A drug-drug interaction study to assess the potential effect of acid-reducing agent, lansoprazole, on quizartinib pharmacokinetics.
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 (Cmax), area under the concentration-time curve to last measurable drug concentration (AUClast), 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 Cmax and AUClast 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.
['Li|Jianke|J|', 'Trone|Denise|D|', 'Mendell|Jeanne|J|', "O'Donnell|Patrick|P|", 'Cook|Natalie|N|']
D000328:Adult D000970:Antineoplastic Agents D052160:Benzothiazoles D004305:Dose-Response Relationship, Drug D004347:Drug Interactions D016903:Drug Monitoring D005260:Female D006801:Humans D064747:Lansoprazole D015470:Leukemia, Myeloid, Acute D008297:Male D008875:Middle Aged D010671:Phenylurea Compounds D054328:Proton Pump Inhibitors D016896:Treatment Outcome D051941:fms-Like Tyrosine Kinase 3
Quizartinib AML Proton pump inhibitor Drug interaction Gastric acid modifier