Chemotherapy
Anticancer Section / Original Paper
Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic LeukemiaMenna P.a · De Grazia U.b · Marchesi F.c · Minotti G.d · Salvatorelli E.daClinical Pharmacology Unit, Campus Bio-Medico University Hospital, Rome, Italy
bFondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, Italy cHematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy dDrug Sciences, Department of Medicine and Center for Integrated Research, University Campus Bio-Medico, Rome, Italy |
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Article / Publication Details
Received: June 09, 2020
Accepted: June 22, 2020
Published online: August 21, 2020
Issue release date: September 2020
Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 2
ISSN: 0009-3157 (Print)
eISSN: 1421-9794 (Online)
For additional information: https://www.karger.com/CHE
Abstract
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.
© 2020 S. Karger AG, Basel
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Article / Publication Details
Received: June 09, 2020
Accepted: June 22, 2020
Published online: August 21, 2020
Issue release date: September 2020
Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 2
ISSN: 0009-3157 (Print)
eISSN: 1421-9794 (Online)
For additional information: https://www.karger.com/CHE
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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