Potential Drug-Drug Interactions with Combination Volasertib + Itraconazole: A Phase I, Fixed-sequence Study in Patients with Solid Tumors
Istvan Lang, Dan Liu, Holger Fritsch, Tillmann Taube, Evgenii Chizhikov, Bela Liptai, Istvan Lang, Dan Liu, Holger Fritsch, Tillmann Taube, Evgenii Chizhikov, Bela Liptai
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.
Keywords: Polo-like kinase 1; itraconazole; pharmacokinetics; volasertib.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed