A case of melphalan sustained accumulation in an 80-year old patient

Abstract

Case We report the case of melphalan accumulation in an 80-year old female with multiple myeloma. Her initial health status was good except for a moderate chronic renal failure (estimated glomerular filtration rate: 31 ml/min) and anemia. Among other drugs, her usual treatment included trimethoprim/sulfamethoxazole and the patient received melphalan from day 1 to day 4 for multiple myeloma. On day 13, she was admitted in intensive care unit for acute renal failure and severe sepsis with pancytopenia. Usual treatments were stopped. Melphalan blood concentrations were 123.6 ng/ml on day 16 and 87.5 ng/ml on day 17 while cerebrospinal fluid concentration was 173.8 ng/ml on day 25. Patient recovered on day 30. Melphalan accumulation may be explained by substrate competition between sulfamethoxazole and melphalan in metabolism pathway and chronic renal failure. Conclusion close clinical and renal monitoring should be performed in patient receiving melphalan and sulfamethoxazole.

Development of an assay for cellular efflux of pharmaceutically active agents and its relevance to understanding drug interactions

“…The results will be useful in investigating drug interactions; drugs that use similar transport mechanisms may affect each other's pharmacokinetics, resulting in altered cytotoxicity and differentially influence the clinical safety profile of cytotoxic agents, especially when used in high-dose chemotherapy. In fact, the pharmacokinetics of busulfan and melphalan, two DNA alkylating drugs used as part of pretransplant conditioning regimens, were altered in patients taking deferasirox and sulfamethoxazole [4, 7]. Based on our present study, the observed low clearance of busulfan and melphalan in these patients may be due to the inhibition of their efflux mediated by deferasirox and sulfamethoxazole.…”

“…The mechanistic nature of these interactions has not been fully characterized and the possible role of glutathione (GSH), known to be involved in Bu metabolism, remains undetermined. Melphalan (Mel), another DNA alkylating agent, was found to accumulate in a multiple myeloma patient taking sulfamethoxazole [7]. In an earlier report, flunarizine, a diphenylpiperazine calcium channel blocker, enhanced Mel cytotoxicity against rhabdomyosarcoma xenograft, which the authors attributed to possible modification of transport mechanisms responsible for cellular Mel retention, but without providing supporting data [8].…”

Considering renal risk while managing cancer

“…Melphalan clearance may be decreased in patients with RI and subsequent progression from RI to renal failure has been reported in a patient receiving treatment for multiple myeloma 71. Dose reductions of 50% are recommended for patients with moderate RI (CrCl 30–50 mL/min) who are not scheduled to receive hematopoietic stem cell transplantation (HSCT), but it should not be used in patients with more severe RI (CrCl <30 mL/min; Table 2).…”