Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients.
BACKGROUND
Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine--as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine--are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk).


METHODS
GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML).


RESULTS
Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%), 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%).


CONCLUSIONS
Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.
Pursche
Stefan
S
Carl Gustav Carus University, Internal Medicine I, Division of Hematology and Oncology, Dresden, Germany.
Schleyer
Eberhard
E
von Bonin
Malte
M
Ehninger
Gerhard
G
Said
Samir Mustafa
SM
Prondzinsky
Roland
R
Illmer
Thomas
T
Wang
Yanfeng
Y
Hosius
Christian
C
Nikolova
Zariana
Z
Bornhäuser
Martin
M
Dresemann
Gregor
G
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood* / Q000627:therapeutic use; D001549:Benzamides; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D005909:Glioblastoma / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000097:blood; D000068877:Imatinib Mesylate; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D055815:Young Adult
D000927:Anticonvulsants; D001549:Benzamides; C464561:CGP 74588; D065692:Cytochrome P-450 CYP3A Inhibitors; D007527:Isoenzymes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006918:Hydroxyurea
J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Jan 5;799(1):23-36
14659433
Wien Klin Wochenschr. 2004 Feb 28;116(4):112-8
15038401
Neurosurg Focus. 2006 Apr 15;20(4):E5
16709036
Ann Oncol. 2005 Oct;16(10):1702-8
16033874
Clin Pharmacokinet. 1996 Dec;31(6):470-93
8968658
Semin Oncol. 2003 Dec;30(6 Suppl 19):49-52
14765386
Int J Clin Oncol. 2006 Jun;11(3):184-9
16850124
J Neurosurg. 1998 Jan;88(1):1-10
9420066
Cancer Chemother Pharmacol. 2004 Feb;53(2):102-6
14605865
Neurosurg Focus. 2006 Apr 15;20(4):E1
16709014
Lancet. 2002 Mar 23;359(9311):1011-8
11937180
Neurosurg Focus. 2006 Apr 15;20(4):E6
16709037
N Engl J Med. 2001 Apr 5;344(14):1031-7
11287972
Eur J Cancer. 2002 Sep;38 Suppl 5:S28-36
12528770
Br J Clin Pharmacol. 2001 Nov;52(5):547-53
11736863
Clin Cancer Res. 2006 Aug 15;12(16):4899-907
16914578
Cancer Chemother Pharmacol. 2004 Apr;53(4):313-23
14658008
Cancer Res. 1992 Jun 1;52(11):3213-9
1317261
J Clin Oncol. 2005 Dec 20;23(36):9359-68
16361636
J Clin Oncol. 2005 Jun 1;23(16):3855-6; author reply 3857-8
15923584
J Clin Oncol. 2004 Mar 1;22(5):935-42
14990650
Cancer Res. 1992 Aug 15;52(16):4550-3
1322795
N Engl J Med. 2005 Mar 10;352(10):987-96
15758009