A drug–drug interaction study to assess the potential effect of acid-reducing agent, lansoprazole, on quizartinib pharmacokinetics

A drug–drug interaction study to assess the potential effect of acid-reducing agent, lansoprazole, on quizartinib pharmacokinetics:

Abstract

Purpose

Quizartinib, a potent, selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, is currently in phase 3 development for patients with FLT3–internal tandem duplication-mutated acute myeloid leukemia (AML). Acid-reducing agents (ARAs; e.g., proton pump inhibitors) are frequently used during AML treatment. Since quizartinib demonstrates pH-dependent solubility, the effect of lansoprazole coadministration on pharmacokinetics (PK) of quizartinib tablet formulation was assessed.

Methods

An open-label, parallel-group study randomized 64 healthy adults to single-dose quizartinib 30 mg alone (reference) or lansoprazole (60 mg once daily, days 1–5) + single-dose quizartinib 30 mg (day 5) (test). Plasma concentrations of quizartinib and its active metabolite, AC886, were measured to 504 h postdose; the effect of lansoprazole on quizartinib PK was assessed by analysis of variance.

Results

Quizartinib geometric mean ratios (test/reference) and 90% confidence intervals for maximum observed plasma concentration (C_max), area under the concentration–time curve to last measurable drug concentration (AUC_last), and AUC to infinity were 86.11% (78.4%, 94.6%), 93.96% (79.6%, 110.9%), and 95.30% (80.2%, 113.3%), respectively. Comparisons showed a modest decrease in quizartinib absorption when co-administered with lansoprazole, with lower limits for C_max and AUC_last just below 80–125% limits. Treatment-emergent adverse events were mild or moderate; the most frequent in either treatment group were headache [quizartinib alone: (n = 3) 10%], upper respiratory tract infection [quizartinib alone: (n = 2) 6.7%; lansoprazole + quizartinib: (n = 3) 9.1%], and muscle tightness [quizartinib alone: (n = 2) 6.7%].

Conclusions

Concomitant lansoprazole had minimal effect on quizartinib PK as a formulated tablet, indicating that quizartinib can be administered with ARAs.