Prospective Evaluation of High-Dose Methotrexate Pharmacokinetics in Adult Patients with Lymphoma Using Novel Determinants of Kidney Function

Jason N. Barreto, PharmD, MSc, BCPS
Assistant Professor of Medicine and Pharmacy,
Mayo Clinic School of Medicine
Clinical Pharmacist - Hematology and Oncology
Mayo Clinic
Rochester, MN

Introduction
High-dose methotrexate (≥1 gram/meter2 [g/m2]; HDMTX) is a cornerstone of treatment for central nervous system (CNS) lymphoma.¹ It has also been integrated into the management of systemic lymphoma as prophylaxis for patients who are at high risk of disease relapse in the CNS.² Despite more than 60 years of utilization, the optimal dose, administration, monitoring, and supportive measures have yet to be determined.³

Methotrexate (MTX) dose selection is a delicate balance between optimizing tumor kill without subjecting the host to excess toxicity.⁴ The standard of care for MTX dose derivation utilizes serum creatinine as a surrogate for glomerular filtration rate (GFR).⁵ As the terminal byproduct of skeletal muscle metabolism, non-renal determinants, including altered muscle mass, deconditioning, and malnutrition, can decrease the accuracy of serum creatinine-based GFR estimation in patients with cancer.^6-8

Cystatin C is a serum marker of GFR that is less dependent on age, sex, race, or muscle mass than creatinine.9 The use of cystatin C to inform drug dosing and monitor dynamic kidney function has recently increased and cystatin C has successfully been used in conjunction with, or as an alternative to, creatinine to dose antineoplastics, including carboplatin and topotecan.^10-13 Given that there is also data to support using cystatin C to estimate GFR prior to HDMTX delivery in patients with creatinine-based estimated that seem suspicious¹⁴, we sought to understand the relationship between HDMTX pharmacokinetics and cystatin C-inclusive GFR estimation equations.

Methods
Our prospective, single-center study included adult patients (≥18 years old) with histologically confirmed lymphoma admitted for administration of HDMTX. Patients prescribed a HDMTX infusion administered longer than 4 hours, patients admitted with new acute kidney injury before the HDMTX infusion, or those receiving renal replacement therapy were excluded.

After enrollment, we collected biospecimen samples at fixed time points from before HDMTX delivery until either 96-hours after the infusion or patient discharge from the hospital. The study procedures did not affect the routine clinical care for patients. Research-related laboratory results were suppressed from the electronic health record and were available only to study personnel. The interdisciplinary care team selected the HDMTX-inclusive treatment without regard to the biomarker levels. Per hospital protocol, serum MTX concentration monitoring began at 48-hours after the drug infusion and then occurred once daily until <0.1 μmol/L, indicative of discharge from the hospital, barring other clinical circumstances. Patients were followed until the next HDMTX dose or for 30 days, whichever occurred first.

The pharmacokinetics of MTX were estimated by standard non-compartmental analysis using the program Phoenix® WinNonlin® Version 8.1(Certara Corporation, Princeton, NJ). The area under the concentration-time curve (AUC) was calculated using the linear trapezoidal approximation. MTX plasma clearance (CLp) was calculated as Dose/AUC. The Spearman correlation coefficient was used to compare pharmacokinetic parameters and patient characteristics. We fit linear regression models to determine whether varying the approach to baseline kidney assessment (eGFR based on Cockcroft Gault (C-G) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations using serum creatinine, cystatin C, or both biomarkers) improved the prediction of drug clearance.

Data were summarized using mean ± standard deviation (SD) or median with the interquartile range (IQR) depending on the distribution. Frequencies (percentages) were used to describe discrete data. The Wilcoxon signed-rank test was used to detect intra-individual differences in kidney function estimates.

Results and discussion
A total of 80 individuals met eligibility criteria and were enrolled. Patients had a median age of 69 (IQR: 59-76) years, 54 (68%) were male, and 74 (93%) were white. The median body weight of the patient population was 80.5 kg (IQR: 70-92) and the median BSA was 1.97 (IQR: 1.80-2.14) as calculated by the Du Bois Method. There were five patients (6%) with a baseline diagnosis of CKD. Baseline estimated kidney function differed according to equation utilized and ranged between a mean of 83 mL/min when calculated using CKD-EPI eGFR-CysC and 99 mL/min when calculated with C-G eGFR.

Seven patients had extremely high values for MTX clearance which influenced these relationships [median clearance 18.8 (IQR: 13.2-38.1) L/hr in these seven patients versus 4.8 (IQR: 3.8-5.8) L/hr in the remaining 73 patients]. Analytical techniques were reviewed and a detailed chart review was performed. Neither revealed common features, nor explanations, for the extreme drug clearance values in these patients. A sensitivity analysis was performed after considering these seven patients to be outliers and excluding them, which strengthened the observed correlations between MTX clearance and kidney function estimates. See Table 1 below.

In the full cohort of 80 patients, there was a modest relationship between MTX clearance and baseline estimated kidney function when calculated using creatinine, cystatin C, or both biomarkers. Interestingly, we found that the eGFR based on cystatin C, whether expressed in mL/min or mL/ min/1.73m2, predicted MTX clearance better than creatinine-based estimating equations (Table 1).

Additionally, the eGFR equation utilizing both serum creatinine and cystatin C also showed a stronger correlation with MTX clearance than the Cockcroft Gault estimated creatinine clearance. This effect seems primarily driven by the cystatin C component, given that the correlation improved when comparing the eGFR based on serum creatinine and the eGFR incorporating both serum creatinine and cystatin C. This differs considerably from the current approach to MTX dosing in clinical practice that relies solely on serum creatinine and estimated creatinine clearance based on the Cockcroft-Gault equation despite pharmacokinetic studies describing the poor performance of serum creatinine and creatinine clearance as a marker of MTX elimination.

Conclusion
This prospective, single-center pharmacokinetic clinical trial demonstrated that novel eGFR equations involving cystatin C appeared to more strongly correlate with MTX clearance than eGFR equations based on serum creatinine alone, highlighting a potential opportunity for enhancing the precision of MTX dosing using novel renal biomarkers. Future research should confirm these findings through population pharmacokinetic modeling analysis and observation of clinical outcomes after doses of HDMTX that utilize creatinine-based kidney function estimation compared to HDMTX doses calculated with cystatin-c-inclusive kidney function estimating equations.

Table 1. Correlation and 95% confidence intervals for glomerular filtrate rate estimation equations with methotrexate clearance.

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