Effect of renal dysfunction in dogs on the disposition and marrow toxicity of melphalan

Abstract

Summary.-The effect of renal failure on melphalan pharmacology and toxicity has been poorly understood. Such information is of interest because melphalan is the most commonly used anticancer drug in the treatment of multiple myeloma, which is frequently associated with renal failure. We have studied the disposition and marrow toxicity of parenteral melphalan in dogs before and after induction of renal failure with subtotal nephrectomy. The surgical procedure decreased the creatinine clearance by an average of 62% (P=0-001). The lowest neutrophil counts following i.v. melphalan (1 mg/kg) averaged 4.9 x 103/mm3 pre-nephrectomy and 0-9 x 103/mm3 post -nephrectomy, respectively (P = 0.002). The mean lowest recorded platelet counts after melphalan (1 mg/kg) were 115 x 103/mm3 in the pre-nephrectomized dogs, and 9-7 x 103/mm3 in those who had been nephrectomized (P=0.002). Following nephrectomy, i.v. melphalan's terminal-phase plasma half-life and renal clearance were both raised (P=0.02) to 75%O over pre-nephrectomy values. These studies show that i.v. melphalan-induced myelosuppression is markedly increased and its plasma elimination and renal clearance significantly decreased in the presence of renal dysfunction in dogs. These data suggest that parenteral melphalan's starting dose be decreased by at least 50%o when used in myeloma patients with renal failure.MELPHALAN continues to be one of the most important anticancer drugs in the treatment of multiple myeloma (Speed et al., 1964;Alexanian et al., 1968;Bergsagel et al., 1979). As many as one third of all myeloma patients will have severely reduced renal function as a result of renal tubular damage from paraprotein deposition and/or the toxic effects of hypercalcaemia (Kayle & Bayrd, 1976). Although the alkylating agent melphalan is commonly used in myeloma patients with renal failure, it is not known whether renal dysfunction alters its pharmacokinetics or marrow toxicity. Speed et al. (1964) suggested that the rate of melphalan urinary excretion might be decreased in the presence of renal failure. We have studied the disposition and marrow toxicity of melphalan in dogs before and after surgically induced renal failure. The results of these studies suggest that severe renal dysfunction can slow the plasma and renal clearance of melphalan and markedly increase neutropenia and thrombocytopenia. MATERIALS ANI) METHODSDogs.-Eight male mongrel dogs, weighing 17-23 kg, which had been previously quarantined for 2-4 weeks in the vivarium, were used. The dogs were without evidence of infection and were not given other drugs during the entire duration of the melphalan studies. Baseline BUN, serum creatinine, and 24h urinary creatinine clearance were measured in each of the animals, and were remeasured after the surgical induction of renal dysfunction.An indwelling 16-gauge catheter was inserted into a superficial leg vein. Melphalan(1 mg/kg body weight) wAas injected i.v. over about 1 min, followed by 10 ml normal

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“…In fact, antineoplastic drugs have a narrow therapeutic index, so that major toxicity can occur in patients with impaired renal function, owing to an increase in dose intensity that is difficult to predict. In this regard, an early study conducted in dogs with renal failure 6 demonstrated an increased hematological toxicity of melphalan related to a longer terminal half-life of the drug. A similar finding has been reported in MM patients receiving oral melphalan, 7 while in another study, the frequency of severe myelosuppression induced by oral melphalan was not related to renal function.…”

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“…This rather surprising grade of myelosuppression is probably due to the use of melphalan intravenously after cisplatinum in the period (day 2) when there is functional tubular damage caused by the latter. Melphalan is highly myelotoxic in the presence of renal function impairment [15], and in fact the combination caused leukopenia and especially thrombocytope nia (median nadir values between the 4th and 5th cycles), which were ameliorated by dropping the hexamethylmelamine from the regimen. A relatively short treatment duration of 4-6 months might also help to restrict the neurotoxicity caused by cis-platinum and possibly enhanced by hexamethylmelamine, which has been described elsewhere [16] by our group.…”

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“…[25][26][27] Melphalan undergoes rapid chemical degradation and has little, if any, active metabolism. 28,29 Early studies revealed increased melphalan-induced myelosuppression in nephrectomized dogs, 30 and renal insufficiency significantly increased melphalan-induced myelosuppression in patients with MM. 31 Reduction of the intravenous dose of melphalan to 50% in patients with elevated BUN reduced the frequency of these complications to levels that were not significantly different from those observed in patients with normal renal function.…”