Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy.
OBJECTIVE
To i) investigate the pharmacokinetics of total and unbound plasma melphalan using a population approach, ii) identify clinical factors that affect melphalan disposition and iii) evaluate the role of melphalan exposure in melphalan-related toxicity and disease response.


METHODS
Population pharmacokinetic modelling (using NONMEM) was performed with total and unbound concentration-time data from 100 patients (36-73 years) who had received a median 192 mg m(-2) melphalan dose. Model derived estimates of total and unbound melphalan exposure (AUC) in patients with serious melphalan toxicity and those who had a good disease response (>or=90% decrease in paraprotein concentrations) were compared using the Mann-Whitney test.


RESULTS
A two compartment model generated population mean estimates for total and unbound melphalan clearance (CL) of 27.8 and 128 l h(-1), respectively. Estimated creatinine clearance, fat free mass and haematocrit were important determinants of total and unbound CL, reducing the inter-individual variability in total CL from 34% to 27% and in unbound CL from 42% to 30%. Total AUC (range 4.9-24.4 mg l(-1) h) and unbound AUC (range 1.0-6.5 mg l(-1) h) were significantly higher in patients who had oral mucositis (>or=grade 3) and long hospital admissions (P < 0.01). Patients who responded well had significantly higher unbound AUC (median 3.2 vs. 2.8 mg l(-1) h, P < 0.05) when assessed from diagnosis to post-melphalan and higher total AUC (median 21.3 vs. 13.4 mg l(-1) h, P= 0.06), when assessed from pre- to post-melphalan.


CONCLUSIONS
Creatinine clearance, fat free mass and haematocrit influence total and unbound melphalan plasma clearance. Melphalan exposure is related to melphalan toxicity while the association with efficacy shows promising trends that will be studied further.
Nath
Christa E
CE
The Children's Hospital at Westmead, Sydney, NSW, Australia. christan@chw.edu.au
Shaw
Peter J
PJ
Trotman
Judith
J
Zeng
Lihua
L
Duffull
Stephen B
SB
Hegarty
Gareth
G
McLachlan
Andrew J
AJ
Gurney
Howard
H
Kerridge
Ian
I
Kwan
Yiu Lam
YL
Presgrave
Peter
P
Tiley
Campbell
C
Joshua
Douglas
D
Earl
John
J
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D003401:Creatine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010266:Paraproteins / Q000378:metabolism; D018709:Statistics, Nonparametric; D014168:Transferrin / Q000378:metabolism; D014182:Transplantation, Autologous
D019653:Myeloablative Agonists; D010266:Paraproteins; D014168:Transferrin; D003401:Creatine; D008558:Melphalan