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

Abstract

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.

High‐dose methotrexate pharmacokinetics and its impact on prognosis of paediatric acute lymphoblastic leukaemia patients: A population pharmacokinetic study

“…The impact of concurrent use of dasatinib on decreased MTX CL has been reported in previous studies 35,36 . This interaction may be mediated through the OATP1B1, as both MTX and TKIs are substrates of the transporter 36–38 .…”

“…The impact of concurrent use of dasatinib on decreased MTX CL has been reported in previous studies. 35,36 This interaction may be mediated through the OATP1B1, as both MTX and TKIs are substrates of the transporter. [36][37][38] In our analysis, we found that the coadministration of dasatinib significantly inf luenced MTX CL, while imatinib had little effect, which is in line with prior research.…”

Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org

“…Several reports have linked the effects of albumin and hypoalbuminemia to altered MTX PKs. 13,[18][19][20][21] Mainly, these reports support the reduction of MTX CL with decreasing albumin. Our parameterization for severe hypoalbuminemia on MTX CL resulted in an estimated ~2% reduction in MTX clearance (Table S1), and did not significantly improve the description of the data.…”

“…Circulating MTX is 50%–60% bound to albumin, 17 which suggests that a decrease in serum albumin would increase the amount of free (unbound) MTX. Several reports have linked the effects of albumin and hypoalbuminemia to altered MTX PKs 13,18–21 . Mainly, these reports support the reduction of MTX CL with decreasing albumin.…”

“…The parameterization for SI on clearance results in an estimated 5% faster MTX CL (L/h/1.73 m 2 ) compared to LI CL estimates (Table 2) and is similar to the previously reported value from the Guardian Research Network. 13 Although this estimate is less than the previously reported between-occasion variability of 20%, 14,15 the inclusion of the SI parameterization improves the model's description of the data and will further improve MTXPK.org's ability to accurately forecast MTX concentrations in patients receiving SI treatment protocols.…”