Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.

PURPOSE: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. METHODS: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. RESULTS: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. CONCLUSION: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

[Stability of 5-fluorouracil-folinic acid mixture: influence of concentrations, container and form of folinic acid]. / Stabilité du mélange 5-fluoro-racil-acide folinique: influence des concentrations, du contenant et de la forme de l'acide olinique.

Since the discovery of the superiority of the combination 5-fluorouracil (5FU)-folinic acid (FA) in comparison to 5FU alone in the treatment of gastrointestinal cancers, the interest of this association has been demonstrated in many other tumors. In the treatment of advanced colorectal carcinoma, FA is usually administered in 1 or 2 h infusion before 5FU. In treatment of other cancers, the two drugs are generally mixed together in the same container and administered as a continuous intravenous infusion over several days. Many studies have demonstrated the stability of 5FU alone in different vials, but results about compatibility of 5FU with AF in racemate (d,l) or levogyre (l) forms are conflicting. The aim of our study was to determine the influence of the container, the concentrations of the two drugs and the form of folinic acid (d, l or l) on the stability of the 5 FU-FA admixtures. Based on drug concentrations corresponding to current 5FU-FA chemotherapeutic protocols, 5FU was used at 50 mg/ml and 6.5 mg/ml in association with equitherapeutic and equimolar doses of FA respectively. Each association has been studied in three types of containers. For all combinations with 5FU 50 mg/ml, flocculation was noted, whatever form or concentration of FA which associated. No influence of the type of containers was noted. No precipitate was observed with the combinations 5FU 6.5 mg/ml. The evolution of the concentrations of 5FU and FA with time have been compared with a regression straight corresponding to a loss of product of 10% in 96 h. The mixtures 5FU 6.5 mg/ml with FA (d,l) 4 mg/ml and FA (l) 2 and 4 mg/ml remained stable in the three types of container. When a precipitate was noted (with 5FU 50 mg/ml), the concentration of 5FU decreased with time, whereas FA was stable in racemate and levogyre forms. Analysis of the precipitate showed that principally 5FU and equal parts of FA and calcium constituted it. Our results allowed to conclude that 5FU mixed with FA (d,l or l) 2 mg/ml and 4 mg/ml remained stable during 96 h in glass vials, PVC infusion bags and cassettes for portable pump in normal conditions of temperature and light. A precipitate of 5FU appears systematically with the concentration 50 mg/ml. These findings do not confirm those obtained in previously published studies. It seems that the precipitation is more a result of the decline of 5FU solubility at high concentrations than the form of folinic acid associated.