Simulation of Y-Site Compatibility of Irinotecan and Leucovorin at Room Temperature in 5% Dextrose in Water in 3 Different Containers

ABSTRACT Background: No data are available on the physical compatibility and chemical stability of irinotecan and leucovorin when these 2 drugs are mixed. Objective: The objective of this study was to evaluate the physical compatibility and chemical stability of irinotecan diluted in 5% dextrose in water (D5W) and combined with the racemic form of leucovorin when stored at 23°C, unprotected from light, conditions that simulate Y-site administration of these drugs. Methods: Six combinations of irinotecan and leucovorin were prepared (0.56 mg/mL and 0.94 mg/mL, 0.53 mg/mL and 0.74 mg/mL, 0.59 mg/mL and 0.66 mg/mL, 0.56 mg/mL and 0.27 mg/mL, 0.32 mg/mL and 3.60 mg/mL, and 0.30 mg/mL and 0.68 mg/mL, respectively), representing the concentrations (dose, volume, and infusion rate) most commonly administered in clinical practice. The stability of each solution was evaluated at room temperature (23°C) in 3 different types of containers: polyvinyl chloride (PVC), polypropylene–polyethylene copolymer, and glass (control). Each solution was visually inspected for precipitate, colour change, and evolution of gas, and the concentration of each drug was measured by high-performance liquid chromatography at time 0 (immediately after mixing) and at 0.5, 1, and 24 h. Each concentration measurement was completed in triplicate. Results: All solutions remained clear and colourless throughout the 24-h study period. More than 96% of the initial concentration of leucovorin and more than 91% of the initial concentration of irinotecan remained after 0.5 h. Rapid degradation of irinotecan was observed in one mixture: irinotecan 0.30 mg/mL and leucovorin 3.60 mg/mL. In this mixture, the concentrations of irinotecan were between 91.57% and 95.09% of the original concentration at 0.5 h, but declined rapidly to between 76.30% and 78.34% by 24 h. This rapid degradation was likely due to the higher pH of the solution created by the high concentration of leucovorin (3.60 mg/mL, equivalent to a dose of 400 mg/m2 body area, in 100 mL, for a 60-min infusion). For all mixtures, the mean concentration of leucovorin at 24 h was greater than 96% of the initial concentration. There was no effect of container type on the rate of degradation of either drug. Conclusions: Given that contact times are likely less than 3 min when standard IV tubing sets are used, it is concluded that irinotecan and leucovorin are physically compatible and chemically stable for a sufficient period of time to allow concurrent infusion via a Y site. RESUME Historique : On ne dispose d’aucune donnee sur la compatibilite physique et la stabilite chimique de l’irinotecan et de la leucovorine lorsque ces deux medicaments sont melanges ensemble. Objectif : Evaluer la compatibilite physique et la stabilite chimique de l’irinotecan dilue dans une solution de dextrose a 5 % dans l’eau (D5W) et melange au compose racemique de leucovorine, puis entrepose a 23 oC, non protege de la lumiere, dans des conditions simulant l’administration de ces medicaments dans un raccord en Y. Methodes : Six melanges d’irinotecan et de leucovorine ont ete prepares (0,56 mg/mL et 0,94 mg/mL; 0,53 mg/mL et 0,74 mg/mL; 0,59 mg/mL et 0,66 mg/mL; 0,56 mg/mL et 0,27 mg/mL; 0,32 mg/mL et 3,60 mg/mL; et 0,30 mg/mL et 0,68 mg/mL, respectivement), representant les concentrations (dose, volume et vitesse de perfusion) les plus frequemment administrees en pratique clinique. On a evalue la stabilite de chaque solution a la temperature ambiante (23 oC) et dans trois differents types de contenants : polychlorure de vinyle (PVC), copolymere de polypropylene et polyethylene, et verre (temoin). Chaque solution a ete inspectee visuellement pour la presence d’un precipite, un changement de couleur et le degagement de gaz, et la concentration de chaque medicament a ete mesuree par chromatographie liquide a haute pression au temps 0 (immediatement apres le melange) puis a 0,5, 1 et 24 h. La concentration de chaque medicament a ete mesuree en triple. Resultats : Toutes les solutions sont demeurees limpides et incolores au cours des 24 heures qu’a dure l'etude. Les solutions ont conserve plus de 96 % de la concentration initiale de leucovorine et plus de 91 % de la concentration initiale d’irinotecan apres 0,5 h. On a observe une degradation rapide de l’irinotecan dans un des melanges : irinotecan a 0,30 mg/mL et leucovorine a 3,60 mg/mL. Dans ce melange, les concentrations d’irinotecan etaient entre 91,57 % et 95,09 % des concentrations initiales a 0,5 h, et elles ont rapidement chute entre 76,30 % et 78,34 % a 24 h. Cette degradation rapide semblait etre attribuable au pH plus eleve de la solution, cause par la forte concentration de leucovorine (3,60 mg/mL, equivalant a une dose de 400 mg/m2 de surface corporelle, dans 100 mL, administree par perfusion d’une duree de 60 minutes). Tous les melanges ont retenu plus de 96 % de la concentration moyenne initiale de leucovorine a 24 h. Le type de contenant n’a pas eu d’effet sur le taux de degradation de l’un ou l’autre medicament. Conclusions : Etant donne que la duree de contact est probablement inferieure a trois minutes avec les tubulures IV standard, on peut conclure que l’irinotecan et la leucovorine sont physiquement compatibles et chimiquement stables durant une periode de temps suffisante pour permettre la perfusion concomitante dans un raccord en Y.

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