Population Pharmacokinetics of Melphalan and Glutathione S-transferase Polymorphisms in Relation to Side Effects

Abstract

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.

The Prospective Oral Mucositis Audit: relationship of severe oral mucositis with clinical and medical resource use outcomes in patients receiving high-dose melphalan or BEAM-conditioning chemotherapy and autologous SCT

“…29,30 Indeed, a recent study by a German group found that patients treated with a melphalan dose X70 mg/m 2 had a 23-fold increased risk of developing mucositis (Po0.001) compared with those receiving lower doses. 30 Thus, we tentatively evaluated whether there was an association between melphalan dose per kg body weight and medical resource use, in MM patients only. No relationship was found, indicating that the observed associations of OM with medical resource use were not directly on account of higher drug doses.…”

Not too little, not too much—just right! (Better ways to give high dose melphalan)

“…The fact that it was possible to recover more than 60% of the dose in three (of nine) patients in one study suggests that renal excretion is likely to be the major elimination pathway for melphalan. 12 Population PK analyses have also identified renal function as a significant determinant of melphalan clearance, 14,15 with renal clearance estimated to be approximately 40%. 15 …”

“…12 Population PK analyses have also identified renal function as a significant determinant of melphalan clearance, 14,15 with renal clearance estimated to be approximately 40%. 15 …”

“…There are also a number of PK studies on melphalan that have related high melphalan exposure with either increased toxicity, 6,14,15,24 improved efficacy 25 or no obvious discernable effect; [26][27][28] these studies are summarised in Table 2. Kühne et al 15 studied 84 adults with mixed diagnoses (but mainly myeloma) at melphalan doses ranging from 10 to 200 mg/m 2 .…”

“…Kühne et al 15 studied 84 adults with mixed diagnoses (but mainly myeloma) at melphalan doses ranging from 10 to 200 mg/m 2 . They found that melphalan area under the concentration-time curve (AUC) was significantly associated with the development of oral mucositis and diarrhoea.…”