title: Effect of phenytoin on celecoxib pharmacokinetics in patients with glioblastoma.
abstract: Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies. Celecoxib, a selective COX-2 inhibitor, is predominantly eliminated by hepatic metabolism. This study was conducted to determine the effects of hepatic enzyme-inducing antiseizure drugs (EIASDs) on the pharmacokinetics of celecoxib. The safety of celecoxib administered with radiation for glioblastoma and the effect of the combined treatment on survival were also evaluated. Patients were stratified based on concomitant use of EIASDs. Celecoxib (400) mg was administered orally twice a day until tumor progression or dose-limiting toxicity. Standard radiation was administered without adjuvant chemotherapy. Sampling was performed to define the plasma concentration/time profile for the initial dose of celecoxib and steady-state trough concentrations. Thirty-five patients (22 +EIASD, 13 -EIASD) were enrolled. There were no significant differences in age, performance status, extent of surgery, or Mini Mental State Exam scores between the two cohorts. The treatment was well tolerated. All patients in the +EIASD arm were taking phenytoin. There were no significant differences in any celecoxib pharmacokinetic parameters between 15 +EIASD and 12 -EIASD patients. With 31 of 35 patients deceased, estimated median survival time for all patients was 12 months (+EIASD, 11.5 months; - EIASD, 16 months; p = 0.11). The pharmacokinetics of celecoxib is not significantly affected by the concomitant administration of phenytoin. Celecoxib administered during and after radiation is well tolerated. The potential difference in survival between the +EIASD and -EIASD groups deserves further evaluation.
authors.affiliation: NABTT CNS Consortium, 1550 Orleans Street, Baltimore, MD 21231, USA. grossman@jhmi.edu
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Olson
authors.forename: Tracy
authors.initials: T
authors.lastname: Batchelor
authors.forename: David
authors.initials: D
authors.lastname: Peereboom
authors.forename: Glenn
authors.initials: G
authors.lastname: Lesser
authors.forename: Serena
authors.initials: S
authors.lastname: Desideri
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.forename: Tarek
authors.initials: T
authors.lastname: Hammour
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D000068579:Celecoxib; D003131:Combined Modality Therapy; D004347:Drug Interactions; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000627:therapeutic use*; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011878:Radiotherapy; D012640:Seizures / Q000517:prevention & control; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D011720:Pyrazoles; D013449:Sulfonamides; D010672:Phenytoin; D000068579:Celecoxib