Skip to main content

Population pharmacokinetic model development and exposure–response analysis of vincristine in patients with malignant lymphoma

Abstract

Purpose

Vincristine (VCR) is a key drug for treating various malignancies. However, few data are available on the pharmacokinetics of VCR, especially in adult patients. The objective of this study was to clarify the population pharmacokinetics and exposure–response relationships of VCR in adult malignant lymphoma patients.

Methods

Blood samples were collected from patients who were administered R-CHOP-like regimens, and the VCR plasma concentration was determined using liquid chromatography–mass spectrometry. Using NONMEM software, population pharmacokinetic parameters were estimated, and covariates were evaluated. The relationships between the individual parameters and adverse events or therapeutic effects were also investigated.

Results

Plasma concentrations were measured in 30 patients. In the final population pharmacokinetics model, body surface area and age were incorporated into clearance as significant covariates. The inter-individual variations in clearance and volume of distribution in the central and third compartments were 17.0, 26.6, and 66.3%, respectively, and the residual variability in the plasma concentration was 23.8%. Although the variability observed in the volume of distribution was large, good predictability was obtained in the individual estimation. The severity of anemia and peripheral neuropathy was correlated with clearance and peak concentration, respectively (adjusted P = 0.040 and 0.024, respectively). In diffuse large B cell lymphoma patients, those with higher area under the curve and dose experienced longer progression-free survival (P = 0.023 and 0.013, respectively).

Conclusion

The population pharmacokinetics of VCR were evaluated in adult malignant lymphoma patients. VCR pharmacokinetic data could explain in part the adverse events and prognosis of these patients.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4):253–265. https://doi.org/10.1038/nrc1317

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    van de Velde ME, Kaspers GL, Abbink FCH, Wilhelm AJ, Ket JCF, van den Berg MH (2017) Vincristine-induced peripheral neuropathy in children with cancer: a systematic review. Crit Rev Oncol Hematol 114:114–130. https://doi.org/10.1016/j.critrevonc.2017.04.004

    Article  PubMed  Google Scholar 

  3. 3.

    Sethi VS, Jackson DV Jr, White DR, Richards F 2nd, Stuart JJ, Muss HB, Cooper MR, Spurr CL (1981) Pharmacokinetics of vincristine sulfate in adult cancer patients. Can Res 41(9 Pt 1):3551–3555

    CAS  Google Scholar 

  4. 4.

    Vendrig DE, Teeuwsen J, Holthuis JJ (1988) Analysis of vinca alkaloids in plasma and urine using high-performance liquid chromatography with electrochemical detection. J Chromatogr 424(1):83–94. https://doi.org/10.1016/s0378-4347(00)81078-6

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Ramírez J, Ogan K, Ratain MJ (1997) Determination of vinca alkaloids in human plasma by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry. Cancer Chemother Pharmacol 39(4):286–290. https://doi.org/10.1007/s002800050574

    Article  PubMed  Google Scholar 

  6. 6.

    Skolnik JM, Barrett JS, Shi H, Adamson PC (2006) A liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of actinomycin-D and vincristine in children with cancer. Cancer Chemother Pharmacol 57(4):458–464. https://doi.org/10.1007/s00280-005-0065-9

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Guilhaumou R, Solas C, Rome A, Giocanti M, Andre N, Lacarelle B (2010) Validation of an electrospray ionization LC/MS/MS method for quantitative analysis of vincristine in human plasma samples. J Chromatogr B Analyt Technol Biomed Life Sci 878(3–4):423–427. https://doi.org/10.1016/j.jchromb.2009.12.015

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Dennison JB, Renbarger JL, Walterhouse DO, Jones DR, Hall SD (2008) Quantification of vincristine and its major metabolite in human plasma by high-performance liquid chromatography/tandem mass spectrometry. Ther Drug Monit 30(3):357–364. https://doi.org/10.1097/FTD.0b013e31816b92c9

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Van den Berg HW, Desai ZR, Wilson R, Kennedy G, Bridges JM, Shanks RG (1982) The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol 8(2):215–219. https://doi.org/10.1007/bf00255487

    Article  PubMed  Google Scholar 

  10. 10.

    Groninger E, Meeuwsen-de Boer T, Koopmans P, Uges D, Sluiter W, Veerman A, Kamps W, de Graaf S (2005) Vincristine pharmacokinetics and response to vincristine monotherapy in an up-front window study of the Dutch Childhood Leukaemia Study Group (DCLSG). Eur J Cancer 41(1):98–103. https://doi.org/10.1016/j.ejca.2004.10.006

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, Hall SD (2006) Selective metabolism of vincristine in vitro by CYP3A5. Drug Metab Dispos 34(8):1317–1327. https://doi.org/10.1124/dmd.106.009902

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Gidding CE, Meeuwsen-de Boer GJ, Koopmans P, Uges DR, Kamps WA, de Graaf SS (1999) Vincristine pharmacokinetics after repetitive dosing in children. Cancer Chemother Pharmacol 44(3):203–209. https://doi.org/10.1007/s002800050968

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Crom WR, de Graaf SS, Synold T, Uges DR, Bloemhof H, Rivera G, Christensen ML, Mahmoud H, Evans WE (1994) Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia. J Pediatr 125(4):642–649. https://doi.org/10.1016/s0022-3476(94)70027-3

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Guilhaumou R, Simon N, Quaranta S, Verschuur A, Lacarelle B, Andre N, Solas C (2011) Population pharmacokinetics and pharmacogenetics of vincristine in paediatric patients treated for solid tumour diseases. Cancer Chemother Pharmacol 68(5):1191–1198. https://doi.org/10.1007/s00280-010-1541-4

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Dennison JB, Jones DR, Renbarger JL, Hall SD (2007) Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther 321(2):553–563. https://doi.org/10.1124/jpet.106.118471

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Bender RA, Castle MC, Margileth DA, Oliverio VT (1977) The pharmacokinetics of [3H]-vincristine in man. Clin Pharmacol Ther 22(4):430–435. https://doi.org/10.1002/cpt1977224430

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Moriyama B, Henning SA, Leung J, Falade-Nwulia O, Jarosinski P, Penzak SR, Walsh TJ (2012) Adverse interactions between antifungal azoles and vincristine: review and analysis of cases. Mycoses 55(4):290–297. https://doi.org/10.1111/j.1439-0507.2011.02158.x

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Desai ZR, Van den Berg HW, Bridges JM, Shanks RG (1982) Can severe vincristine neurotoxicity be prevented? Cancer Chemother Pharmacol 8(2):211–214. https://doi.org/10.1007/bf00255486

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Plasschaert SLA, Groninger E, Boezen M, Kema I, de Vries EGE, Uges D, Veerman AJP, Kamps WA, Vellenga E, de Graaf SS, de Bont ESJM (2004) Influence of functional polymorphisms of the MDR1 gene on vincristine pharmacokinetics in childhood acute lymphoblastic leukemia. Clin Pharmacol Ther 76(3):220–229. https://doi.org/10.1016/j.clpt.2004.05.007

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Pinkerton CR, McDermott B, Philip T, Biron P, Ardiet C, Vandenberg H, Brunat-Mentigny M (1988) Continuous vincristine infusion as part of a high dose chemoradiotherapy regimen: drug kinetics and toxicity. Cancer Chemother Pharmacol 22(3):271–274. https://doi.org/10.1007/bf00273423

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Kellie SJ, Koopmans P, Earl J, Nath C, Roebuck D, Uges DR, De Graaf SS (2004) Increasing the dosage of vincristine: a clinical and pharmacokinetic study of continuous-infusion vincristine in children with central nervous system tumors. Cancer 100(12):2637–2643. https://doi.org/10.1002/cncr.20220

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Griffin PT, Ho VQ, Fulp W, Nishihori T, Shain KH, Alsina M, Baz RC (2015) A comparison of salvage infusional chemotherapy regimens for recurrent/refractory multiple myeloma. Cancer 121(20):3622–3630. https://doi.org/10.1002/cncr.29533

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Kitamura Y, Yoshida K, Kusama M, Sugiyama Y (2014) A proposal of a pharmacokinetic/pharmacodynamic (PK/PD) index map for selecting an optimal PK/PD index from conventional indices (AUC/MIC, Cmax/MIC, and TAM) for antibiotics. Drug Metab Pharmacokinet 29(6):455–462. https://doi.org/10.2133/dmpk.DMPK-14-RG-013

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Maurer MJ, Ghesquières H, Jais JP, Witzig TE, Haioun C, Thompson CA, Delarue R, Micallef IN, Peyrade F, Macon WR, Jo Molina T, Ketterer N, Syrbu SI, Fitoussi O, Kurtin PJ, Allmer C, Nicolas-Virelizier E, Slager SL, Habermann TM, Link BK, Salles G, Tilly H, Cerhan JR (2014) Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol 32(10):1066–1073. https://doi.org/10.1200/jco.2013.51.5866

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Maurer MJ, Bachy E, Ghesquières H, Ansell SM, Nowakowski GS, Thompson CA, Inwards DJ, Allmer C, Chassagne-Clément C, Nicolas-Virelizier E, Sebban C, Lebras L, Sarkozy C, Macon WR, Feldman AL, Syrbu SI, Traverse-Glehan A, Coiffier B, Slager SL, Weiner GJ, Witzig TE, Habermann TM, Salles G, Cerhan JR, Link BK (2016) Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. Am J Hematol 91(11):1096–1101. https://doi.org/10.1002/ajh.24492

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lonnerholm G, Frost BM, Abrahamsson J, Behrendtz M, Castor A, Forestier E, Heyman M, Uges DR, de Graaf SS (2008) Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia. Br J Haematol 142(4):616–621. https://doi.org/10.1111/j.1365-2141.2008.07235.x

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Groninger E, Meeuwsen-De Boer T, Koopmans P, Uges D, Sluiter W, Veerman A, Kamps W, De Graaf S (2002) Pharmacokinetics of vincristine monotherapy in childhood acute lymphoblastic leukemia. Pediatr Res 52(1):113–118. https://doi.org/10.1203/00006450-200207000-00021

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28(27):4184–4190. https://doi.org/10.1200/jco.2010.28.1618

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE (2014) Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 32(31):3490–3496. https://doi.org/10.1200/jco.2013.53.9593

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the patients who participated in this study and their families.

Funding

This study did not receive any specific grant from public, commercial, or nonprofit organizations.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Toshiaki Igarashi.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

We conducted this study in accordance with the guidelines of the Declaration of Helsinki. All procedures were approved by the Institutional Review Board of University of Fukui Hospital.

Consent to participate

Written informed consent was obtained from all patients.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

280_2020_4220_MOESM1_ESM.pdf

Supplementary file 1 (PDF 124 KB) Table: Inter-individual and residual variabilities, estimated in the covariate model-building process of the population pharmacokinetic analysis.

280_2020_4220_MOESM2_ESM.pdf

Supplementary file 2 (PDF 317 KB) Figure: (A) ROC curve providing the best AUCROC with the threshold of VCR AUC for PFS2 in DLBCL patients. (B) ROC curve providing the best AUCROC with the threshold of mean dose of VCR for PFS2 in DLBCL patients.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Igarashi, T., Kishi, S., Hosono, N. et al. Population pharmacokinetic model development and exposure–response analysis of vincristine in patients with malignant lymphoma. Cancer Chemother Pharmacol 87, 501–511 (2021). https://doi.org/10.1007/s00280-020-04220-y

Download citation

Keywords

  • Population pharmacokinetics
  • Pharmacodynamics
  • Vincristine
  • Malignant lymphoma