Introduction
Previous pharmacokinetic (PK) studies of intravenous high dose melphalan based in surface area have shown wide interindividual variations in the PK parameters. For children with renal failure, high melphalan exposure has been previously related with increased toxicity. We studied the possibility of using a test-dose of melphalan to determine the individual clearance and subsequently, the optimal therapeutic dose for each child with renal failure undergoing high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT).
Patients and methods
A test-dose of melphalan, consisting of 10% of the full scheduled dose of melphalan was performed in 13 patients with renal failure several days before melphalan-based HDCT and ASCT since 2011 at Gustave Roussy. The target AUC of melphalan was set at 423 mg/L.min. The patient received the lower dose between the calculated and the theoretical dose. After the full dose, PK was performed to evaluate real melphalan exposure. Toxicity and efficacy were evaluated after the completion of treatment.
Results
PK estimations led to reduce doses in 9 patients since the median predicted AUC was 572 mg/L.min (232-1522). A correlation test between EDTA and melphalan clearances during the test-dose showed that renal function and melphalan clearance were linked (p=0.0279). Melphalan full dose was administered according to the theoretical full dose in 4 patients and to the reduced dose calculated according to PK estimations in 9 patients. The median obtained AUC after full dose was 396 mg/L.min (224-956) with a target AUC after full dose (+/-50%) reached for 9 patients. There was no increased toxicity of HDCT in these patients.
Conclusion
This PK study allowed us to administer melphalan in patients with renal failure avoiding increased toxicity. These results confirm the useful of a test-dose to determine the optimal full dose to achieve the targeted exposure based on AUC calculation.