title: Plasma pharmacokinetics of high-dose oral melphalan in patients treated with trialkylator chemotherapy and autologous bone marrow reinfusion.
abstract: The pharmacokinetics of melphalan following high-dose p.o. administration were determined in 17 patients with various malignancies for the purpose of assessing interpatient and intrapatient pharmacokinetic variability. All patients underwent bone marrow harvest on day -8 (relative to bone marrow reinfusion). On days -7, -6, and -5, melphalan was given p.o. and the dose was escalated on each cohort consisting of at least 3 patients (beginning at 0.75 mg/kg). On days -6, -4, and -2, cyclophosphamide at 2.5 g/m2 and thiotepa at 225 mg/m2 were given i.v. On day -7 the peak melphalan concentration was 1.64 +/- 0.89 (SD) microM with a terminal half-life of 1.56 +/- 0.86 h. The area under the plasma concentration time curve (AUC) and oral clearance were 217.9 +/- 115.1 microM/min and 30.2 +/- 14.2 ml/min/kg. There was only a moderate correlation between the melphalan dose and both the peak concentration (r = 0.50, P less than 0.05) and AUC (r = 0.64, P less than 0.01) over the dosage range of 0.75-2.5 mg/kg. There was a trend towards greater interpatient variability in peak concentration, AUC, and oral clearance observed at the higher doses of melphalan. Analysis of intrapatient pharmacokinetic variability in 8 patients showed a significant difference between the doses given on days -7 and -5 in the peak concentration (2.09 versus 1.07 microM, P = 0.02), AUC (264.9 versus 134.8 microM/min, P = 0.01), and oral clearance (25.1 versus 53.1 ml/min/kg, P = 0.05) but no significant difference in the time to peak and terminal half-life. We conclude that there is marked interpatient and intrapatient variability in melphalan pharmacokinetics following high-dose p.o. administration. The data are consistent with saturable absorptive pathways for melphalan, which might be especially sensitive to concurrent high-dose chemotherapy.
authors.affiliation: Lynn Sage Clinical Pharmacology Laboratory for Cancer Research, University of Chicago Pritzker School of Medicine, Illinois.
authors.forename: K E
authors.initials: KE
authors.lastname: Choi
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: S F
authors.initials: SF
authors.lastname: Williams
authors.forename: J A
authors.initials: JA
authors.lastname: Golick
authors.forename: J C
authors.initials: JC
authors.lastname: Beschorner
authors.forename: L J
authors.initials: LJ
authors.lastname: Fullem
authors.forename: J D
authors.initials: JD
authors.lastname: Bitran
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D016026:Bone Marrow Transplantation; D005260:Female; D005502:Food; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D011446:Prospective Studies
chemical_list: D008558:Melphalan