Bayesian population model of methotrexate to guide dosage adjustments for folate rescue in patients with breast cancer

Monjanel-Mouterde, Suzanne; Lejeune, C; Ciccolini, Joseph; Merite, N.; Hadjaj, Djamal; Bonnier, Pascal; Piana, P; Durand, Alain

doi:10.1046/j.1365-2710.2002.00402.x

Cited by 19 publications

(11 citation statements)

References 19 publications

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“…In agreement with the previous study, a high inter-individual pharmacokinetic variability was obtained. With regard to CL, the estimation (7.45 L Á h À1 ) is in accordance with values of CL reported by Faltaos (7.1 L Á h À1 ) [21], Piard (8.8 L Á h À1 ) [22] and Monjanel-Mouterde (8.16 L h À1 ) [23]. The estimation value of V 1 (25.9 L) is close to the previous literature data reported by Faltaos (25.1 L) [21] and Piard (26.8 L) [22].…”

Section: Discussionsupporting

confidence: 90%

High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancy

et al. 2009

Biopharm & Drug Disp

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The purpose of present study was to develop a population pharmacokinetic model of high dose methotrexate (HD-MTX) infusion in patients with lymphoid malignancy, to investigate the biological and clinical covariates related to the drug distribution and elimination. It is also the purpose to propose a limited sampling strategy (LSS) for the estimation of the time above the threshold (0.2 micromol.L(-1)). A total 82 patients with lymphoid malignancy were involved in the study. A pharmacokinetic model was developed using nonlinear mixed-effect model. The influence of demographic characteristics, biological factors, and concurrent administration were investigated. The final predictive performance was validated by bootstrap and cross-validation. Bayesian estimation was evaluated. The pharmacokinetics of HD-MTX was described by a two-compartment model. The pharmacokinetic parameters and the inter-individual variability were as follows: the clearance CL, 7.45 L.h(-1) (inter-individual variability 50.6%), the volume of the central and peripheral compartment V(1), 25.9 L (22.5%), V(2), 9.23 L (97.8%), respectively, and the intercompartmental clearance Q, 0.333 L.h(-1) (70.4%). The influence of serum creatinine on CL and weight on V(1) was retained in the final model. The protocol involved one sampling time at 44 h after the start of the infusion, allowing one to predict the time at which the MTX concentration reached the expected threshold (0.2 micromol.L(-1)). Serum creatinine and weight showed significant influence on methotrexate CL and V(1), respectively. Furthermore, a Bayesian estimation based on the covariates and 44 h sample was developed, allowing prediction of the individual methotrexate pharmacokinetic parameters and the time to 0.2 micromol.L(-1).

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Section: Discussionsupporting

confidence: 90%

High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancy

et al. 2009

Biopharm & Drug Disp

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“…MTX plasma concentrations were measured by fluorescence polarization immunoassay with a TDX FLX analyzer (Abbott Laboratories, Abbott Park, Illinois, USA). The limit of quantification of this assay was 0.01 mmol/l with an interday precision of 6.7% [14].…”

Section: Methotrexate Assaymentioning

confidence: 89%

“…Correlations between MTX PK parameters and tumor responses have been examined in several studies [3,26]. We previously demonstrated that therapeutic drug monitoring of HD-MTX was feasible in a routine clinical setting in patients with inflammatory breast cancer, and that it did indeed reduce interpatient variability [11,14].…”

Section: Discussionmentioning

confidence: 99%

“…Like MTX, 7-OH-MTX is also polyglutamylated in the cells, and the retention of these polyglutamated forms in the erythrocytes could therefore contribute to MTX toxicity. One of our principal aims was to estimate when the MTX concentration dropped below 0.2 mmol/l [14,30], as soon as possible after the event. Accurate early estimation of this reaching of the 0.2-mmol/l threshold would indeed avoid daily sampling of the patients.…”

Section: Discussionmentioning

confidence: 99%

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

Dupuis¹,

Mercier²,

Yang³

et al. 2008

Anti-Cancer Drugs

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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.

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“…To date, there are many reports on population pharmacokinetics of high‐dose MTX in adult patients with various malignant tumours (8–14); however, the majority of these studies (8–11) did not fully investigate factors affecting the drug’s pharmacokinetics. Moreover, although the key determinant of MTX pharmacokinetics is the urinary excretion process (60–90% of MTX is recovered in urine as unchanged drug during the first 24 h after the infusion) (15, 16), none of the earlier analyses examined urinary excretion and used serum concentration data only (8–14). It is important to also use urine concentration data to more accurately estimate the population pharmacokinetic parameters of high‐dose MTX.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of high-dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

Fukuhara

Ikawa

Morikawa

et al. 2008

Journal of Clinical Pharmacy and Therapeutics

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Bayesian population model of methotrexate to guide dosage adjustments for folate rescue in patients with breast cancer

Abstract: The Bayesian estimation presented in this study was an easy and convenient method to efficiently detect patients with impaired MTX elimination in routine clinical practice. This information enabled the introduction of strategies for minimizing the risk of severe drug toxicity.

Cited by 19 publications

References 19 publications

High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancy

High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancy

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

Population pharmacokinetics of high-dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

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