Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute Kidney Injury and Delayed Methotrexate Clearance in Pediatric Patients With Philadelphia Chromosome-positive B-Cell Acute Lymphoblastic Leukemia

Pommert, Lauren; Liberio, Nicole; Ng, John S; Egelund, Tosha A; Siver, Molly J; Katzenstein, Howard M.; Burke, Michael J.

doi:10.1097/mph.0000000000001816

Cited by 13 publications

(8 citation statements)

References 19 publications

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“…It is unclear whether the association of the administration of diuretics and MTX CL is because of the nephrotoxicity caused by diuretics or due to MTX‐induced nephrotoxicity that triggers the clinical use of diuretics. The association between an increase in MTX CL and concomitant use of TKIs has also been described previously 58,59 and has caused some paediatric hospitals to hold TKIs from the start of HDMTX until it is cleared. This drug–drug interaction may be mediated by the SLCO1B1 transporter because both MTX and TKIs are substrates of the transporter and the TKIs may also regulate the transporter's function 60‐62 .…”

Section: Discussionmentioning

confidence: 63%

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing

Ibarra

Combs²,

Taylor

et al. 2022

Brit J Clinical Pharma

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Aims High‐dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity. Methods Anonymized, de‐identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non‐profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite. Results A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three‐compartment model adequately fitted the data. Time‐dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose‐normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence. Conclusion We developed a population pharmacometric model that considers weight, albumin and time‐dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.

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Section: Discussionmentioning

confidence: 63%

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing

Ibarra

Combs²,

Taylor

et al. 2022

Brit J Clinical Pharma

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“… 10 There have also been recent case reports of delayed MTX clearance caused by concomitant use of imatinib. 18 , 19 The TKI mechanisms affecting MTX metabolism need to be studied further.…”

Section: Discussionmentioning

confidence: 99%

Effects of genetic polymorphisms on methotrexate levels and toxicity in Chinese patients with acute lymphoblastic leukemia

et al. 2022

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Methotrexate (MTX) has an antitumor effect when used for the treatment of acute lymphoblastic leukemia (ALL). This study aims at evaluating the associations between 14 polymorphisms of six genes involved in MTX metabolism with serum MTX concentration and toxicity accompanying high-dose MTX. Polymorphisms in 183 Chinese patients with ALL were analyzed using TaqMan single nucleotide polymorphism genotyping assay. The serum MTX concentration was determined using homogeneous enzyme immunoassay. MTX-related toxicities were also evaluated. Renal toxicity was significantly associated with higher serum MTX concentrations at 24, 48, and 72 hours, and MTX elimination delay (P = 0.001, P < 0.001, P < 0.001, and P < 0.001, respectively), whereas SLCO1B1 rs4149056 was associated with serum MTX concentrations at 48 and 72 hours, and MTX elimination delay in candidate polymorphisms (P = 0.014, P = 0.019, and P = 0.007, respectively). SLC19A1 rs2838958 and rs3788200 were associated with serum MTX concentrations at 24 hours (P = 0.016, P = 0.043, respectively). MTRR rs1801394 was associated with serum MTX concentrations at 72 hours (P = 0.045). Neutropenia was related to SLC19A1 rs4149056 (odds ratio [OR]: 3.172, 95% confidence interval [CI]: 1.310-7.681, P = 0.011). Hepatotoxicity was associated with ABCC2 rs2273697 (OR: 3.494, 95% CI: 1.236-9.873, P = 0.018) and MTRR rs1801394 (OR: 0.231, 95% CI: 0.084-0.632, P = 0.004). Polymorphisms of SLCO1B1, SLC19A1, ABCC2, and MTRR genes help predict higher risk of increased MTX levels or MTX-related toxicities in adult ALL patients.

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“…Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].…”

Section: Discussionmentioning

confidence: 99%

Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment

Alsdorf¹,

Karagiannis²,

Langebrake

et al. 2020

The Oncologist

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Background. High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy. Materials and Methods. The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP). Results. In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group. Conclusion. The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events. The Oncologist 2020;25:1-6 Implications for Practice: High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.

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Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute Kidney Injury and Delayed Methotrexate Clearance in Pediatric Patients With Philadelphia Chromosome-positive B-Cell Acute Lymphoblastic Leukemia

Cited by 13 publications

References 19 publications

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing

Effects of genetic polymorphisms on methotrexate levels and toxicity in Chinese patients with acute lymphoblastic leukemia

Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment

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