High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy

Abstract

Preoperative high-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is still a mainstay in the treatment of osteosarcoma. This anticancer agent is characterized by a narrow therapeutic index and wide interpatients variability. To ensure effective and safe administration of HD-MTX, we had earlier developed an adaptive-dosing schedule with a feedback strategy. In our institute, the MTX dosage was tailored according to individual pharmacokinetics parameters, determined in real time both from two blood samples (3.5 and 4.5 h) and from Bayesian population parameters. Up to 20 g of MTX was safely administered as 8-h infusions. Low MTX elimination rate has, however, been reported in 15-20% of the patients, and forecasting the MTX elimination phase and the management of leucovorin rescue is still a challenging issue in clinical oncology. This study aims at identifying the clinical or biological covariates related to impaired MTX clearance, and at validating a new limited sampling strategy (LSS), allowing for the accurate prediction of the MTX terminal elimination phase. This retrospective study was carried out on 49 patients (30 men, 19 women; mean age, 26.7 years) treated for osteosarcoma with HD-MTX. The population and individual pharmacokinetics parameters were computed, before the identification of the relevant covariates. Different LSSs were then tested, to predict accurately when the MTX plasma concentrations would drop below 0.2 micromol/l, the threshold associated with the end of the rescue of leucovorin with alkaline hydration. Two main covariates (creatinemia clearance and alanine aminotransferase) were correlated with MTX clearance. Conversely, the impact of body surface area on MTX pharmacokinetics was weak, suggesting that dosing schedules based on body surface area were inadequate and potentially hazardous. A new LSS predicting accurately when the MTX concentration would reach 0.2 micromol/l has been validated; blood samples are stopped as soon as the MTX concentration drops to 1 micromol/l. With this LSS, our retrospective study suggests that 60% of the patients would have left the hospital earlier than they actually did owing to a better forecasting of the MTX decrease, thus improving their quality of life while improving the cost-effectiveness for the institute. HD-MTX can be administered safely using an adaptive-dosing strategy with drug monitoring. Moreover, pharmacokinetic modeling permits the accurate forecasting of the MTX elimination profile, thus allowing for a better management of the postinfusion care of cancer patients treated with particularly high doses of this drug.

Risk factors associated with delayed methotrexate clearance and increased toxicity in pediatric patients with osteosarcoma

“…Similar to prior adult studies, we showed that among our pediatric cohort BSA and BMI were inconsistently associated with adverse treatment outcomes. Patients with lower BSA were more likely to have chemotherapy holds and neutropenia, while patients with higher BMI experienced more thrombocytopenia …”

Synthesis and biological evaluation of 3′,4′,5′-trimethoxychalcone analogues as inhibitors of nitric oxide production and tumor cell proliferation

“…The IC 50 values were determined by interpolation from dose-response curves. A total of 100 lM was chosen as maximal concentration because much higher doses do not normally reach the blood plasma, 19 and we are looking for compounds with high activity (low IC 50 ) which could eventually be used in the future as a drug for chemotherapy with very low to no side effects.…”

“…, 4-bromo(17), and 4-nitro (18) or an electron donating group like 4-methoxyl (13) and 4-methyl(19) exhibited moderate activities with IC 50 values of 25.7, 22.5, 43.0, 46.4 and 41.5 lM, respectively. Furthermore, compound 7 bearing 3-methoxy-4-hydroxy group and 9 bearing 2,5-dihydroxy group exhibited negligible anti-proliferation response in both the cell lines Hep G2 and Colon 205.…”

Utility of Limited Sampling Strategies for Anticancer Agents in the Clinical Arena: A Systematic Review

“…Table 2 summarizes LSSs for various anticancer agents and their level of evidence. There were 8 citations for bulsufan (one level II-1, 6 level II-2, one level III) [12][13][14][15][16][17][18][19], one citation for cladribine (level II-1) [20], one citation for cyclophosphamide (level II-1) [21], two citations for docetaxel (one level II-1, one level III) [22,23], one citation for doxorubicin (level II-1) [24], 3 citations for epirubicin (one level II-1, 2 level III) [25][26][27], 7 citations for etoposide (3 level I, 2 level II-1, one level II-2, one level III) [3,[28][29][30][31][32][33][34], 4 citations for 5-fluorouracil (one level II-1, one level II-2, 2 level III) [35][36][37][38], 6 citations for irinotecan (2 level I, 3 level II-2, one level III) [39][40][41][42][43][44], one citation for melphalan (level I) [45], 4 citations for methotrrexate (2 level II-1, one level II-2) [46][47][48][49], one citation for temozolamide (level I) [10], one citation for thiotepa (level III) [50], 6 citations for topotecan (3 level I, one l...…”