title: Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study.
abstract: BACKGROUND
  Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided individualized dosing to reduce the interpatient variability in pazopanib exposure.
  
  
  METHODS
  Thirteen patients were treated with pazopanib for 3 consecutive periods of 2 weeks. During the first period, all patients received 800 mg of pazopanib once daily to reach steady-state exposure. During the second period, the patients either received a PK-guided individualized pazopanib dose or the registered fixed 800-mg dose. During the third period, these 2 dosing regimens were switched.
  
  
  RESULTS
  The interpatient variability in pazopanib AUC0-24h during fixed dosing (27.3 coefficient of variation) was not significantly different when compared with the variability in AUC0-24h during PK-guided dosing (24.8 coefficient of variation). The percentage of patients within the target window during PK-guided dosing (53.9%) was not significantly different from the percentage during fixed dosing (46.2%). Both Ctrough and C24 were significantly (P < 0.001) correlated to pazopanib AUC0-24h (R = 0.596 and R = 0.940, respectively). Pazopanib AUC0-24h decreased 17% over time.
  
  
  CONCLUSIONS
  PK-guided dosing did not reduce the interpatient variability in pazopanib exposure. In this study, the intrapatient variability in pazopanib exposure was relatively large compared with interpatient variability. This makes it challenging to achieve a target exposure within a predefined window. The causes of intrapatient variability must first be better understood and controlled, before PK-guided dosing can reduce the interpatient variability.
authors.affiliation: *Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center; †Department of Clinical Pharmacy, Radboud University Medical Center, Nijmegen; Departments of ‡Medical Statistics, and §Clinical Oncology, Leiden University Medical Center; and ¶Department of Clinical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Djoeke
authors.initials: D
authors.lastname: de Wit
authors.forename: Nielka P
authors.initials: NP
authors.lastname: van Erp
authors.forename: Jan
authors.initials: J
authors.lastname: den Hartigh
authors.forename: Ron
authors.initials: R
authors.lastname: Wolterbeek
authors.forename: Margret
authors.initials: M
authors.lastname: den Hollander-van Deursen
authors.forename: Mariëtte
authors.initials: M
authors.lastname: Labots
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Henk M
authors.initials: HM
authors.lastname: Verheul
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine / Q000379:methods*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib