Pharmacokinetics of temozolomide administered in combination with O6-benzylguanine in children and adolescents with refractory solid tumors

Abstract

Purpose: 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.

Figures

Fig. 1

Mean plasma concentration–time profile for temozolomide in the four patients studied at the 55 mg/m2 per day dose level. Error bars represent 1 standard deviation

Fig. 2

Relationship between the administered dose per m2 of body surface area and the AUC0–∞ of temozolomide. The line of proportionality was generated by normalizing all of the AUCs to a dose of 100 mg/m2, taking the mean of the normalized AUCs, and plotting a line from 0,0 through 100, mean normalized AUC

Fig. 3

Relationship between patient age at study entry and apparent clearance of temozolomide normalized to body surface area

Fig. 4

Relationship between the administered dose normalized to body surface area (a) and the AUC0–∞ (b) and the percent decrease in the absolute neutrophil count (ANC) on cycle 1 of therapy. Closed symbols represent patients who had a nadir ANC <500/mcL and open symbols represent patients who had a nadir ANC >500/mcL