title: Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.
abstract: BACKGROUND
  Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.
  
  
  METHODS
  Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade ⩾3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade ⩾3 toxicity, the sunitinib dose was lowered by 12.5 mg.
  
  
  RESULTS
  Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ⩾3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.
  
  
  CONCLUSIONS
  In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.
authors.forename: N A G
authors.initials: NA
authors.lastname: Lankheet
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
authors.forename: J S L
authors.initials: JS
authors.lastname: Kloth
authors.affiliation: 1] Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: C G M
authors.initials: CG
authors.lastname: Gadellaa-van Hooijdonk
authors.affiliation: 1] Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Cirkel
authors.affiliation: 1] Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands [2] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: R H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: 1] Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: M P J K
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: 1] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 12, 1066 CX Amsterdam, The Netherlands.
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: 1] Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: E E
authors.initials: EE
authors.lastname: Voest
authors.affiliation: 1] Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands [2] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: 1] Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands [2] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: M J A
authors.initials: MJ
authors.lastname: de Jonge
authors.affiliation: Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 12, 1066 CX Amsterdam, The Netherlands.
authors.forename: J B A G
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: 1] Center for Personalised Cancer Treatment, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 12, 1066 CX Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Steeghs
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005221:Fatigue / Q000139:chemically induced; D005240:Feasibility Studies; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009422:Nervous System Diseases / Q000139:chemically induced; D010865:Pilot Projects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016879:Salvage Therapy; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C544393:SU 12662; D000077210:Sunitinib
references.citation: N Engl J Med. 2011 Feb 10;364(6):501-13
references.pmid: 21306237
references.citation: Br J Cancer. 2011 Sep 27;105(7):938-44
references.pmid: 21878940
references.citation: Mol Cancer Ther. 2003 May;2(5):471-8
references.pmid: 12748309
references.citation: Clin Pharmacol Ther. 2013 Mar;93(3):228-30
references.pmid: 23419487
references.citation: Br J Cancer. 2008 Jul 22;99(2):259-65
references.pmid: 18594533
references.citation: Lancet. 2006 Oct 14;368(9544):1329-38
references.pmid: 17046465
references.citation: Cancer Treat Rev. 2011 Jun;37(4):251-60
references.pmid: 20833478
references.citation: Mol Cancer Ther. 2003 Oct;2(10):1011-21
references.pmid: 14578466
references.citation: Clin Genitourin Cancer. 2012 Dec;10(4):239-45
references.pmid: 23000202
references.citation: Clin Pharmacokinet. 2005;44(2):147-73
references.pmid: 15656695
references.citation: Cancer Chemother Pharmacol. 2010 Jul;66(2):357-71
references.pmid: 19967539
references.citation: Clin Cancer Res. 2011 Jan 15;17(2):353-62
references.pmid: 21224369
references.citation: Clin Cancer Res. 2003 Jan;9(1):327-37
references.pmid: 12538485
references.citation: Br J Cancer. 2009 Nov 3;101(9):1543-8
references.pmid: 19826424
references.citation: J Clin Oncol. 2012 Nov 10;30(32):4017-25
references.pmid: 22927532
references.citation: Ther Drug Monit. 2013 Apr;35(2):168-76
references.pmid: 23503442
references.citation: J Clin Oncol. 2009 Sep 1;27(25):4068-75
references.pmid: 19652072
references.citation: J Clin Oncol. 2006 Jan 1;24(1):25-35
references.pmid: 16314617
references.citation: J Clin Oncol. 2009 Sep 10;27(26):4406-12
references.pmid: 19667267
references.citation: Oncologist. 2012;17(9):1204-12
references.pmid: 22752067
references.citation: Clin Exp Metastasis. 2003;20(8):757-66
references.pmid: 14713109
references.citation: Invest New Drugs. 2012 Oct;30(5):2046-9
references.pmid: 22038662
references.citation: J Clin Pharmacol. 2013 May;53(5):491-504
references.pmid: 23553560
references.citation: J Clin Oncol. 2006 Jan 1;24(1):16-24
references.pmid: 16330672
references.citation: Clin Pharmacokinet. 2014 Mar;53(3):261-269
references.pmid: 24234588
references.citation: Clin Cancer Res. 2012 Oct 15;18(20):5780-7
references.pmid: 22850565
references.citation: Eur J Cancer. 2009 Jul;45(11):1959-68
references.pmid: 19282169
references.citation: J Clin Oncol. 2012 Apr 20;30(12):1371-7
references.pmid: 22430274
references.citation: Cancer. 2012 Mar 1;118(5):1252-9
references.pmid: 21898376