PHARMACOKINETICS AND PHARMACODYNAMICS OF MX2 HYDROCHLORIDE IN PATIENTS WITH ADVANCED MALIGNANT DISEASE

The purpose of the present study was to investigate the pharmacokineti cs and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-esc alation study in the first cycle of treatment with drug given i.v. at doses of 10-50 mg/m(2) (total dose 16.8-107.5 mg). The mean total syst emic plasma clearance (CL) of MX2 was 2.98 +/- 1.68 l/min, the mean vo lume of distribution at steady state was 1460 +/- 749 l and mean elimi nation half-life was 10.8 +/- 5.1 h. The area under the plasma concent ration-time curve (AUC) of MX2 was linearly related to the dose per ki logram and the dose per body surface area (r(2) = 0.43, P < 0.01 and r (2) = 0.44, P < 0.01, respectively). CL did not correlate with total b ody weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 +/- 5.0, 21. 9 +/- 11.8, 19.0 +/- 11.3 and 12.3 +/- 6.3 h, respectively. The fracti onal E-max model produced a much better fit to the relative nadir neut rophil count versus dose data (r(2) = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (C-max) data (r(2) = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients h ad a nadir neutrophil count of less than 0.5 x 10(9)/l. This study sho ws that the pharmacokinetics of MX2 are similar to those of other anth racyclines. With other anthracyclines the degree of myelosuppression s eems to depend more on the AUC and C-max than on the delivered dose; h owever, with MX2 the degree of myelosuppression depends more on the do se given than on drug exposure expressed as the AUC or C-max.