irinotecan

INTRODUCTION

Irinotecan (IR; Camptosar; 7-ethyl-10-[4-(1-piperidino)- 1-piperidino] carbonyl oxycamptothecin, or CPT-11) was introduced in Canada in late 1997 for the treatment of relapsed or refractory colorectal cancer. The product monograph indicates that IR may be diluted with a variety of IV solutions, including 0.9% sodium chloride (normal saline; NS) and 5% dextrose in water (D5W), and that such solutions should be used within 12 h when stored at room temperature or 48 h when refrigerated.

Previous evaluations of IR degradation have indicated that the first step involves hydrolysis of the lactone ring to form a ring-opened carboxylate derivative, a reversible, pH-dependent process. At a pH of less than 5 equilibrium favours IR, whereas at a pH of greater than 8, virtually all IR is present as the ring-opened carboxylate. As the pH increases from 5 to 8, an increas­ing proportion of IR exists as the carboxylate at equilibrium. The rate of conversion from IR to the carboxylate is also pH-dependent, increasing 4-fold between pH 5 and pH 8, such that equilibrium is established more rapidly at higher pH. The carboxylate derivative also appears to be more photosensitive than IR, and at least 5 degradation products are produced under fluorescent light when the ring-opened carboxylate12 h, whereas LV diluted with dextrose 10% in saline is stable for only 6 h.4 The Lederle, Cyanamid Canada product monograph for LV states that the drug is stable for 24 h when diluted in D5W, D10W, or dextrose 10% in saline and stored at room temperature. Lauper and Benvenuto and others reported that LV is stable for 24 h after mixing in D5W, whereas Smith and others demonstrated stability with floxuridine over 72 h. Although these data may be limited to studies of short duration, they suggest that LV should be stable for at least 24 to 72 h when diluted in D5W and stored at room temperature.
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Current protocols for treatment of metastatic colorectal cancer call for sequential administration of 180 mg/m2 of IR and either 200 mg/m2 of l-LV or 400 mg/m2 of the racemic mixture of LV, followed by infusion of 5-fluorouracil (5FU). Approximately 3.5 h is required to sequentially administer the IR (90-min infusion) and LV (120-min infusion). Patients would spend much less time in the clinic, and more patients could potentially be treated in a given period of time, if IR and LV could be administered concurrently.

European data have indicated that IR and LV are stable when administered concurrently. Although that study concluded that IR and LV were physically and chemically compatible (because both precipitate and degradation products were absent from the IR-LV mixture after a 2-h incubation) the L-isomer of LV was used in these experiments. Thus, the stability achieved with IR and racemic LV may not be accurately represented by these results.
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The objective of this study was to evaluate the compatibility of IR diluted in D5W with the racemic mixture of LV also diluted in D5W when mixed together at concentrations typically encountered during Y-site administration at 23°C, in 3 types of containers, unprotected from light.