Temozolomide in patients with advanced cancer: phase I and pharmacokinetic study

Pharmacotherapy. 2004 Jan;24(1):16-25. doi: 10.1592/phco.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Alkaline Phosphatase / blood
  • Alkylating Agents / adverse effects
  • Alkylating Agents / metabolism
  • Alkylating Agents / pharmacokinetics
  • Area Under Curve
  • Bilirubin / blood
  • Capsules
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / chemistry
  • Dacarbazine / metabolism
  • Dacarbazine / pharmacokinetics*
  • Dacarbazine / toxicity
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Half-Life
  • Humans
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neutropenia / chemically induced
  • Neutropenia / complications
  • Temozolomide
  • Thrombocytopenia / chemically induced
  • Thrombocytopenia / complications
  • Tissue Distribution
  • Treatment Failure


  • Alkylating Agents
  • Capsules
  • Dacarbazine
  • Alkaline Phosphatase
  • 5-(3-methyl-1-triazeno)imidazole-4-carboxamide
  • Bilirubin
  • Temozolomide