ISSN:
1432-0843
Keywords:
Key words MX2
;
Pharmacokinetics
;
Pharmacodynamics
;
Anthracyclines
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10–50 mg/m2 (total dose 16.8–107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 ± 1.68 l/min, the mean volume of distribution at steady state was 1460 ± 749 l and mean elimination half-life was 10.8 ± 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram 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 body 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 fractional E max model produced a much better fit to the relative nadir neutrophil 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 had a nadir neutrophil count of less than 0.5 × 109/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and C max than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or C max.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002800050647
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