Temozolomide in Patients With Advanced Cancer: Phase 1 and Pharmacokinetic Study

Michelle A. Rudek, Pharm.D.; Ph.D., Ross C. Donehower, M.D.; Paul Statkevich, Ph.D.; Vijay K. Batra, M.D.; David L. Cutler, M.D.; Sharyn D. Baker, Pharm.D.

Disclosures

Pharmacotherapy. 2004;24(1) 

In This Article

Abstract and Introduction

Study Objective: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and potential antitumor activity of temozolomide administered as a single dose every 28 days.
Design: Open label, phase I, dose-escalation trial.
Setting: University-affiliated cancer center.
Patients: Eleven patients aged 33–73 years with a documented solid tumor or lymphoma who failed therapy of proven efficacy for their disease or had a disease for which no conventional therapy was available.
Intervention: Temozolomide 500 mg/m2 was administered as a single oral dose every 28 days. Doses were escalated to 750 or 1000 mg/m2. No intrapatient dose escalation was allowed. At least two patients were enrolled at each dose level. Patients who did not have progressive disease and did not experience a dose-limiting toxicity, or experienced a dose-limiting toxicity but were eligible for dose reduction, were eligible to continue on the study.
Measurements and Main Results: Pharmacokinetic analysis was performed for temozolomide and its active metabolite, 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC). Neutropenia and thrombocytopenia were dose limiting at 1000 mg/m2. Temozolomide was absorbed rapidly (mean time to maximum concentration 1.4 hrs) and eliminated, with average half-life and apparent oral systemic clearance values of 1.8 hours and 97 ml/minute/m2, respectively. Mean systemic exposure to MTIC was 3.7% of temozolomide. No objective responses were observed. The maximum tolerated dose of temozolomide was 750 mg/m2.
Conclusion: Temozolomide 750 mg/m2 administered orally every 28 days was well tolerated. Alternate temozolomide dosing schedules such as continuous daily administration may enhance antitumor activity through sustained depletion of the DNA repair protein O6-alkylguanine DNA alkyltransferase.

Temozolomide (Temodar; Schering-Plough Research Institute, Kenilworth, NJ), an imidazotetrazine derivative, is a cytotoxic alkylating agent with anticancer activity in patients with recurrent and refractory high-grade glioma and metastatic melanoma.[1–6] Unlike the first-generation imidazotetrazine derivative dacarbazine, which is converted enzymatically to the active metabolite 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC), temozolomide is degraded chemically to MTIC in an irreversible, pH-dependent process; MTIC is further degraded to 5-aminoimidazole-4-carboxamide. Both temozolomide and MTIC alkylate and form N7-methylguanine, O6-methylguanine, and O3-methyladenine adducts.[7–9] The formation of the O6-methylguanine adduct has been hypothesized to be the main cytotoxic pathway for temozolomide. Resistance arises with the reversal of the DNA adducts by a DNA repair protein such as O6-alkylguanine DNA alkyltransferase (AGT) or by DNA mismatch repair deficiency.[10,11]

Temozolomide has demonstrated activity at 150–200 mg/m2/day when administered once/day for 5 days, repeated every 4 weeks.[1–4,12] The principal toxicity noted in these studies was myelosuppression, both neutropenia and thrombocytopenia. Continuous daily schedules of 75–100 mg/m2/day for up to 3–7 weeks have shown less myelotoxicity, but an improvement in efficacy remains to be shown.[13–16]

After oral administration, temozolomide is completely (bioavailability 1.09, range 0.67–1.36) and rapidly absorbed.[1] Temozolomide is eliminated principally from plasma, by chemical conversion to MTIC, with minimal excretion as unchanged drug in the urine.[1,5,12,17,18] When pharmacokinetic parameters (mean ± SD) were determined on day 1 of a once-daily, 5-day regimen,[1] the apparent volume of distribution was 28 ± 11 L, terminal half-life 1.8 ± 0.4 hours, and apparent oral clearance 12 ± 4 L/hour. In a subsequent phase I trial with a once-daily, 5-day regimen, the terminal half-life range was 1.3–2.0 hours (mean 1.8 hrs) with no accumulation between days 1 and 5.[5] No difference in apparent oral clearance was noted between days 1 and 5 within the cohorts; however, patients who had prior treatment with a nitrosourea had a statistically significant lower clearance than that of patients without prior treatment.[5] The active metabolite MTIC was detected in plasma within 1 hour of temozolomide administration, had a terminal half-life of 1.5 hours, and had total systemic exposure of 2.2% of temozolomide.[18] In another phase I trial with a once-daily, 5-day regimen, the average terminal half-life and apparent oral clearance were 1.8 hours and 6.9 L/hour/m2, respectively.[12] Body surface area–based dosing for temozolomide reduces interpatient variability in drug exposure by up to 35%, which was confirmed in a population pharmacokinetic analysis.[12,19] On an extended continuous oral schedule, the terminal half-life and apparent oral clearance of temozolomide were consistent with those of other pharmacokinetic studies, and no plasma accumulation of temozolomide was noted during 7 weeks of administration.[13]

Alternate regimens for administration of temozolomide are being investigated. This study was conducted to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic behavior, and potential antitumor activity of temozolomide administered as a single dose every 28 days in minimally pretreated patients.

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