Abstract
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Objectives In current clinical practice, highly concentrated amino acid solutions (e.g. Aminosyn II 10%), used for renal protection during 177Lu peptide therapies, are associated with high patient morbidity. Excessive amounts of the unnecessary amino acids that are co-administered along with the renal protectants, L-Lysine and L-Arginine, cause severe nausea and vomiting, and may lead to arrhythmias. Additionally, the relatively high osmolality of 840 mOsm/kg, combined with a rapid infusion rate of 250-500 mL/h for four hours, results in potential tissue damage at the site of injection. The goal of this study was to develop a formulation that could be used to provide protection without the excessive side effects associated with current solutions. Specifically, this formulation will contain only the renal protectants L-Lysine and L-Arginine [both 1.25% (w/v)], be isotonic, of physiologic pH, endotoxin-free, clear-and-particulate-free, and sterile.
Methods We began by testing the pH and osmolality of the L-Lysine and L-Arginine in 0.45% sodium chloride solution. The pH was determined to be 9.0 and the osmolality was 394 mOsm/kg. Using this information, we tested various concentrations of NaCl (range: 0.1125-0.225%, n=5) and percent added 1N HCl (range: 5-8% v/v, n=5), that would need to be used to yield an isotonic (280-320 mOsm/kg) and pH neutral (pH=6.8-7.8) solution. Based on the obtained data, we developed the following finalized procedure for clinical preparation: first, a 3000 mL of bulk solution was prepared containing 1 part of 0.9% NaCl Solution, USP, to 6 parts Sterile Water for Injection, USP. Next, L-Lysine Hydrochloride, USP, and L-Arginine, USP, were weighed out in proportional amounts to yield at least 2150 mL of solution containing 1.25% (w/v) L-Argininine and 1.25% (w/v) L-Lysine. Based on the amounts of amino acids weighed, the volumes of the normal saline: water solution and 1N HCl, USP, were calculated and then added to the mixing vessel. Following complete dissolution, the solution was sterile filtered through a 0.22 µM sterilizing filter. The solution was then aseptically transferred to a sterile 3000 mL IV bag and QC samples were withdrawn.
Results We performed a total of three validation studies using the finalized procedure. Each validation study took ~2.5 hours to perform. The pH range of the prepared batches was 6.8-7.5. The osmolality ranged from 286-315 mOsm/Kg. In all three batches, the endotoxin content was less than 0.5 EU/mL, and the solution was clear, particle-free, and sterile.
Conclusions We have developed a procedure for the clinical preparation of a renal protectant solution designed to minimize patient toxicity during infusions. This solution can be prepared by registered pharmacists for patients receiving 177Lu-peptide therapy, pursuant to a physician order, and in compliance with the practice of pharmacy regulations (i.e. Section 503A of the Federal Food, Drug, and Cosmetic Act). RESEARCH SUPPORT: The MSKCC Radiochemistry & Molecular Imaging Probes Core, supported in part by NIH Cancer Center Support Grant P30CA008748-48.