Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group.
OBJECTIVE
To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD).


METHODS
Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588.


RESULTS
In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (+/- SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) were 162 +/- 155, 171 +/- 72, 182 +/- 157, and 185 +/- 172 (mug/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups.


CONCLUSIONS
Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.
Ramanathan
Ramesh K
RK
Translational Genomics Research Institute, 13208 E Shea Blvd, Ste 100, Scottsdale, AZ 85259, USA. rramanathan@tgen.org
Egorin
Merrill J
MJ
Takimoto
Chris H M
CH
Remick
Scot C
SC
Doroshow
James H
JH
LoRusso
Patricia A
PA
Mulkerin
Daniel L
DL
Grem
Jean L
JL
Hamilton
Anne
A
Murgo
Anthony J
AJ
Potter
Douglas M
DM
Belani
Chandra P
CP
Hayes
Michael J
MJ
Peng
Bin
B
Ivy
S Percy
SP
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides; D001663:Bilirubin / Q000097:blood; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D000068877:Imatinib Mesylate; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism; D008111:Liver 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; D001663:Bilirubin