y, Chen EP, Gorycki PD, Ho MY (2013) Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Xenobiotica 43(5):443–453
Suttle AB, Ball HA, Molimard M, Hutson TE, Carpenter C, Rajagopalan D, Lin Y, Swann S, Amado R, Pandite L (2014) Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma. Br J Cancer 111(10):1909–1916
Yau T, Chen PJ, Chan P, Curtis CM, Murphy PS, Suttle AB, Gauvin J, Hodge JP, Dar MM, Poon RT (2011) Phase I dose-finding study of pazopanib in hepatocellular carcinoma: evaluation of early efficacy, pharmacokinetics, and pharmacodynamics. Clin Cancer Res 17(21):6914–6923
Yu H, Steeghs N, Nijenhuis CM, Schellens JH, Beijnen JH, Huitema AD (2014) Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors: focus on the pharmacokinetic targets. Clin Pharmacokinet 53(4):305–325
Baker SD, Li J, Ten Tije AJ, Figg WD, Graveland W, Verweij J, Sparreboom A (2005) Relationship of systemic exposure to unbound docetaxel and neutropenia. Clin Pharmacol Ther 77(1):43–53
Stewart CF, Arbuck SG, Fleming RA, Evans WE (1991) Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin Pharmacol Ther 50(4):385–393
Haouala A, Widmer N, Guidi M, Montemurro M, Leyvraz S, Buclin T, Eap CB, Decosterd LA, Csajka C (2013) Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours. Br J Clin Pharmacol 75(4):1007–1018
Hamberg P, Verweij J, Sleijfer S (2010) (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist 15(6):539–547
Waters NJ, Jones R, Williams G, Sohal B (2008) Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding. J Pharm Sci 97(10):4586–4595
Arellano C, Gandia P, Lafont T, Jongejan R, Chatelut E (2012) Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC-MS/MS assay and ultrafiltration method. J Chromatogr B Analyt Technol Biomed Life Sci 907:94–100
Imbs DC, Negrier S, Cassier P, Hollebecque A, Varga A, Blanc E, Lafont T, Escudier B, Soria JC, Perol D, Chatelut E (2014) Pharmacokinetics of pazopanib administered in combination with bevacizumab. Cancer Chemother Pharmacol 73(6):1189–1196
Combes O, Barre J, Duche JC, Vernillet L, Archimbaud Y, Marietta MP, Tillement JP, Urien S (2000) In vitro binding and partitioning of irinotecan (CPT-11) and its metabolite, SN-38, in human blood. Invest New Drugs 18(1):1–5
Gandia P, Arellano C, Lafont T, Huguet F, Malard L, Chatelut E (2013) Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed? Cancer Chemother Pharmacol 71(2):531–536
Villarroel MC, Pratz KW, Xu L, Wright JJ, Smith BD, Rudek MA (2012) Plasma protein binding of sorafenib, a multi kinase inhibitor: in vitro and in cancer patients. Invest New Drugs 30(6):2096–2102
Herve F, Urien S, Albengres E, Duche JC, Tillement JP (1994) Drug binding in plasma. A summary of recent trends in the study of drug and hormone binding. Clin Pharmacokinet 26(1):44–58
Keisner SV, Shah SR (2011) Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs 71(4):443–454
Otagiri M (2005) A molecular functional study on the interactions of drugs with plasma proteins. Drug Metab Pharmacokinet 20(5):309–323
Sethuraman VA, Na K, Bae YH (2006) pH-responsive sulfonamide/PEI system for tumor specific gene delivery: an in vitro study. Biomacromolecules 7(1):64–70
Li J, Brahmer J, Messersmith W, Hidalgo M, Baker SD (2006) Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients. Invest New Drugs 24(4):291–297
Acknowledgments
Diane-Charlotte Imbs received a grant from the GIRCI SOOM (Groupement interrégional de recherche clinique et d'innovation Sud-Ouest Outre-Mer).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interests.
Additional information
Diane-Charlotte Imbs and Marie-Noelle Paludetto are associated first co-authors
Rights and permissions
About this article
Cite this article
Imbs, DC., Paludetto, MN., Négrier, S. et al. Determination of unbound fraction of pazopanib in vitro and in cancer patients reveals albumin as the main binding site. Invest New Drugs 34, 41–48 (2016). https://doi.org/10.1007/s10637-015-0304-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-015-0304-9