Desmethylmisonidazole (Ro 05-9963): clinical pharmacokinetics after multiple oral administration

The O-demethylated metabolite of misonidazole, Ro 05-9963, has been administered orally, prior to irradiation, to over 50 patients with malignant disease in order to assess the effectiveness of this compound as a hypoxic cell radiosensitizer. This paper reports the pharmacokinetic data observed in those patients who received multiple doses to a total of 12 gm-2. The mean time and magnitude of the peak plasma concentration was determined together with the plasma profile and half-life at the start and finish of each regime of 6, 20, 25 or so fractions. Half-life was independent of drug dose while peak plasma levels rose with increasing amount of drug given. The importance of urinary clearance for this polar drug is indicated by the figure of approximately 50% of administered dose excreted by this route over 24 hours, compared to less than 25% for misonidazole. It was also illustrated by the increased half-life shown by one patient who suffered renal failure during treatment. Peak plasma concentration appeared to be slightly later and were more variable than in the more ideal conditions of the normal volunteer study. In addition, this study confirmed the latter study's findings that absorption is rapid following oral administration of Ro 05-9963, yielding peak plasma levels nearly as high as those seen with misonidazole. Administration in capsules rather than aqueous solution lead to slower absorption, but the peak level did not change.