Clinical pharmacology of intermediate-dose oral methotrexate

Smith, Diane K.; Omura, George; Ostroy, F.

doi:10.1007/bf00254032

Cited by 27 publications

(4 citation statements)

References 7 publications

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“…The proposed mechanism for the interaction between MTX and levetiracetam is that the inactive metabolite of levetiracetam, UCB L057, may compete with MTX for tubular secretion in the kidney 35–37 . Based on this mechanism, it is possible that higher doses of levetiracetam would result in an increased risk of delayed MTX elimination.…”

Section: Discussionmentioning

confidence: 99%

Lack of drug interaction between levetiracetam and high‐dose methotrexate in patients with lymphoma

et al. 2021

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Study Objective To determine whether there is a drug‐drug interaction precluding the concomitant use of levetiracetam and high‐dose methotrexate (HDMTX). Design Retrospective analysis. Setting Large academic tertiary care medical center. Patients Adult lymphoma patients who received HDMTX as a 4‐h infusion with or without concomitant levetiracetam. Measurements and Main Results Generalized estimating equations clustered on patient were used to assess each outcome. The primary outcome was the incidence of delayed MTX elimination (MTX level >1 µmol/L at 48 h). Secondary outcomes included incidence of acute kidney injury (AKI) and hospital length of stay (LOS). The 430 included patients receiving 1993 doses of HDMTX had a median (IQR) age of 66 (57.5, 72.6) years, 88 (20.5%) received concomitant levetiracetam with at least one dose of MTX, 267 (62.1%) were male, and 397 (92.3%) were Caucasian. HDMTX doses ranged from 1 to 8 g/m2. The most common lymphoma diagnoses were systemic diffuse large B‐cell lymphoma (DLBCL; 58.5%) and systemic DLBCL with central nervous system (CNS) involvement (32.8%). Rates of delayed elimination with and without levetiracetam were 13.4% and 16.3%, respectively (OR = 0.80, 95% CI 0.47–1.34, p = 0.39). AKI occurred in 15.6% and 17.0% of patients with and without concomitant levetiracetam, respectively (OR = 0.83, 95% CI 0.52–1.33, p = 0.28). The median LOS with and without levetiracetam was 4.2 and 4.1 days, respectively (p = 0.039). On multivariable analyses, only age, body surface area, diagnosis of systemic DLBCL with CNS involvement, serum creatinine, hemoglobin, total bilirubin, and dose of HDMTX were associated with delayed elimination. Conclusions High‐dose methotrexate administered with concomitant levetiracetam was not associated with increased risk for delayed MTX elimination or AKI. These results support that levetiracetam and HDMTX are safe for coadministration.

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Section: Discussionmentioning

confidence: 99%

Lack of drug interaction between levetiracetam and high‐dose methotrexate in patients with lymphoma

et al. 2021

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“…On the other hand, no effect of feeding has been observed in RA patients (24). The BA of MTX in humans is high at less than 30 mg/m 2 corresponding to 44 mg (24), and it falls to 10-20% at over 80 mg/m2 corresponding to 118 mg (25) due to saturated absorption (26). Since it is expected that the intestinal absorption of MTX in RA patients is not saturated due to the low dosage (3)(4)(5)8), and that the effect of feeding on the intestinal absorption of MTX is larger under saturated condition, the discrepancy between rats and humans seems to be resulted from the differences of the extent of saturation.…”

Section: Discussionmentioning

confidence: 99%

Variability of oral bioavailability for low dose methotrexate in rats

Kuroda¹,

Namba²,

Torimaru³

et al. 2001

Eur. J. Drug Metab. Pharmacokinet.

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The effects of food, antibiotics, diclofenac sodium (DS) and methotrexate (MTX) on oral bioavailability (BA) of MTX were examined in rats. Feeding didn't vary the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but enhanced those after oral dosing, and the oral BA. The twice daily oral doses of 40 mg/kg neomycin sulfate (NS) or mixed antibiotics (200 mg/kg NS + 200 mg/kg streptomycin sulfate + 200 mg/kg bacitracin) for 5 days didn't influence the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but induced the decreased Cmax and the delayed MRT after oral dosing. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats orally dosed with 1 or 5 mg/kg/day DS for 4 days were similar to those in the control rats, while the pre-treatment of 25 mg/kg/day DS delayed the elimination of MTX but didn't change the oral BA. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats, which received the intermittent oral doses of 7.5 mg/kg/3 doses/week MTX for 4 weeks, were comparable to those in the control rats, but the daily pre-treatment of 0.2 mg/kg/day MTX for 4 weeks increased the plasma concentrations after oral dosing, and the BA.

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“…At doses of greater than 80 mg/m 2 plasma levels are 10% of those achieved after intravenous administration (Freeman-Narrod et al 1975;Henderson et al 1965;Smith et al 1980). At doses of greater than 80 mg/m 2 plasma levels are 10% of those achieved after intravenous administration (Freeman-Narrod et al 1975;Henderson et al 1965;Smith et al 1980).…”

Section: Bioavailabilitymentioning

confidence: 99%

Therapeutic Drug Monitoring in Oncology

Moore

Erlichman

1987

Clinical Pharmacokinetics

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Therapeutic drug monitoring is now widely used in many areas of medicine. With its proliferation has come an understanding of the clinical situations in which it is likely to be of value. Factors that can limit the usefulness of therapeutic drug monitoring and situations where it is less likely to be of benefit have also been identified. At present, the routine use of therapeutic drug monitoring in antineoplastic therapy is limited to measurement of plasma methotrexate concentrations after high-dose methotrexate therapy. The lack of a more widespread application of therapeutic drug monitoring in oncology has been due to deficiencies in knowledge about the clinical pharmacology of antineoplastic agents and to factors specific to the chemotherapy of neoplasms. These factors include the broad heterogeneity of malignant neoplasms, the complexities of the drug-tumour interaction, difficulties in assessment of this interaction and the use of combinations of antineoplastic agents with cumulative efficacies and toxicities. Despite these problems, there are many areas in antineoplastic therapy where the use of therapeutic drug monitoring could prove of benefit. The prevention of the chronic pulmonary toxicity of bleomycin, the assessment of the bioavailability of oral chemotherapy, and monitoring drug disposition in the presence of hepatic or renal dysfunction are just some of the potential applications. If recent emphasis on dose as a critical factor in the success of cancer chemotherapy is substantiated, then the need to apply therapeutic drug monitoring within oncology will become more pressing.

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Clinical pharmacology of intermediate-dose oral methotrexate

Cited by 27 publications

References 7 publications

Lack of drug interaction between levetiracetam and high‐dose methotrexate in patients with lymphoma

Lack of drug interaction between levetiracetam and high‐dose methotrexate in patients with lymphoma

Variability of oral bioavailability for low dose methotrexate in rats

Therapeutic Drug Monitoring in Oncology

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