Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group.
OBJECTIVE
This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients.


METHODS
Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long.


RESULTS
The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose.


CONCLUSIONS
Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.
Gibbons
Joseph
J
Case Comprehensive Cancer Center, Ireland Cancer Center at University Hospitals of Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Egorin
Merrill J
MJ
Ramanathan
Ramesh K
RK
Fu
Pingfu
P
Mulkerin
Daniel L
DL
Shibata
Stephen
S
Takimoto
Chris H M
CH
Mani
Sridhar
S
LoRusso
Patricia A
PA
Grem
Jean L
JL
Pavlick
Anna
A
Lenz
Heinz-Josef
HJ
Flick
Susan M
SM
Reynolds
Sherrie
S
Lagattuta
Theodore F
TF
Parise
Robert A
RA
Wang
Yanfeng
Y
Murgo
Anthony J
AJ
Ivy
S Percy
SP
Remick
Scot C
SC
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001549:Benzamides; D001682:Biological Availability; D003404:Creatinine / Q000097:blood / Q000652:urine; D005260:Female; D006207:Half-Life; D006801:Humans; D017674:Hypophosphatemia / Q000139:chemically induced; D000068877:Imatinib Mesylate; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003404:Creatinine