The combination of multiple doses of etanidazole and pimonidazole in 48 patients: a toxicity and pharmacokinetic study.

The two radiosensitizers etanidazole and pimonidazole, currently in clinical phase 3 trials, have different toxicities. The former produces a peripheral neuropathy after cumulative doses and the latter presents an accurate but transient central nervous system syndrome after each dose. A strategy for improving on the maximum radiosensitization achievable using either drug alone, has been investigated in the study reported in this paper. Escalating doses of the two drugs were given together to determine toxicity up to a maximum of 15 doses of 2.0 g/m2 etanidazole and 0.75 g/m2 pimonidazole/dose. 25 neuropathies were seen in the total of 48 patients (48%). This included 6 grade 2 neuropathies (12.5%) or 15% of those receiving 9 or more infusions. There were no significant correlations between the incidence of neuropathy and various dose and AUC parameters for the 31 patients receiving 10 or more infusions. However, in the selected group of 26 patients planned to receive multiple doses of etanidazole at 2 g/m2/dose with pimonidazole at 0.75 g/m2, significant correlations were seen with the cumulative dose, with single and cumulative AUCs for pimonidazole and also for the cumulative dose and the cumulative AUC for etanidazole, but not its single AUC. In the light of these observations and the recent reports of higher peripheral neuropathy rates than previously reported in studies in the USA, it is concluded that it is not possible at this time to determine whether there is toxicity interaction between the two drugs. There remains the possibility that, on the basis of the combined drug dosage achieved, an increased therapeutic efficacy can be reached with either drug alone.