Dj. Morgan et al., PHARMACOKINETICS AND PHARMACODYNAMICS OF MX2 HYDROCHLORIDE IN PATIENTS WITH ADVANCED MALIGNANT DISEASE, Cancer chemotherapy and pharmacology, 40(3), 1997, pp. 202-208
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.