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The estimated pharmacokinetic curve by population pharmacokinetic analysis over 24 h and the measured samples
Source publication
Purpose:
Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients.
Methods:
The dasatinib concentration requir...
Citations
... However, like with nilotinib, no differences were observed in progression-free survival or overall survival between patients treated with imatinib and dasatinib [120]. The peak plasma levels after daily administration of 100 mg dasatinib ranged from 12 to 493 nM [121]. Dasatinib is an active site type I inhibitor and has shown to be highly effective against most of the clinically relevant imatinib-resistant BCR::ABL1 isoforms except for the T315I mutation [122,123]. ...
Chronic myeloid leukemia (CML) is a hematologic neoplasm characterized by the expression of the BCR::ABL1 oncoprotein, a constitutively active tyrosine kinase, resulting in uncontrolled growth and proliferation of cells in the myeloid lineage. Targeted therapy using tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib has drastically improved the life expectancy of CML patients. However, treatment resistance occurs in 10–20% of CML patients, which is a multifactorial problem that is only partially clarified by the presence of TKI inactivating BCR::ABL1 mutations. It may also be a consequence of a reduction in cytosolic TKI concentrations in the target cells due to transporter-mediated cellular distribution. This review focuses on drug-transporting proteins in stem cells and progenitor cells involved in the distribution of TKIs approved for the treatment of CML. Special attention will be given to ATP-binding cassette transporters expressed in lysosomes, which may facilitate the extracytosolic sequestration of these compounds.
... Dasatinib exhibits exposure time-dependent effect where plasma concentrations above inhibitory concentration (IC 50 CD 34+ cells) for more than 12.8 h led to a better clinical response [19]. Therefore, the efficacious levels may be expected to be a prerequisite for sufficient therapeutic response and well predictable in case of low variation. ...
Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00–125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.
In a drug–drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.
The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
... 9,16 Obtaining optimal dasatinib plasma exposure-time profiles is clinically important in CML as high plasma concentrations increases the risk of adverse effects, while the anti-leukemic effect appears suboptimal when below the defined threshold concentrations over time. [17][18][19] Several practical solutions have been suggested to avoid drug-drug interactions between dasatinib and gastric acid regulators. These include dose separation, 16 co-administration of dasatinib with betaine-hydrochloride, 13 and co-administration of dasatinib with acidic soft drinks. ...
Background
Dasatinib and other tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML). However, as a lipophilic weak base, crystalline monohydrate, dasatinib (Sprycel®) is poorly soluble, rendering a pH‐dependent absorption and a highly variable bioavailability. Thus, co‐medication with proton pump inhibitors (PPI) profoundly impairs dasatinib uptake and is clearly recommended against.
XS004 is a novel oral immediate release and amorphous solid dispersion (ASD) formulation of dasatinib and is bioequivalent to the original crystalline dasatinib at 30% lower dosages. XS004 is designed to mitigate gastric pH dependency, thus optimizing absorption and bioavailability.
Methods
We investigated the prevalence of dasatinib and PPI co‐medication among chronic‐phase CML patients in a real‐world setting and assessed the plasma pharmacokinetics (PK) of XS004 with and without PPI co‐medication (omeprazole) in healthy volunteers.
Results
Using the Swedish CML and Prescribed Drug Registers, we identified 676 TKI‐treated CML patients; 320 (47%) had been prescribed PPI at some point after CML diagnosis. Among dasatinib‐treated patients, the 2‐year cumulative PPI co‐medication was 24%. Interestingly, the 5‐year overall survival was significantly lower for TKI‐treated CML patients with versus without PPI co‐medication (79% vs. 94%; hazard ratio 3.5; 95% confidence interval, 2.1–5.3; p < .0001).
When assessing PK of XS004, neither Cmax nor area under the plasma concentration curve levels in plasma were significantly altered by the PPI co‐medication.
Conclusion
In conclusion, despite warnings, PPI co‐medication is common among dasatinib‐treated CML patients in a real‐world setting. The new XS004 ASD formulation of dasatinib provided, in contrast to original crystalline dasatinib, superior pH independence with stable bioavailability, thereby minimizing drug–drug interactions. This may improve the long‐term efficacy and tolerability of dasatinib in CML.
... The maximum inhibition reached at ~ 3 h after the dose and got completely reversed after 24 h. In general, recovery and inhibition seemed dosedependent a directly correlated with the plasma level of dasatinib at different doses [26]. ...
... Dasatinib is a new, oral, and multi-targeted inhibitor of tyrosine kinase, which has time-dependent properties for showing anti-leukemic effects and also improves prognosis after 12.8 h. exposure to the drug [26]. Absorption of dasatinib is remarkable and shows its effect on gastric pH and if there is any change in the pH of the gut then the interactions must take place by modulation [19]. ...
Dasatinib is the 2nd generation TKI (Tyrosine Kinase Inhibitor) having the potential to treat numerous forms of leukemic and cancer patients and it is 300 times more potent than imatinib. Cancer is the major cause of death globally and need to enumerate novel strategies to coping with it. Various novel therapeutics introduced into the market for ease in treating various forms of cancer. We reviewed and evaluated all the related aspects of dasatinib, which can enhance the knowledge about dasatinib therapeutics methodology, pharmacodynamic and pharmacokinetics, side effects, advantages, disadvantages, various kinds of interactions and its novel formulations as well.
... dasatinib and ponatinib in BCR::ABL1 leukemias can be used as a benchmark for these agents in LCK-activated T-ALL. In chronic myeloid leukemia (CML) patients, dasatinib exposure was considered as sufficient to elicit a clinical response if the time above 50% pCRKL inhibition is 12.8 h per day [46]. This is in line with our estimated duration of pLCK inhibition in human T-ALL by dasatinib at 140 mg and ponatinib at 45 mg once daily in human T-ALL. ...
LCK is a novel therapeutic target in ~40% of T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib can act as LCK inhibitors with therapeutic effects. We herein report a comprehensive preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib in LCK-activated T-ALL. In 51 human T-ALL cases, these two drugs showed similar patterns of cytotoxic activity, with ponatinib being slightly more potent. Given orally in mice, ponatinib was associated with slower clearance with a longer Tmax and higher AUC0-24 h, although maximum pLCK inhibition was comparable between the two drugs. After establishing the exposure-to-response models, we simulated the steady-state pLCK inhibitory effects of each drug at currently approved dosages in humans: dasatinib at 140 mg and ponatinib at 45 mg once daily are both sufficient to achieve >50% pLCK inhibition for 13.0 and 13.9 h/day, respectively, comparable to pharmacodynamic profiles of these agents in BCR::ABL1 leukemias. Moreover, we developed a dasatinib-resistant T-ALL cell line model with LCK T316I mutation, in which ponatinib retained partial activity against LCK. In conclusion, we described the pharmacokinetic and pharmacodynamic profiles of dasatinib and ponatinib as LCK inhibitors in T-ALL, providing critical data for the development of human trials of these agents.
... Thus, the bioavailability of ASD was 198.7 and 145.7% when calculated with respect to AUC0-∞ and Cmax, respectively compared to PM. A plasma concentration Cmax of 50 ng/mL is required to maintain clinical response and Cmin concentration of <2.5 ng/mL is required to avoid pleural effusion [46][47][48]. A Cmin concentration of 2.5 ± 2.0 and 3.1 ± 0.6 ng/mL was achieved at 24 h in PM and ASD, respectively. ...
... Thus, the bioavailability of ASD was 198.7 and 145.7% when calculated with respect to AUC 0-∞ and C max , respectively compared to PM. A plasma concentration C max of 50 ng/mL is required to maintain clinical response and C min concentration of <2.5 ng/mL is required to avoid pleural effusion [46][47][48]. A C min concentration of 2.5 ± 2.0 and 3.1 ± 0.6 ng/mL was achieved at 24 h in PM and ASD, respectively. ...
The aim of this study was to improve the physicochemical properties and oral bioavailability of dasatinib (DST) by the amorphous solid dispersion (ASD) approach using cellulose acetate butyrate (CAB) as a carrier. Various formulations of ASD (DST:CAB 1:1 to 1:5) were prepared by the solvent evaporation method. ASDs were characterized for physicochemical attributes, stability and pharmacokinetics. Scanning electron microscopy, Fourier transformed infrared, X-ray powder diffraction, and differential scanning calorimetry confirmed the transformation of the crystalline drug into amorphous phase. ASD formation resulted in a 3.7–4.9 fold increase in dissolution compared to DST or physical mixture. The ASDs formulation exhibited relative stability against transformation from the unstable amorphous phase to a stable crystalline phase that was indicated by spectral and X-ray powder diffraction data, and insignificant (p > 0.05) decrease in dissolution. Tmax, Cmax and AUC0-∞ of ASD were 4.3-fold faster and 2.0 and 1.5 fold higher than the corresponding physical mixture. In conclusion, the ASD of DST significantly improved dissolution and oral bioavailability which may be translated into a reduction in dose and adverse events.
... That said, the teratogenicity of imatinib is reported to be due to off-target, most likely inhibition of the mast/stem cell growth factor receptor (c-kit), platelet-derived growth factor (PDGFR) during organogenesis [15]. The second-generation TKIs also affect multiple receptor tyrosine kinases, including the proto-oncogene c-Src and the ephrin receptor kinases [16]. The literature suggests that children born to men taking imatinib at conception did not increase the risk for congenital malformations [17]. ...
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) that accounts for 10% of pregnancy-associated leukemias. The Philadelphia chromosome balanced translocation, t (9:22) (q34; q11.2), is the classic mutation seen in CML. The BCR-ABL oncoprotein encoded by this mutation is a constitutively active tyrosine kinase. Tyrosine kinase inhibitor (TKI) therapy is considered a first-line treatment for CML. However, the literature has revealed risks of teratogenicity with TKI therapy during pregnancy. Understanding the risks and benefits of TKI therapy and alternative therapies such as interferon-alpha (IFN-α) will help clinicians and pregnant patients develop a personalized CML treatment plan. This manuscript presents a case series detailing the management of five pregnancies in two pregnant patients with CML and a literature review of CML management in pregnancy.
... Very high interpatient variability of dasatinib exposure was observed on maximum plasma drug concentration (C max ), 70-80%, and on area under the plasma concentration-time curve (AUC), 40-54% Ishida et al., 2016;Chandani et al., 2017). Moreover, one study suggested that the variability in exposure of dasatinib was greater within subjects than between subjects (Dai et al., 2008). ...
Dasatinib is an oral second-generation tyrosine kinase inhibitor known to be used widely in Philadelphia chromosome-positive (Ph⁺) chronic myeloid leukemia (CML) and Ph⁺ acute lymphoblastic leukemia (ALL). Notably, although a high pharmacokinetic variability in patients and an increased risk of pleural effusion are attendant, fixed dosing remains standard practice. Retrospective studies have suggested that dasatinib exposure may be associated with treatment response (efficacy/safety). Therapeutic drug monitoring (TDM) is gradually becoming a practical tool to achieve the goal of individualized medicine for patients receiving targeted drugs. With the help of TDM, these patients who maintain response while have minimum adverse events may achieve long-term survival. This review summaries current knowledge of the clinical pharmacokinetics variation, exposure-response relationships and analytical method for individualized dosing of dasatinib, in particular with respect to therapeutic drug monitoring. In addition, it highlights the emerging insights into several controversial issues in TDM of dasatinib, with the aim of presenting up-to-date evidence for clinical decision-making and insights for future studies.
... Previous investigations indicated that both pharmacokinetic and pharmacodynamic analyses were essential to achieve the best therapeutic effect of dasatinib treatment. 29,30 Therefore, the initial dose of dasatinib for newly diagnosed patients with chronic myeloid leukaemia in the chronic phase might need to be re-examined. ...
Background
BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase.
Methods
DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0–2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period.
Findings
Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5–83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48–71), with a median follow-up of 366 days (IQR 353–372). Grade 3–4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3–4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed.
Interpretation
Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population.
Funding
Bristol-Myers Squibb.
... Additionally, there was synergism for the dasatinib and hydrocortisone combination for the glucocorticoid activity in the MDA-kb2 cell line. We observed the effects of TKIs on nuclear receptors at concentrations in the range of maximal therapeutic concentrations or lower, i.e., at 1 μM for dasatinib (Broniscer et al., 2018;Duska et al., 2019;Ishida et al., 2016), at 100 nM for erlotinib (Bigot et al., 2017;Gruber et al., 2018;Lankheet et al., 2014), at 10 nM for ibrutinib (De Jong et al., 2015;Tobinai et al., 2016;Yasu et al., 2019), at 5 μM for imatinib (Belsey et al., 2021;Peng et al., 2005), at 100 nM for nilotinib (Larson et al., 2012;Miura, 2015), at 100 nM for regorafenib (Bruix et al., 2013;Mross et al., 2012), and at 2.5 μM for sorafenib (Fucile et al., Furuse et al., 2008). We did not see effects of TKIs on nuclear receptors at predicted or measured environmental concentrations, which are up to 10 nM in surface water for all TKIs studied, namely up to 7.3 ng/mL for ibrutinib (CHMP, Committee for Medicinal Products for Human Use, 2016); 8.1 ng/L for erlotinib (Isidori et al., 2016); 37.8 ng/L for sorafenib (CHMP, Committee for Medicinal Products for Human Use, 2014); 577 ng/L for imatinib (Olalla et al., 2018); 600 ng/L for regorafenib (CHMP, Committee for Medicinal Products for Human Use, 2013); 1800 ng/mL for dasatinib (CHMP, Committee for Medicinal Products for Human Use, 2018); 4000 ng/mL for nilotinib (CHMP, Committee for Medicinal Products for Human Use, 2017). ...
... Conversely, we have shown here that dasatinib has antiestrogenic activity with an IC 50 of 0.5 μM. This is the most potent antiestrogenic activity we observed with any of the TKIs tested here, and it is in the range of the maximum plasma concentration of dasatinib in patients (Duska et al., 2019;Ishida et al., 2016). Interestingly, we also observed strong glucocorticoid activity of dasatinib, although this was only evident in combination with plasma levels of hydrocortisone, and not with dasatinib alone. ...
Modern anticancer therapies favor a targeted approach. Tyrosine kinase inhibitors (TKIs) are drugs that target molecular pathways involved in various types of malignancies. Although TKIs are safe and well tolerated, they remain not completely selective; e.g., endocrine-mediated adverse events have been observed with their use. In the present study, the effects of seven TKIs were determined on the activities of androgen receptor, estrogen receptor α (ERα), glucocorticoid receptor and thyroid receptor in vitro using stably transfected cell lines expressing firefly luciferase reporter gene: AR-EcoScreen, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cells, respectively. Antiandrogenic activity was seen for erlotinib, estrogenic activity for imatinib, antiestrogenic activity for dasatinib, erlotinib, nilotinib, regorafenib and sorafenib, glucocorticoid activity for erlotinib and ibrutinib, antiglucocorticoid activity for regorafenib and sorafenib, and antithyroid activity for ibrutinib. Additionally, synergism was seen for 1–5 μM dasatinib and 500 nM hydrocortisone combination for glucocorticoid activity in MDA-kb2 cells. The estrogenic activity of imatinib was confirmed as mediated through ERα, and interference of the TKIs with the reporter gene assays was ruled out in a cell-lysate-based firefly luciferase enzyme inhibition assay. Imatinib in combination with 4-hydroxytamoxifen showed concentration-dependent effects on the metabolic activity of ERα-expressing AN3CA, MCF-7, and SKOV3 cells, and on cell proliferation and adhesion of MCF-7 cells. These findings contribute to the understanding of the endocrine effects of TKIs, in terms of toxicity and effectiveness, and define the need to further evaluate the endocrine disrupting activities of TKIs to safeguard human and environmental health.
