Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Chemotherapy, ISSN: 1421-9794, Vol: 65, Issue: 1-2, Page: 35-41
2020
- 3Citations
- 13Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
Citation Benchmarking is provided by Scopus and SciVal and is different from the metrics context provided by PlumX Metrics.
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- Citations3
- Citation Indexes3
- CrossRef3
- Captures13
- Readers13
- 13
Article Description
Introduction: Ponatinib (PNT) is a tyrosine kinase inhibitor approved for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), or chronic myeloid leukemia, resistant or intolerant to other tyrosine kinase inhibitor or showing T315I mutation of BCR-ABL. Unfortunately, the clinical use of PNT is limited by the possible occurrence of vascular occlusive events. The incidence of vascular events seems to correlate with PNT dose intensity and plasma exposure. Dose reductions from 45 mg to 30 or 15 mg/day are increasingly considered to improve PNT safety but a plasma threshold of ∼40 nM must be achieved to ensure that antileukemic activity is preserved. Therapeutic drug monitoring (TDM) would be appropriate for patients treated by PNT. We, therefore, developed and validated a liquid chromatography tandem mass spectrometry (HPLC-MS/MS) assay to measure PNT plasma levels. Methods: PNT and its deuterated internal standard were extracted from human plasma by one-step protein precipitation. PNT was separated and quantified by HPLC-MS/MS operating in the multiple reaction monitoring acquisition mode. Results: The method was linear from 9.4 to 940 nM PNT. Limits of detection and lower limits of quantification (LLOQ) were, respectively, 1 and 9.4 nM. Selectivity, sensitivity, matrix effect, short-, and long-term stability met criteria of international guidelines for bioanalytical method validation. Intra- and inter-day accuracy and precision were calculated on 4 different concentrations (QCLow, QCMedium, QCHigh, and LLOQ), with all values being <15%. The method was successfully probed in leukemia Ph + ALL patients to show that PNT doses <45 mg/day caused lower plasma exposure but still achieved PNT levels at or above the 40 nM threshold. Conclusions: We developed a highly sensitive and selective HPLC-MS/MS method to quantify PNT in human plasma. This method might be used for TDM and to guide dose reductions if unnecessary high PNT levels are detected in a patient.
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