Pazopanib exposure decreases as a result of an ifosfamide-dependent drug-drug interaction: results of a phase I study

Abstract

Background: The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.

Methods: In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m(-2) per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.

Results: Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.

Conclusion: Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m(-2) per cycle, every 3 weeks) is 800 mg daily.

Figure 1

Study design. Abbreviation: Ifos=ifosfamide.

Figure 2

Mean concentrations (plus s.d.) of ifosfamide administered alone (closed symbols: bars up) or in combination with pazopanib (open symbols, bars down) during the 3 days continuous infusions.

Figure 3

Mean concentrations (plus s.d.) of ifosfamide administered alone (closed symbols, bars up) or in combination with pazopanib (open symbols, bars down) during 3 consecutive bolus infusion days.

Figure 4

Median plasma pazopanib concentration time profile (dose escalation, in patients with continuously given ifosfamide).

Figure 5

Pazopanib AUC administered as single agent (day 21, cycle 1) vs combined administration with continuous ifosfamide (day 3, cycle 2) in the dose expansion phase.