Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 2, pp 385–392 | Cite as

Pharmacokinetic interaction between pazopanib and cisplatin regimen

  • Diane-Charlotte Imbs
  • Véronique Diéras
  • Thomas Bachelot
  • Mario Campone
  • Nicolas Isambert
  • Florence Joly
  • Marta Jimenez
  • Thierry Lafont
  • Etienne ChatelutEmail author
Original Article

Abstract

Purpose

A phase I study combining daily oral pazopanib and cisplatin (given iv every 3 weeks) was performed in order to determine the maximum tolerated dose of both drugs in combination. Pharmacokinetic interactions were evaluated.

Methods

Plasma pazopanib and ultrafilterable cisplatin concentrations were obtained in 32 patients treated according to four levels of dose corresponding to 200, 400 or 600 mg daily dose of pazopanib and 60 or 75 mg/m2 of cisplatin. Two sequences of treatment were performed in order to explore any interaction of cisplatin on pazopanib pharmacokinetics and inversely. Data were analyzed using the NONMEM program.

Results

Maximum tolerated dose was 400 mg of pazopanib and 75 mg/m2 of cisplatin. Mean (CV % for inter-individual variability) cisplatin clearance was 10.3 L/h (33.2 %) and appeared not to be influenced by pazopanib. However, pazopanib pharmacokinetics was significantly modified by the cisplatin regimen. Mean (CV %) of oral pazopanib clearance was 0.66 L/h (55 %) at Day 0 (before cisplatin administration), 24.8 % lower at Day 1 and 32.9 % lower at Day 2. The interaction is less likely to be due to cisplatin than to a competitive inhibition of pazopanib metabolism and efflux by aprepitant, an antiemetic drug systematically administered with cisplatin. The plasma pazopanib exposures observed at Day 0 with a 400 mg dose were similar to those observed at the recommended dose of pazopanib in monochemotherapy (800 mg) during the first-in-man phase 1 study.

Conclusion

The observed pazopanib plasma overexposure probably contributed to the poor tolerance encountered during this phase 1 study.

Keywords

Tyrosine kinase inhibitors Platinum compounds Population pharmacokinetics 

Notes

Acknowledgments

The authors wish to thank Dr Melanie White-Koning and Dr Anne Visbecq for their helpful comments on the manuscript.

Funding

This work was funded by GlaxoSmithKline and by the charity Ligue Nationale Contre le Cancer.

Compliance with ethical standards

Disclosures

Véronique Diéras discloses advisory board for Novartis and GSK. Thomas Bachelot discloses advisory board and research funding from Novartis, Roche and GSK. Marta Jimenez reports grants and other from GSK, during the conduct of the study. All remaining authors have declared no conflict of interest.

References

  1. 1.
    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 17:6608–6614CrossRefPubMedGoogle Scholar
  2. 2.
    Nagai N, Kinoshita M, Ogata H, Tsujino D, Wada Y, Someya K, Ohno T, Masuhara K, Tanaka Y, Kato K, Nagai H, Yokoyama A, Kurita Y (1996) Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients. Cancer Chemother Pharmacol 39:131–137CrossRefPubMedGoogle Scholar
  3. 3.
    LeRoy AF, Wehling ML, Sponseller HL, Friauf WS, Solomon RE, Dedrick RL, Litterst CL, Gram TE, Guarino AM, Becker DA (1977) Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochem Med 18:184–191CrossRefPubMedGoogle Scholar
  4. 4.
    Urien S, Lokiec F (2004) Population pharmacokinetics of total and unbound plasma cisplatin in adult patients. Br J Clin Pharmacol 57:756–763PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    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 73:1189–1196CrossRefPubMedGoogle Scholar
  6. 6.
    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 15:4220–4227CrossRefPubMedGoogle Scholar
  7. 7.
    Cvitkovic E, Hayes DM, Golbey RB, Krakoff IH (1991) Cisplatin nephrotoxicity: diethyldithiocarbamate, WR2721, or just water? J Clin Oncol 9:707–709PubMedGoogle Scholar
  8. 8.
    Ekins S, Andreyev S, Ryabov A, Kirillov E, Rakhmatulin EA, Sorokina S, Bugrim A, Nikolskaya T (2006) A combined approach to drug metabolism and toxicity assessment. Drug Metab Dispos 34:495–503PubMedGoogle Scholar
  9. 9.
    Keisner SV, Shah SR (2011) Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs 71:443–454PubMedGoogle Scholar
  10. 10.
    Aapro MS, Walko CM (2010) Aprepitant: drug–drug interactions in perspective. Ann Oncol 21:2316–2323CrossRefPubMedGoogle Scholar
  11. 11.
    Loos WJ, de Wit R, Freedman SJ, van Dyck K, Gambale JJ, Li S, Murphy GM, van Noort C, de Brujin P, Verweij J (2007) Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients. Cancer Chemother Pharmacol 59:407–412CrossRefPubMedGoogle Scholar
  12. 12.
    Nygren P, Hande K, Petty KJ, Fedgchin M, van Dyck K, Majumdar A, Panebianco D, de Smet M, Ahmed T, Murphy MG, Gottesdiener KM, Cocquyt V (2005) Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol 55:609–616CrossRefPubMedGoogle Scholar
  13. 13.
    Vincenzi B, Tonini G, Santini D (2010) Aprepitant for erlotinib-induced pruritus. N Engl J Med 363:397–398CrossRefPubMedGoogle Scholar
  14. 14.
    Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans JK, Blum RA (2004) Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 44:215–223CrossRefPubMedGoogle Scholar
  15. 15.
    Burris HA III, Dowlati A, Moss RA, Infante JR, Jones SF, Spigel DR, Levinson KT, Lindquist D, Gainer SD, Dar MM, Suttle AB, Ball HA, Tan AR (2012) Phase I study of pazopanib in combination with paclitaxel and carboplatin given every 21 days in patients with advanced solid tumors. Mol Cancer Ther 11:1820–1828CrossRefPubMedGoogle Scholar
  16. 16.
    Bonetti A, Franceschi T, Apostoli P, Messori A, Sperotto L, Cetto GL, Molino A, Leone R (1995) Cisplatin pharmacokinetics using a five-day schedule during repeated courses of chemotherapy in germ cell tumors. Ther Drug Monit 17:25–32CrossRefPubMedGoogle Scholar
  17. 17.
    Daley-Yates PT, McBrien DC (1984) Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin. Biochem Pharmacol 33:3063–3070CrossRefPubMedGoogle Scholar
  18. 18.
    Majumdar AK, McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M, Goldberg MR, Murphy G, Gottesdiener KM, Lines CR, Petty KJ, Blum RA (2003) Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther 74:150–156CrossRefPubMedGoogle Scholar
  19. 19.
    Goh BC, Reddy NJ, Dandamudi UB, Laubscher KH, Peckham T, Hodge JP, Suttle AB, Arumugham T, Xu Y, Xu CF, Lager J, Dar MM, Lewis LD (2010) An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5 + 1 cocktail in patients with advanced solid tumors. Clin Pharmacol Ther 88:652–659CrossRefPubMedGoogle Scholar
  20. 20.
    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 111:1909–1916PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Diane-Charlotte Imbs
    • 1
    • 2
  • Véronique Diéras
    • 3
  • Thomas Bachelot
    • 4
  • Mario Campone
    • 5
  • Nicolas Isambert
    • 6
  • Florence Joly
    • 7
  • Marta Jimenez
    • 8
  • Thierry Lafont
    • 1
    • 2
  • Etienne Chatelut
    • 1
    • 2
    Email author
  1. 1.Institut Claudius-Regaud, IUCT-OToulouseFrance
  2. 2.EA4553Université Paul-SabatierToulouseFrance
  3. 3.Department of Medical OncologyInstitut CurieParisFrance
  4. 4.Department of Medical OncologyCentre Léon-BérardLyonFrance
  5. 5.Centre de Recherche du Cancer Nantes-Angers, UMR-INSERM U892/CNRS 6299Institut de Cancérologie de l’OuestNantesFrance
  6. 6.Department of Medical OncologyCentre Georges François-LeclercDijonFrance
  7. 7.Department of Medical OncologyCentre François-BaclesseCaenFrance
  8. 8.UnicancerParisFrance

Personalised recommendations