Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours

• Published in: British journal of cancer Vol. 110; no. 10; pp. 2441 - 2449
• Main Authors: Lankheet, N A G, Kloth, J S L, Gadellaa-van Hooijdonk, C G M, Cirkel, G A, Mathijssen, R H J, Lolkema, M P J K, Schellens, J H M, Voest, E E, Sleijfer, S, de Jonge, M J A, Haanen, J B A G, Beijnen, J H, Huitema, A D R, Steeghs, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-05-2014; Nature Publishing Group
• Subjects: 631/67/1059; 631/92/436/1729; Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Clinical Study; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Drug Monitoring; Drug Resistance; Epidemiology; Fatigue - chemically induced; Feasibility Studies; Female; Gastrointestinal Diseases - chemically induced; Hematologic Diseases - chemically induced; Humans; Indoles - administration & dosage; Indoles - adverse effects; Indoles - blood; Indoles - pharmacokinetics; Male; Medical sciences; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - enzymology; Nervous System Diseases - chemically induced; Oncology; Patients; Pharmacokinetics; Pilot Projects; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - blood; Pyrroles - pharmacokinetics; Salvage Therapy; Therapeutic drug monitoring; Toxicity; Tumors; Netherlands; sunitinib; personalised medicine; kinase and phosphatase inhibitors; biodistribution/toxicology; therapeutic drug monitoring; pharmacokinetics and pharmacodynamics; Antineoplastic agent; Solid tumor; Phosphoric monoester hydrolases; Esterases; Posology; Therapeutic drug monitoring; Sunitinib; Toxicology; Cancerology; Advanced stage; Antiangiogenic agent; Protein-tyrosine kinase; Human; Pharmacodynamics; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Malignant tumor; Biological activity; Guidance; Medicine; Kinase; Hydrolases; Feasibility; Multikinase inhibitor; Pharmacokinetics; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.194

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.