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Plasma Pharmacokinetics of High-Dose Oral Melphalan in Patients Treated with Trialkylator Chemotherapy and Autologous Bone Marrow Reinfusion¹

Lynn Sage Clinical Pharmacology Laboratory for Cancer Research [K. E. C., M. J. R.], Joint Section of Hematology/Oncology [K. E. C., M. J. R., S. F. W., J. A. G., J. C. B., L. J. F., J. D. B.], Department of Medicine, and the Committee on Clinical Pharmacology [M. J. R.], University of Chicago Pritzker School of Medicine and Michael Reese Hospital and Medical Center, Chicago, Illinois 60616

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 mephalan concentration was 1.64 ± 0.89 (SD) µM 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 µM/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 < 0.05) and AUC (r = 0.64, P < 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 µM, P = 0.02), AUC (264.9 versus 134.8 µM/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.

¹ Supported in part by the Lynn Sage Fund for Cancer Research and the Deborah Goldfine-Reva Smilgoff Memorial Club.

² Present address: Kyung E. Choi, Department of Pharmacokinetics and Clinical Research, Cheil Sugar R and D Center, Samsung Corporation, 522-1 Dukpyung-Ri, Majang-Myun, Yichun-Kun, Kyungki-Do, South Korea.

³ Recipient of a Clinical Oncology Career Development Award from the American Cancer Society. To whom requests for reprints should be addressed, at Michael Reese Hospital and Medical Center, Joint Section of Hematology/Oncology, Room L231 Blood Center, Lake Shore Drive at 31st Street, Chicago, IL 60616.

Received 5/11/88. Revised 11/16/88. Accepted 12/ 2/88.