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A drug–drug interaction study to assess the potential effect of acid-reducing agent, lansoprazole, on quizartinib pharmacokinetics
- Source :
- Cancer Chemotherapy and Pharmacology
- Publication Year :
- 2019
- Publisher :
- Springer Berlin Heidelberg, 2019.
-
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 (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. Electronic supplementary material The online version of this article (10.1007/s00280-019-03915-1) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Adult
Male
Cancer Research
medicine.drug_class
Drug interaction
Cmax
Lansoprazole
Proton-pump inhibitor
Antineoplastic Agents
Pharmacology
Proton pump inhibitor
Toxicology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Pharmacokinetics
AML
medicine
Humans
Pharmacology (medical)
Drug Interactions
Benzothiazoles
Adverse effect
Active metabolite
Quizartinib
Dose-Response Relationship, Drug
business.industry
Phenylurea Compounds
Proton Pump Inhibitors
Gastric acid modifier
Middle Aged
Leukemia, Myeloid, Acute
030104 developmental biology
Treatment Outcome
Oncology
chemistry
fms-Like Tyrosine Kinase 3
030220 oncology & carcinogenesis
Original Article
Female
Drug Monitoring
business
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14320843 and 03445704
- Volume :
- 84
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Cancer Chemotherapy and Pharmacology
- Accession number :
- edsair.doi.dedup.....c74ada719d85b42877692c3f711f1cd0