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Lee, Kim, Lee, Koo, and Kim: Pharmacokinetics of High-dose Intravenous Melphalan in Patients Undergoing Autologous Stem Cell Transplantation
Original Article

Korean J Hematol 2007;42(2):122-128.

Published online: 19 June 2007

DOI: https://doi.org/10.5045/kjh.2007.42.2.122

Pharmacokinetics of High-dose Intravenous Melphalan in Patients Undergoing Autologous Stem Cell Transplantation

So Young Lee, M.D.1, Jung A Kim, M.D.2, Jung Won Lee, M.S.3, Hyo Jung Koo, Ph.D.3, Hoon-Kyo Kim, M.D2,

1Health Promotion Center, St. Mary's Hospital, Korea

2Department of Internal Medicine, St. Vincent's Hospital, Suwon, Korea

3Department of Biomedicine, The Catholic University of Korea College of Medicine, Seoul, Korea

Correspondence to：Hoon-Kyo Kim, M.D. Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea College of Medicine 93-6, Ji-dong, Paldal-gu, Suwon 442-723, Korea Tel: ＋82-31-249-7127, Fax: ＋82-31-253-8898 E-mail: kimhoonkyo@yahoo.co.kr

Received 10 November 2006       Revised 28 December 2006       Accepted 14 May 2007

Copyright © 2007 Korean Society of Hematology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background:

Melphalan is frequently used in conditioning regimens prior to autologous stem cell transplantation. The pharmacokinetics of melphalan have shown great interindividual variations. This study aims to investigate the pharmacokinetics of melphalan and to study those influences on renal function and the clinical outcomes.

Methods:

The pharmacokinetics of melphalan following high dose (100∼140mg/m2) i.v. administration was determined in 11 patients suffering with advanced malignancies and who were undergoing autologous stem cell transplantation. The plasma level of melphalan was assayed by a specific HPLC method.

Results:

The pharmacokinetics parameters (median AUC: 625.2mg/L/min, steady-state volume of distribution (Vdss): 14.87L/m2, total body clearance: 0.2L/min/m2, half life: 55.9 min, and maximal plasma concentration: 7.61mg/L) were similar to those reported in the literature. No relationship between the pharmacokinetics of melphalan and creatinine clearance, the non-hematologic toxicities and relapse was observed. Only Vdss was correlated with myelosuppression (P＜0.05).

Conclusion:

The pharmacokinetics of melphalan were similar to those reported in Caucasians. The PK parameters did not correlate with the clinical outcomes in patients with normal renal function. Further studies on patients with renal failure are needed.

Keywords: Melphalan, Pharmacokinetics, High dose chemotherapy

REFERENCES

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Fig. 1
Representative profile of concentration-time curve in a patient given intravenous administration of melphalan 140mg/m2.
kjh-42-122f1.tif
Table 1.
Conditioning regimens according to diagnosis
Drugs Dosing regimen Days of administration No. patients (disease)
Cytarabine 1,500mg/m2 IV q 12 h×6 Day -6, -5, -4  
Melphalan 140mg/m2 IV q 24 h×1 Day -3 4 (AML†=3, ALL‡=1)
TBI∗ 1,200cGY×3 Day -9, -8, -7  
Melphalan 100mg/m2 IV q 24 h×2 Day -3, -2 6 (MM§)
Carmustine 300mg/m2 IV×1 Day -7  
Etoposide 200mg/m2 IV×4 Day -6, -5, -4, -3 1 (NHL∥=1)
Cytarabine 100mg/m2 IV×4 Day -6, -5, -4, -3 1 (NHL =1)
Melphalan 140mg/m2 IV×1 Day -2  

∗Total body irradiation;

† Acute myeloid leukemia;

‡ Acute lymphoid leukemia;

§ Multiple myeloma;

∥ Non-Hodgkin's lymphoma

Table 2.
Serious adverse events of patients treated wit intravenous melphalan
Case Age (yr) Sex BMI∗ (kg/m2) Diagnosis † CCR (mL/min) Toxicities (grade III/IV)
1 16 M 20.6 NHL 183 Diarrhea
2 56 F 26.4 MM 76.8 Mucositis, diarrhea
3 51 M 21.7 MM 81.3 Pneumonia & mucositis (grade II)
4 60 F 26.2 MM 91.7 Diarrhea
5 48 M 26 MM 121 Mucositis (grade II)
6 57 F 24.5 MM 88.7 Mucositis, diarrhea, nausea/ vomiting
7 45 M 22.5 AML 112 Mucositis (grade II)
8 27 F ? 17.8 AML 111 Mucositis, diarrhea
9 55 M 22.8 AML 91.5 Mucositis (grade II)
10 40 F 17.5 ALL 108.6 Mucositis, diarrhea, nausea/ vomiting
11 27 M 16.8 MM 160 Mucositis, diarrhea, liver toxicity

∗Body mass index;

† Creatinine clearance.

Table 3.
Transplant outcomes
Case ANC∗>500/μL (days) ? Platelet＞ 20,000/μL (days) Current status DFS†
1 8 9 Alive; relapse 2 months
2 9 11 Alive 17+months
3 13 17 Alive 37+months
4 13 15 Alive; relapse 12 months
5 10 12 Alive; relapse 1.5 months
6 12 12 Alive 2+months ?
7 12 12 Alive 12+months
8 14 22 Alive 16+months
9 10 10 Died; relapse 2 months
10 11 16 Alive 19+months
11 12 14 Died; relapse 2 months

∗Absolute neutrophil count;

† Disease-free survival.

Table 4.
Pharmacokinetic parameters of melphalan
Case Day Cmax∗ (mg/L) † (min) t1/2 AUC‡ (mg/L×min) § (L/min/m2) ClT MRT∥ (min) Vdss (L/m2)
1 1 21.94 55.9 1,157.2 0.119 43.2 5.15
2 1 10.45 43.2 772.9 0.127 57.6 7.32
  2 8.99 47.7 926.1 0.107 78.7 8.43
3 1 6.81 60.2 510.5 0.191 65.3 12.49
  2 3.09 150.2 411.1 0.235 149.5 35.12
4 1 3.48 46.7 347.6 0.285 75.3 21.47
  2 7.16 71.4 493.1 0.199 62.9 12.55
5 1 11.31 93.0 711.6 0.128 79.8 10.18
  2 5.46 72.0 445.8 0.220 75.9 16.67
6 1 12.97 22.7 859.9 0.116 48.6 5.64
  2 9.7 55.5 919.2 0.107 76.5 8.23
7 1 6.03 24.7 588.7 0.236 64.5 15.24
8 1 7.61 63.4 736.1 0.174 87.7 15.31
9 1 8.69 70.4 661.2 0.200 71.2 14.22
10 1 6.73 38.5 625.2 0.218 68.1 14.87
11 1 4.05 43.8 297.4 0.330 56.7 18.71
  2 4.06 62.8 324.8 0.304 69.4 21.07
Median 7.61 55.9 625.2 0.200 68.2 14.87
Quartile range 4.40 31.3 388.7 0.117 14.8 9.13

∗Maximal plasma concentration;

† Half-life;

‡ Area under the plasma concentration curve;

§ Total body clearance;

∥ Mean residence time;

Steady-state volume of distribution.

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