Pharmacokinetics of temozolomide administered in combination with O6-benzylguanine in children and adolescents with refractory solid tumors.
OBJECTIVE
Temozolomide pharmacokinetics were evaluated in children receiving concurrent O(6)-benzylguanine (O(6)BG), which enhanced the hematological toxicity of temozolomide.


METHODS
Temozolomide was administered orally, daily for 5 days starting at 28 mg/m(2) per day with escalations to 40, 55, 75 and 100 mg/m(2) per day with O(6)BG intravenously daily for 5 days at doses of 60, 90 or 120 mg/m(2) per day. Plasma samples were drawn over 48 h after the day 5 dose. Temozolomide was quantified with a validated HPLC/tandem mass spectroscopic assay.


RESULTS
Temozolomide was rapidly absorbed (mean T (max), 2.1 h). The mean apparent clearance (CL/F) (96 mL/min/m(2)) was similar to the CL/F for temozolomide alone and was not age- or gender-dependent. There was minimal inter-patient variability.


CONCLUSIONS
The enhanced hematologic toxicity resulting from combining O(6)BG with temozolomide does not appear to be the result of a pharmacokinetic interaction between the agents.
Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bldg. 10 CRC/Rm. 1-5750, Bethesda, MD 20892, USA. hmeany@cnmc.org
Holly J
HJ
Meany
Katherine E
KE
Warren
Elizabeth
E
Fox
Diane E
DE
Cole
Alberta A
AA
Aikin
Frank M
FM
Balis
D000293:Adolescent; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006402:Hematologic Diseases / Q000139:chemically induced*; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D012737:Sex Factors; D053719:Tandem Mass Spectrometry / Q000379:methods; D000077204:Temozolomide; D055815:Young Adult
C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D000077204:Temozolomide