Effect of filgrastim on the pharmacokinetics of MX2 hydrochloride in patients with advanced malignant disease.
OBJECTIVE
To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2.


METHODS
A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50-80 mg/m2 (74-152 mg) with concomitant filgrastim (G-CSF, 5 microg/kg) given daily beginning at 24 h after the dose of MX2.


RESULTS
The mean fast distribution half-life (1.5 +/- 1.0 min) and the mean plasma clearance (2.18 +/- 0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8-107.5 mg) alone (3.3 +/- 2.2 min and 2.98 +/- 1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8 +/- 14.7 and 11.8 +/- 5.0 h for M1 and 14.8 +/- 4.1 and 12.3 +/- 6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2-filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2.


CONCLUSIONS
This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism.
Morgan
D J
DJ
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Melbourne, Australia.
Hill
J S
JS
Clarke
K
K
Stylli
S S
SS
Park
S J
SJ
Cebon
J
J
Basser
R L
RL
Kaye
A H
AH
Geldard
H
H
Maher
D W
DW
Green
M D
MD
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002360:Carubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects; D011994:Recombinant Proteins
D000903:Antibiotics, Antineoplastic; D011994:Recombinant Proteins; C053537:morpholinoanthracycline MX2; D016179:Granulocyte Colony-Stimulating Factor; D002360:Carubicin; D000069585:Filgrastim