Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies

Abstract

Background: This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide.

Methods: Patients with advanced solid tumours, good performance score, good organ function, and no standard therapy available were eligible. Continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g m(-2) for 3 days or 6 g m(-2) for 5 days, administered every 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed.

Results: With growth-factor support, the MTD of sunitinib combined with either ifosfamide schedule was 12.5 mg in 32 patients enrolled. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed.

Conclusion: With growth-factor support, the MTD of sunitinib with both ifosfamide schedules was 12.5 mg. Ifosfamide produced decreased sunitinib blood levels because of CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this also holds true for anti-tumour activity needs to be further explored.

Figure 1

Mean concentrations (plus s.d.) of ifosfamide, 4-hydroxy-ifosfamide (4-OH-ifosfamide), 2-dechloroethyl-ifosfamide (N2-DCE-ifosfamide), and 3-dechloroethyl-ifosfamide (N3-DCE-ifosfamide) administered alone (open red symbols: bars up) or in combination with sunitinib (closed blue symbols, bars down) during the 3-day (open and closed circles) and 5-day (open and closed triangles) continuous infusions (The colour reproduction of this figure is available on the html full text version of the manuscript).

Figure 2

Individual plasma concentration time curves of sunitinib in combination with 3-day (n=6) and 5-day (n=5) ifosfamide schedule (upper graphs) and of SU12662 in combination with 3-day (n=6) and 5-day (n=5) ifosfamide schedule (lower graphs). One patient in the 5-day schedule has not been included in the figure as cycle two was delayed by 2 weeks. Bars represent the ifosfamide infusion schedules and arrows the first sunitinib administrations.

Figure 3

Absolute concentration of sunitinib (upper panel), SU12262 (middle panel), and the sum of sunitinib plus SU12662 (lower panel) in patients after the 3-day and 5-day continuous infusions of ifosfamide. P-values (Wilcoxon signed rank test) of significant lower or higher relative trough concentrations compared with the trough concentrations observed before the start of ifosfamide infusions (that is, day 0, lime bars) are presented. Day –1 (brown bars) is the sample taken the day before the start of ifosfamide infusion and days 1 (red bars), 2 (blue bars), and 3 (rose bars) are the samples taken 24, 48, and 72 h after the start of ifosfamide infusions, respectively. Data are presented as the mean±s.d. of six observations; n=5 for day 2 in the 3-day schedule (The colour reproduction of this figure is available on the html full text version of the manuscript).

Figure 4

Linear relationship (R²=0.47; P=0.019) between auto-induction of ifosfamide and decrease in sunitinib trough concentrations during the 3-day (closed red circles) and 5-day (closed blue triangles) ifosfamide infusions (The colour reproduction of this figure is available on the html full text version of the manuscript).