Safe administration of high‐dose methotrexate with minimal drug level monitoring: Experience from a center in north India

Abstract

Background: High-dose methotrexate (HDMTX) is recommended to be administered with serial monitoring of methotrexate (MTX) levels, which may not be universally feasible in resourcelimited settings. In this study, we evaluated the overall experience of administration of HDMTX at our center by monitoring a single drug level at 54 h from the start of MTX infusion. Methods: This retrospective study was performed at a tertiary level hospital in north India, over a 5-year period (2011-2015). All patients <18 years of age with newly diagnosed acute lymphoblastic leukemia (ALL) and T-non-Hodgkin lymphoma (T-NHL) were enrolled in the study. Details of HDMTX and all significant toxicities requiring prolonged or repeat hospitalization were retrieved from the medical records. All eligible patients received HDMTX as per the recommendations followed by at least three doses of leucovorin rescue, before drug levels were sent at 54 h. Subsequent leucovorin doses were adjusted accordingly. Results: The records of 598 cycles of HDMTX in 184 patients were reviewed. A total of 531 of 598 cycles (88.7%) were managed with monitoring only a single plasma drug level at 54 h from the beginning of infusion. Delayed MTX clearance was seen in 260 of 598 cycles (43.5%). Only three episodes (0.5%) were associated with significant toxicity. There were no deaths. Conclusions: The strategy of monitoring MTX concentration at 54 h was safe in our cohort. Although recommended, dynamic monitoring of plasma drug levels may not always predict toxicity.

Past, present and future perspectives of therapeutic drug monitoring in India

“…A recent Indian study reported that amongst 598 cycles of high dose methotrexate, 88.7% cycles were managed by a single plasma drug level monitoring at 54 hours. Kapoor et al reported similar results at 42 hours of drug level monitoring 34,35 . However, more Indian studies need to be conducted to evaluate the efficacy of TDM for anticancer drugs apart from methotrexate in the Indian population.…”

Utility of repeated drug level measurements after high dose methotrexate infusion for treatment planning in pediatric leukemia

“…In a study conducted with 32 pediatric patients, Sari et al analyzed 68 treatment cycles following ≥1 g/m 2 /day MTX administration, two measurements were carried out at the 24 th and 48 th hours, and no correlation was found between the MTX level and clinical toxicity in these measurements (20). In the study by Dhingra et al, consisting of 184 patients, it was reported that a single plasma drug level measurement at the 54 th hour, together with long-term hydration, was sufficient for the safe management of MTX in 89% of the 598 MTX treatments (14). In another study, 231 MTX infusions given to 61 pediatric patients were analyzed, and it was declared that pharmacokinetic parameters could be determined precisely and accurately by twolevel measurements at the 24 th and 48 th hours, and thus the time when MTX concentration reached the prescribed threshold could be predicted (16).…”

“…Several studies have suggested that serial monitoring of drug levels until the MTX level becomes <0.1 µmol/L is critical for the successful management of MTX-related toxicity (9,10,11). However, some studies have reported that a safety/toxicity balance can be obtained through clinical and laboratory findings in centers where level monitoring cannot be carried out, while other studies have suggested that only one or two post-infusion blood MTX measurements are sufficient (14,16,19). Vaishnavi et al monitored 100 MTX cycles and reported that administration of 3 or 5 g/m 2 MTX without measuring MTX levels is safe by monitoring long-term hydration, additional leucovorin doses, and serum creatinine and urine pH (12).…”

“…However, the amount and number of doses are estimated according to serum MTX levels (9)(10)(11). In studies conducted to date, a wide range of recommendations based on MTX level has been made, ranging from "this measurement is not required" to "a single measurement is sufficient" or "a follow-up at six-hour intervals is needed until MTX level falls below the determined level" (9,(12)(13)(14). This study reviewed the similarities and differences among the repeated MTX levels in pediatric patients who were given repeated high-dose MTX due to ALL and researched the utility of these repeated measurements.…”

Curing the Curable: Managing Low-Risk Acute Lymphoblastic Leukemia in Resource Limited Countries

“…Although the adjustment of the start time for administration can allow MTX level monitoring during office hours, this infrequently utilized test is generally not available and not cost-effective in most LMIC settings. Although various groups have devised various strategies [57,58] to overcome challenges of giving HDMTX, we review alternatives to HD-MTX in Table 3. [21] trial were treated with intermediate doses of MTX but were given a combination of other drugs such as Teniposide, L-asp, and Cytarabine as well.…”