title: Plasma concentrations of tyrosine kinase inhibitors imatinib, erlotinib, and sunitinib in routine clinical outpatient cancer care.
abstract: BACKGROUND
  The objectives of this study were to evaluate the plasma concentrations of the tyrosine kinase inhibitors (TKIs), imatinib, erlotinib, and sunitinib, in a cohort of patients with cancer in routine clinical practice and to find the possible factors related to plasma concentrations below the target level.
  
  
  METHODS
  An observational study was performed in an unselected cohort of patients using TKIs for cancer treatment. Randomly timed plasma samples were drawn together with regular laboratory investigations during routine outpatient clinic visits. The plasma concentrations of TKIs were determined using a validated high-performance liquid chromatography coupled with tandem mass spectrometry detection method. Trough concentrations were estimated using the interval between the last dose intake and blood sampling and the mean elimination half-life of the TKIs and were compared with target trough concentrations. Outpatient medical records were reviewed to collect data on patient- and medication-related factors that could have contributed to the variation in TKI plasma concentrations.
  
  
  RESULTS
  Only 26.8%, 88.9%, and 51.4% of the calculated trough plasma concentrations of imatinib, erlotinib, and sunitinib samples, respectively, reached the predefined target concentration (imatinib: 1100 ng/mL, erlotinib: 500 ng/mL, and sunitinib: 50 ng/mL). Interpatient variability was high with coefficients of variation of 39.1%, 40.1%, and 29.2% for imatinib, erlotinib, and sunitinib, respectively. High variation in plasma concentrations could only partly be explained by patient- or medication related factors.
  
  
  CONCLUSIONS
  Almost half of the plasma concentrations in the outpatient population seemed to be below the target level with a risk of treatment failure. It is not possible to predict which patients are at a risk of plasma concentrations below the target level based on patient- or medication-related factors. Thus, therapeutic drug monitoring could play a crucial role in routine cancer care to identify patients that are in need of individual adjusted dosages. Further research is required to investigate the safety and efficacy of therapeutic drug monitoring.
authors.affiliation: *Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands; †Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; and ‡Division of Pharmaco-epidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Nienke A G
authors.initials: NA
authors.lastname: Lankheet
authors.forename: Lotte M
authors.initials: LM
authors.lastname: Knapen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Neeltje
authors.initials: N
authors.lastname: Steeghs
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001549:Benzamides / Q000493:pharmacokinetics / Q000627:therapeutic use; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005744:Gastric Acid / Q000737:chemistry; D006207:Half-Life; D006635:Histamine H2 Antagonists; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010045:Outpatients; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077210:Sunitinib; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D006635:Histamine H2 Antagonists; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D054328:Proton Pump Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; D000068877:Imatinib Mesylate; D000069347:Erlotinib Hydrochloride; D000077210:Sunitinib