High dose methotrexate in adult patients with osteosarcoma: Clinical and pharmacokinetic results

Comandone, Alessandro; Passera, Roberto; Boglione, Antonella; Tagini, Valentina; Ferrari, Stefano; Cattel, Luigi

doi:10.1080/02841860510029770

Cited by 47 publications

(44 citation statements)

References 12 publications

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“…Estimated values of the pharmacokinetic parameters determined by nonlinear regression analysis of the plasma and ECF concentration–time profiles are given in Table 2. The plasma pharmacokinetics of MTX were similar in all four patients and in excellent agreement with data from a previously reported study of high dose MTX [27]. The C max in plasma ranged from 1,321 to 1,407 μM and the CL values ranged from 3.44 to 4.58 l/h/m 2 .…”

Section: Resultssupporting

confidence: 87%

Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study

et al. 2008

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Purpose Determining whether potentially therapeutic drug exposure is achieved within brain tumors in an exploratory clinical investigation would provide a rational basis for selecting agents for evaluation in phase II trials. This study investigated the use of microdialysis to assess intratumoral drug distribution in patients with recurrent high grade gliomas (HGG). Patients and Methods Microdialysis catheters were placed during surgery for residual HGG 1-day before giving methotrexate (MTX) 12-g/m2 by 4-h i.v. infusion. MTX was measured by Liquid Chromatography/Mass Spectrometry (LC/MS) in plasma and microdialysate during the infusion and for 24-h thereafter. Blood brain barrier (BBB) permeability of tissue in which the microdialysis probe was located was determined by digitally fusing brain CT and contrast enhanced MRI images. Results The microdialysis probe was located in contrast enhancing tumor in two patients and nonenhancing tissue in two others. Cerebral drug penetration, as indicated by the ratio of the area under the MTX concentration–time curves in brain extracellular fluid and plasma, was considerably greater in contrast enhancing tumor (0.28–0.31) than nonenhancing tissue (0.032–0.094). Nevertheless, MTX concentrations in ECF exceeded 2-μM, the average concentration for 50% cell kill against glioma cell lines in vitro, for 20–26 h in both regions of the tumor. Conclusions Microdialysis is a very informative technique for characterizing the intratumoral pharmacokinetics of drugs, such as MTX, that do not freely penetrate the BBB. Establishing the catheter probe location relative to areas of BBB disruption is required to properly assess the significance of microdialysis data in this context.

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Section: Resultssupporting

confidence: 87%

Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study

et al. 2008

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“…There was an obvious intra-patient and inter-patient variability in HDMTX serum concentrations, as previously described in the literature [21,22].…”

Section: Discussionmentioning

confidence: 81%

“…The median age was 18 years (range: [15][16][17][18][19][20][21][22][23][24][25]. A total of 344 cycles, including the pre-operative and post-operative treatments, were evaluable for toxicity and for HDMTX pharmacokinetics (Table 4).…”

Section: Resultsmentioning

confidence: 99%

Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in patients with osteosarcoma

Mir

Ropert

Babinet

et al. 2010

Cancer Chemother Pharmacol

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(204 words)Purpose: To evaluate the reliability and renal safety of an original schedule of high-dose methotrexate (HDMTX) administration with hyper-alkalinization, and without hyperhydration.Methods: Osteosarcoma patients received HDMTX (8-12 g/m²) as a 4-hour infusion.Hypertonic 8.4% sodium bicarbonate was infused prior to HDMTX, then once daily for 3 days. Methotrexate serum concentrations was measured at hour 4 (Cmax), hour 24, hour 48 and hour 72. Urinary pH was measured on each miction. Serum creatinine was assessed on days 1, 3 and 8.Results: Twenty-six patients (median age: 18 years, range: 15-25) received a total of 344 cycles of HDMTX, including 16 patients treated in an outpatient basis. Urinary pH remained constantly higher than 7.5 in all patients. Grade 1 creatininemia toxicity was observed in 31 cycles (9%), and grade 2 creatinine toxicity was observed in one patient. No episode of acute severe nephrotoxicity was observed. No significant worsening was observed in serum creatinine and calculated creatinine clearance from baseline to the end of therapy (p = 0.74).The main extra-renal toxicity was alkalinization-related hypokalemia from H48. No rehospitalisation was required. Conclusion:Hyper-alkalinization appears an efficient and reliable method to prevent the acute renal toxicity of HDMTX, and allows its safe administration in the outpatient setting.

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“…10 However, exposure values (AUC) higher than 12,000 mMÁh have been related to toxicity. 11 Many authors have described the pharmacokinetic (PK) profile of MTX in both adults and children with osteosarcoma under a variety of circumstances. All these studies have been performed by fitting a 2-or 3-compartment open model to the concentration-time data by the nonlinear least squares regression approach.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of High-Dose Methotrexate After Intravenous Administration in Pediatric Patients With Osteosarcoma

Colom¹,

Farre²,

Soy³

et al. 2009

Therapeutic Drug Monitoring

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The goal of this study was to establish the population pharmacokinetics (PK) of high-dose methotrexate (HD-MTX) treatment in children with osteosarcoma and to explore the influence of patient covariates and between-occasion variability on drug disposition. Patient covariates and concentration-time data were collected. PK data analysis from 209 HD-MTX cycles from 14 patients was performed using the population approach (NONMEM V). Internal and external validations were performed to confirm the model. PK of methotrexate was best described by a 2-compartment open PK model with first-order elimination from the central compartment. Between-subject variability (BSV) was included in total plasma clearance (CL) and in central compartment distribution volume (V1) [coefficient of variation (CV) 11.9% and 8.9%, respectively]. The CV of BSV in the residual error was 25.5%. Between-occasion variability was only retained for CL (CV 8.2%). RE consisted of a proportional error of 41.6%. Age and body weight in CL and body weight in V1 were identified as the appropriate covariates. The final estimates of total CL and V1 were given by the equations CL = 88.5.(AGE/15) + 27.4 x (WGT/50) L/d and V1 = 11.0 + 5.6 x (WGT/50) L, respectively. Internal validation results showed that the 95% confidence interval covered all the observed MTX concentrations. Mean bias and precision of the individual predicted concentrations, calculated in a validation dataset, resulted in -1.36% and 19.71%, respectively. A population PK model was developed for HD-MTX in children with osteosarcoma. Validation studies confirmed the suitability of the model for further dose individualization by means of a Bayesian approach.

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High dose methotrexate in adult patients with osteosarcoma: Clinical and pharmacokinetic results

Cited by 47 publications

References 12 publications

Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study

Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study

Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in patients with osteosarcoma

Population Pharmacokinetics of High-Dose Methotrexate After Intravenous Administration in Pediatric Patients With Osteosarcoma

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