Marked variability of melphalan plasma drug levels during regional hyperthermic isolated limb perfusion.
BACKGROUND: Hyperthermic isolated limb perfusion (HILP) with melphalan as treatment for locally recurrent or in-transit malignant melanoma is frequently performed but the principle for calculating drug dosage remains poorly understood. METHODS: This study examined the pharmacokinetic profile of 14 consecutive patients to determine what variables were associated with toxicity and tumor responses. RESULTS: Marked fourfold variability was noted in patient plasma melphalan concentrations. We defined a factor--the ratio of estimated limb volume (Vesti) to melphalan volume of distribution (Vss), Vesti/Vss--that was much more strongly correlated with acute regional toxicity than either area under concentration-time curve or peak plasma concentration. In addition, we found that AUX2 was the best correlate of tumor response. CONCLUSIONS: Pharmacokinetic evaluation of prospective HILP trials is critical to not only understand response and toxicity outcomes but also to potentially improve the therapeutic index of regional perfusion.
Cheng, T-Y; Grubbs, E; Abdul-Wahab, O; Leu, S-Y; Hung, C-F; Petros, W; Aloia, T; Fedrau, R; Pruitt, S; Colvin, M; Friedman, H; Tyler, D
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