title: Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence.
abstract: OBJECTIVE
  Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation.
  
  
  METHODS
  We performed studies in male FVB-mice aged 8-12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration-time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times.
  
  
  RESULTS
  Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14-27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (C trough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (C trough-1 p.m. 66.0 ng/mL; C trough-6 p.m. 58.9 ng/mL; C trough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times.
  
  
  CONCLUSIONS
  Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower C trough values, probably resulting from differences in elimination. This can have implications for therapeutic drug monitoring.
authors: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands, j.kloth@erasmusmc.nl.
authors: Jacqueline S L
authors: JS
authors: Kloth
authors: Lisette
authors: L
authors: Binkhorst
authors: Annelieke S
authors: AS
authors: de Wit
authors: Peter
authors: P
authors: de Bruijn
authors: Paul
authors: P
authors: Hamberg
authors: Mei H
authors: MH
authors: Lam
authors: Herman
authors: H
authors: Burger
authors: Ines
authors: I
authors: Chaves
authors: Erik A C
authors: EA
authors: Wiemer
authors: Gijsbertus T J
authors: GT
authors: van der Horst
authors: Ron H J
authors: RH
authors: Mathijssen
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019454:Chronotherapy / Q000379:methods; D002940:Circadian Rhythm / Q000502:physiology; D018592:Cross-Over Studies; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C544393:SU 12662; D000077210:Sunitinib
references: Cancer Treat Rev. 2009 Dec;35(8):692-706
references: 19733976
references: Cancer Chemother Pharmacol. 2010 Jul;66(2):357-71
references: 19967539
references: Pharmacogenetics. 2000 Apr;10(3):187-216
references: 10803676
references: J Clin Oncol. 2009 Sep 1;27(25):4068-75
references: 19652072
references: Eur J Cancer. 2009 Jul;45(11):1959-68
references: 19282169
references: Pharmacogenet Genomics. 2007 Dec;17(12):1047-56
references: 18004209
references: Nat Rev Drug Discov. 2007 Sep;6(9):734-45
references: 17690708
references: Fundam Clin Pharmacol. 2007 Apr;21(2):191-7
references: 17391292
references: N Engl J Med. 2007 Jan 11;356(2):115-24
references: 17215529
references: J Clin Pharmacol. 2006 Feb;46(2):229-34
references: 16432275
references: Anticancer Drugs. 2006 Mar;17(3):353-8
references: 16520665
references: N Engl J Med. 2011 Feb 10;364(6):501-13
references: 21306237
references: Cancer Treat Rev. 2011 Jun;37(4):251-60
references: 20833478
references: Chronobiol Int. 2012 May;29(4):443-53
references: 22489638
references: Clin Pharmacokinet. 2014 Apr;53(4):305-25
references: 24566736
references: Nat Rev Clin Oncol. 2014 May;11(5):272-81
references: 24663127
references: Br J Cancer. 2014 May 13;110(10):2441-9
references: 24736581
references: Eur Rev Med Pharmacol Sci. 2014 Aug;18(16):2393-9
references: 25219843
references: Lancet. 2006 Oct 14;368(9544):1329-38
references: 17046465