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



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.


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.


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).


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.

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


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

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Corresponding author

Correspondence to Toshiaki Igarashi.

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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.

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Written informed consent was obtained from all patients.

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Supplementary Information

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


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.

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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).

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  • Population pharmacokinetics
  • Pharmacodynamics
  • Vincristine
  • Malignant lymphoma