Potential Drug-Drug Interactions with Combination Volasertib + Itraconazole: A Phase I, Fixed-Sequence Study in Patients with Solid Tumors.

Abstract Purpose This drug–drug interaction study determined whether the metabolism and distribution of the Polo-like kinase 1 inhibitor, volasertib, is affected by co-administration of the P-glycoprotein and cytochrome P-450 3A4 inhibitor, itraconazole. Methods This was an uncontrolled, open-label, fixed-sequence trial of two 21-day treatment cycles in patients with various solid tumors. In cycle 1 (test), eligible patients were administered volasertib (day 1) plus itraconazole (days −3 to 15). In cycle 2 (reference), patients received volasertib monotherapy. The primary end point was the influence of co-administration of itraconazole on the pharmacokinetic profile (AUC0–tz; Cmax) of volasertib and its main metabolite, CD 10899, compared with that of volasertib monotherapy. Other end points included tolerability and preliminary therapeutic efficacy. Findings Concurrent administration of itraconazole resulted in a slight reduction in the AUC0–tz (geometric mean ratio, 93.6%; 90% CI, 82.1%–106.8%) and a 20% reduction in Cmax (geometric mean ratio, 79.4%; 90% CI, 64.9%–97.1%) of volasertib compared with monotherapy. Of note, concurrent administration of itraconazole + volasertib had no effect on the AUC0–∞ of volasertib. More patients reported at least one drug-related adverse event in cycle 1 than in cycle 2 (75% vs 71%). The most commonly reported drug-related adverse events (cycles 1 and 2) were thrombocytopenia (68% and 33%, respectively), leukopenia (50% and 46%), and anemia (36% and 33%). No objective responses were observed. Stable disease was observed in 25 of 28 patients (89%). Implications While there was no clear evidence of a pharmacokinetic interaction between volasertib and itraconazole, co-administration reduced the tolerability of volasertib. Clinicaltrials.gov identifier: NCT01772563.