Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects.
Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose > or = 70 mg/m(2) had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.
Kühne
A
A
Department of Clinical Pharmacology, Georg-August-University, Göttingen, Germany. akuehne@med.uni-goettingen.de [corrected]
Sezer
O
O
Heider
U
U
Meineke
I
I
Muhlke
S
S
Niere
W
W
Overbeck
T
T
Hohloch
K
K
Trümper
L
L
Brockmöller
J
J
Kaiser
R
R
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic
D018906:Antineoplastic Agents, Alkylating; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D008558:Melphalan; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human