title: The multi-dose clinical tolerance and pharmacokinetics of the combined radiosensitizers, Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole).
abstract: The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) have differing physico-chemical properties and clinical toxicities. The former is basic, lipophilic and produces an acute but transient central nervous system syndrome; the latter is neutral, hydrophilic and causes cumulative peripheral neuropathy. We therefore investigated the possibility of combining these agents to achieve additive radiosensitization with no enhancement of toxicity, as demonstrated in a rodent tumor model. Following a single dose study which showed a lack of interaction with respect to both toxicity and pharmacokinetics, twenty-one patients have now completed simultaneous drug administration on an escalating, multiple dose schedule. There has been no adverse acute interaction up to 0.75 g/m2 Ro 03-8799 with 2 g/m2 SR 2508 for 15 doses. At this dose-level, however, all patients experienced peripheral neuropathy. There was no adverse pharmacokinetic interaction, or perturbation of plasma pharmacokinetics between initial and final infusions. Tumor concentrations were determined in 48 biopsy samples 0-60 min after administration. Mean values normalized to a dose of 0.75 g/m2 Ro 03-8799 plus 2 g/m2 SR 2508 were 33 micrograms/g Ro 03-8799 and 74 micrograms/g SR 2508. These would be expected to produce a single-dose sensitizer enhancement ratio of around 1.5. The combination is predicted to be around 6.8 times more active than misonidazole, and superior to any single agent tested to date. The current schedules are reaching the limits of clinical tolerance, and an attempt is now being made to define the optimal regimen for use in a randomized clinical trial of the combination.
authors.affiliation: MRC Unit of Clinical Oncology and Radiotherapeutics, Cambridge, U.K.
authors.forename: H F
authors.initials: HF
authors.lastname: Newman
authors.forename: R
authors.initials: R
authors.lastname: Ward
authors.forename: P
authors.initials: P
authors.lastname: Workman
authors.forename: N M
authors.initials: NM
authors.lastname: Bleehen
mesh_terms: D000328:Adult; D000368:Aged; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D017341:Etanidazole; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; C033815:pimonidazole