A multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole).

The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.