MELPHALAN DOSING REGIMENS FOR MANAGEMENT OF RECURRENT MELANOMA BY ISOLATED LIMB PERFUSION - APPLICATION OF A PHYSIOLOGICAL PHARMACOKINETIC MODEL-BASED ON MELPHALAN DISTRIBUTION IN THE ISOLATED-PERFUSED RAT HINDLIMB

The optimal dosing schedule for melphalan therapy of recurrent maligna nt melanoma in isolated limb perfusions has been examined using a phys iological pharmacokinetic model with data from isolated rat hindlimb p erfusions (IRHP), The study included a comparison of melphalan distrib ution in IRHP under hyperthermia and normothermia conditions. Rat hind limbs were perfused with Krebs-Henseleit buffer containing 4.7% bovine serum albumin at 37 or 41.5 degrees C at a flow rate of 4 ml/min. Con centrations of melphalan in perfusate and tissues were determined by h igh performance liquid chromatography with fluorescence detection, The concentration of melphalan in perfusate and tissues was linearly rela ted to the input concentration. The rate and amount of melphalan uptak e into the different tissues was higher at 41.5 degrees C than at 37 d egrees C. A physiological pharmacokinetic model was validated from the tissue and perfusate time course of melphalan after melphalan perfusi on. Application of the model involved the amount of melphalan exposure in the muscle, skin and fat in a recirculation system was related to the method of melphalan administration: single bolus > divided bolus > infusion, The peak concentration of melphalan in the perfusate was al so related to the method of administration in the same order, Infusing the total dose of melphalan over 20 min during a 60 min perfusion opt imized the exposure of tissues to melphalan whilst minimizing the peak perfusate concentration of melphalan. It is suggested that this metho d of melphalan administration may be preferable to other methods in te rms of optimizing the efficacy of melphalan whilst minimizing the limb toxicity associated with its use in isolated limb perfusion.