How ‘Optimal’ are Optimal Sampling Times for Tyrosine Kinase Inhibitors in Cancer? Practical Considerations

Abstract

Tyrosine kinase inhibitors have been marketed as a fixed dose, ‘one size fits all’ treatment strategy. Physicians have also been interested in this method of dosing, knowing the complex planning of other current cancer therapies administered on a mg/m² or mg/kg basis and subsequent occurrence of dosing error or concern for underdosing. The ‘simple and safe’ strategy of a single dose of tyrosine kinase inhibitor for cancer has thus been widely adopted. However, the benefits purported to exist in the clinical trials do not appear to be borne out in clinical practice, particularly in solid tumours. In order to investigate whether pharmacokinetic variability is a contributor to the variable outcomes, pharmacokinetic targets to enable individualisation of tyrosine kinase inhibitor administration are now emerging. Evidence suggests there is not a clear relationship of a single dose to maximum plasma concentration (C _max), steady-state trough concentration (C _trough) or area under the curve (AUC). Furthermore, a significant number of questions remain related to the specific timing and frequency of sample collection required to achieve optimal outcomes. This article reviews the wide variability in the literature on this topic, specifically the different pharmacokinetic targets of the same drug for different cancers, for different states of cancer, and changing pharmacokinetic parameters over a treatment interval in cancer. It appears the optimal sampling times to enable appropriate dose recommendations across patients and diseases may vary, and are not always trough concentrations at steady state. Importantly, the need to be pragmatic in a clinical setting is paramount. Lastly, international collaborations to increase sample size are highly recommended to ensure enough patients are sampled to be sure of a clinical benefit from this concentration-directed methodology.

Appendix

A database search using the terms (Axitinib or Dasatanib or Erlotinib or Imatinib or Nilotinib or Pazopanib or Regorafenib or Sorafenib or Sunitinib or Vemurafenib or Tyrosine Kinase Inhibitor or Protein Kinase Inhibitor) in the title, abstract and keywords, and (Drug Monitoring or Concentration or Target or Trough or Level* or Exposure or Pharmacokinetic*) in the title, abstract and keywords, and (Response or Outcome or Efficacy or Adverse or Tolerability or Toxic* or Individual* or Guid* or Optim* or Sampl*) in the title, abstract and keywords was undertaken using the following databases (^† indicates run concurrently):

• CINAHL

• Cochrane Library

• EMBASE^†

• International Pharmaceutical Abstracts^†

• Medline^†

• Medline in Process^†

The search identified 21,906 papers. A title and abstract search for ‘Timing’ resulted in 440 articles; after removal of duplicates, 419 were screened, of which no original articles described the optimal timing of therapeutic drug monitoring of tyrosine kinase inhibitors.