Abstract
PurposeQuizartinib, 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.MethodsAn 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.ResultsQuizartinib 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%].ConclusionsConcomitant lansoprazole had minimal effect on quizartinib PK as a formulated tablet, indicating that quizartinib can be administered with ARAs.
Highlights
The majority of patients with acute myeloid leukemia (AML) have poor prognosis despite recent advances in therapy because of disease heterogeneity driven by clonal
We report results from a phase 1 study that examined the effects of lansoprazole, a pump inhibitors (PPIs), on the PK of quizartinib and its active metabolite AC866
For AC886 at the lower limit of quantitation (LLOQ), precision was 6.0% coefficient of variation (CV) and accuracy was 0.2% bias across 14 runs; accuracy ranged from −7.9 to 10.6% bias within runs
Summary
The majority of patients with acute myeloid leukemia (AML) have poor prognosis despite recent advances in therapy because of disease heterogeneity driven by clonal. Patients with mutations in the internal tandem duplication (ITD) region of the FMS-like tyrosine kinase 3 (FLT3) gene, one of the most common driver mutations in AML, have poor prognosis following conventional chemotherapy [1, 2, 4]. Quizartinib is an orally administered, highly potent and selective next-generation FLT3 inhibitor currently in phase 3 development in patients with FLT3–ITD-mutated AML (QuANTUM-R: NCT02039726; QuANTUM-First: NCT02668653). Quizartinib treatment in previous phase 2 trials demonstrated composite complete remission (CRc) rates of 44–47% in patients with relapsed or refractory FLT3–ITD-mutated AML, and 34–42% of patients were bridged to potentially curative hematopoietic stem cell transplant [5,6,7]. Quizartinib was generally well tolerated; the main adverse events (AEs) were manageable myelosuppression and QT prolongation that was
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call