Population pharmacokinetics of melphalan, infused over a 24-hour period, in patients with advanced malignancies.
OBJECTIVE
The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies.


METHODS
Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity.


RESULTS
Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3+/-4.5 l/h per m2) than in female patients (12.3+/-4.5 l/h per m2). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m2). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels.


CONCLUSIONS
The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.
Mougenot
Philippe
P
Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, University Montpellier I, 15 Avenue Ch. Flahault, BP 14 491, 34093 Montpellier Cedex 5, France.
Pinguet
Frédéric
F
Fabbro
Michel
M
Culine
Stéphane
S
Poujol
Sylvain
S
Astre
Cécile
C
Bressolle
Françoise
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan