Development of a dried blood spot sampling method towards therapeutic monitoring of radotinib in the treatment of chronic myeloid leukaemia

J Clin Pharm Ther. 2020 Oct;45(5):1006-1013. doi: 10.1111/jcpt.13124. Epub 2020 Feb 5.

Abstract

What is known and objective: Dried blood spot (DBS) sampling is a minimally invasive method of blood sampling that enables monitoring of drug concentrations to be more convenient. This study aimed at developing a DBS sampling method for an accurate and precise prediction of radotinib plasma concentrations (Cp ) in patients with chronic myeloid leukaemia (CML).

Methods: Dried blood spot and venous blood samples were simultaneously collected from fifty CML patients who had been receiving radotinib for at least a week. Radotinib concentrations were measured using a high-performance liquid chromatographic method with tandem mass spectrometric detection. Unmeasured Cp was predicted directly based on a Deming regression between DBS concentrations (CDBS ) and Cp . Unmeasured Cp was also predicted from CDBS corrected by each patient's haematocrit (Hct). Both prediction methods were evaluated for their accuracy and precision using Deming regression and Bland-Altman analysis.

Results and discussion: The Deming regression equation between CDBS and Cp was obtained as follows: Cp = 1.34∙CDBS + 4.26 (r2 = .97). Cp was directly predictable using Cp,pred1 = 1.34∙CDBS + 4.26. With Hct correction, Cp was alternatively predictable using Cp,pred2 = CDBS / (1-Hct + Hct2 ). The slopes of Deming regression line between predicted and measured Cp were 0.99 and 1.02 for the direct and Hct-corrected method, respectively. The mean biases (accuracy) were -0.44% and 1.6% with the 95% limits of agreement (precision) of -22.4% to 21.5% and -20.5% to 23.7%, respectively. More than 93% of predicted and measured Cp pairs had their differences within 20% of the mean of each pair in both methods.

What is new and conclusions: Radotinib CDBS are highly correlated with radotinib Cp. Radotinib Cp can be accurately and precisely predicted from CDBS using direct or Hct-corrected prediction methods. Both appear to be appropriate for the therapeutic monitoring of radotinib in patients with CML.

Keywords: blood-to-plasma ratio; chronic myeloid leukaemia; dried blood spot sampling; haematocrit; radotinib.

Publication types

  • Comparative Study
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Benzamides / administration & dosage*
  • Benzamides / pharmacokinetics
  • Chromatography, High Pressure Liquid / methods
  • Dried Blood Spot Testing / methods*
  • Drug Monitoring / methods
  • Female
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pyrazines / administration & dosage*
  • Pyrazines / pharmacokinetics
  • Reproducibility of Results
  • Tandem Mass Spectrometry / methods
  • Young Adult

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl)-3-(4-pyrazin-2-ylpyrimidin-2-ylamino)benzamide
  • Benzamides
  • Protein Kinase Inhibitors
  • Pyrazines