Conversion of etoposide phosphate to etoposide under ambulatory infusion conditions

Abstract

Objective: To determine the extent of conversion of etoposide phosphate, a water-soluble prodrug for etoposide, to etoposide at concentrations and temper atures likely to occur during ambulatory infusion.

Design: Etoposide phosphate solutions were prepared at equivalent etoposide concentrations of 15 and 1.5 mg/mL in ambulatory infusion cassettes and stored protected from light at 18 to 20°C and 37°C. Daily samples were taken for 7 days.

Main Outcome Measure: Instability was as sessed as percentage conversion of etoposide phos phate to etoposide. Both drugs were measured using high-performance liquid chromatography.

Results: At room temperature, there was less than 2% conversion of etoposide phosphate to etopo side. At 37°C, there was a cumulative conversion to etoposide of 6.6% after 7 days at both the low and high concentrations.

Conclusion: Etoposide phosphate displays a temperature-dependent, concentration-independent conversion to etoposide over 7 days of less than 7%. Previous studies have confirmed the chemical stabil ity of etoposide up to 96 hours but have suggested that the maximum recommended etoposide concen tration to prevent crystal formation in infusion solu tions is 0.4 mg/mL. To be conservative, if the maxi mum conversion of etoposide phosphate to etoposide over 7 days is estimated to be 10%, and 0.3 mg/mL is selected as the maximum etoposide concentration, then the maximum concentration of etoposide phos phate should be the equivalent of 3.0 mg/mL etopo side. Therefore, prepared under aseptic conditions in a laminar flow cytotoxic safety cabinet, up to 3.0 mg/mL etoposide as etoposide phosphate in 0.9% sodium chloride can be delivered by ambulatory infusion, protected from light, over 96 hours. This will permit therapeutic doses of etoposide, as etopo side phosphate, to be delivered continuously by ambulatory infusion. Given that the extent of conver sion to etoposide was temperature dependent, it is recommended that the infusion cassette remain be low 37°C and preferably as close to room temperature as possible.