Optimizing the dose in cancer patients treated with imatinib, sunitinib and pazopanib

Br J Clin Pharmacol. 2017 Oct;83(10):2195-2204. doi: 10.1111/bcp.13327. Epub 2017 Jul 4.

Abstract

Aim: Fixed dose oral tyrosine kinase inhibitors imatinib, sunitinib and pazopanib show a high interpatient variability in plasma exposure. A relationship between plasma exposure and treatment outcome has been established, which supports the rationale for dose optimization of these drugs. The aim of this study was to monitor how many patients reached adequate trough levels after therapeutic drug monitoring-based dose optimization in daily practice.

Methods: A cohort study was performed in patients treated with imatinib, sunitinib or pazopanib of whom follow-up drug levels were measured between August 2012 and April 2016. Patients' characteristics were collected by reviewing electronic patient records. Drug levels were measured using high-performance liquid chromatography coupled with tandem mass spectrometry and trough levels were estimated using a predefined algorithm. Dose interventions were proposed based on trough levels.

Results: In total, 396 trough levels were determined in 109 patients. Median sample frequency per patient was 3. During the first measurement only 38% of patients showed trough levels within the predefined target ranges despite standard dosing; 52% of the patients showed drug levels below and 10% above the target range. In 35 out of 41 patients (85%) dose interventions led to adequate trough levels. Eventually, 64% of the total cohort reached adequate trough levels.

Conclusions: Dose optimization proved an effective tool to reach adequate trough levels in patients treated with imatinib, sunitinib and pazopanib. The percentage of patients with adequate trough levels increased from 38 to 64%. Therapeutic drug monitoring may add to the improvement of efficacy and reduction of toxicity and costs of these treatments.

Keywords: imatinib; individualized dosing; pazopanib; pharmacokinetics; sunitinib; therapeutic drug monitoring.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Child
  • Chromatography, High Pressure Liquid / methods
  • Drug Monitoring*
  • Feasibility Studies
  • Female
  • Humans
  • Imatinib Mesylate / pharmacokinetics*
  • Imatinib Mesylate / therapeutic use
  • Indoles / pharmacokinetics*
  • Indoles / therapeutic use
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / therapeutic use
  • Pyrroles / pharmacokinetics*
  • Pyrroles / therapeutic use
  • Retrospective Studies
  • Sulfonamides / pharmacokinetics*
  • Sulfonamides / therapeutic use
  • Sunitinib
  • Tandem Mass Spectrometry / methods
  • Treatment Outcome
  • Young Adult

Substances

  • Antineoplastic Agents
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Sulfonamides
  • pazopanib
  • Imatinib Mesylate
  • Sunitinib