Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

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 spectrom-etry (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.

BCR::ABL1 tyrosine kinase inhibitors hamper the therapeutic efficacy of blinatumomab in vitro

“…Stock concentrations were 20 mM for DASA, IMA and PONA, and 3 mM for NILO, respectively. Peak and IC 50 concentrations were chosen according to the literature: DASA 150 nM (peak) and 10 nM (IC 50 ); IMA 3000 nM (peak) and 600 nM (IC 50 ); NILO 3000 nM (peak) and 30 nM (IC 50 ); PONA 145 nM (peak) and 70 nM (IC 50 ) (Peng et al 2004 ; Kantarjian et al 2006 , 2010 ; Rix et al 2007 ; Weisberg et al 2007 ; Cortes et al 2012 ; Menna et al 2020 ). Direct effects of DMSO (maximum level was 0.1% v/v in NILO peak samples) were ruled out by including DMSO only as control throughout all experiments.…”

Asciminib Maintains Antibody-Dependent Cellular Cytotoxicity against Leukemic Blasts

“…Peak and IC50 concentrations were chosen based on clinical studies which reported serum levels in patient samples. Peak levels as well as steady-state concentrations (from here on: IC50) were based on these data [20][21][22][23][24][25][26][27]. The concentrations were chosen as follows: ASCI 806 nM (peak) and 28 nM (IC50); BOSU 600 nM (peak) and 2.4 nM (IC50); DASA 150 nM (peak) and 10 nM (IC50); IMA 3000 nM (peak) and 600 nM (IC50); NILO 3000 nM (peak) and 30 nM (IC50); PONA 145 nM (peak) and 70 nM (IC50).…”

Therapeutic drug monitoring for the cancer patient: challenges and opportunities

“…A be useful. Therapeutic windows of 1000-1100 to 3000 ng/ml for imatinib (28)(29)(30), 50 to 100 ng/ml for sunitinib (23,24), 20 to 46-50 ng/ml for pazopanib (25)(26)(27), have been proposed on the basis of TDM.…”

“…Ponatinib was approved at the dose of 45 mg/day, which resulted in plasma concentrations significantly higher than those associated with antileukemic activity (40 nM): however, ponatinib caused serious cardiovascular toxicity when used at this dose level (28). Continued TDM may allow for reducing ponatinib dose to 15-30 mg/day, with this regimen causing plasma concentrations of approximately 40 nM while also reducing risk of cardiovascular events (29,30).…”