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1.
Blood ; 131(4): 397-407, 2018 01 25.
Article in English | MEDLINE | ID: mdl-29141948

ABSTRACT

Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m2) and romidepsin (12 to 14 mg/m2) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis × 2; grade 4 sepsis × 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140.


Subject(s)
Aminopterin/analogs & derivatives , Antibiotics, Antineoplastic/therapeutic use , Depsipeptides/therapeutic use , Folic Acid Antagonists/therapeutic use , Lymphoma, T-Cell/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Aminopterin/administration & dosage , Aminopterin/adverse effects , Aminopterin/blood , Aminopterin/therapeutic use , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/adverse effects , Antibiotics, Antineoplastic/blood , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Depsipeptides/administration & dosage , Depsipeptides/adverse effects , Depsipeptides/blood , Female , Folic Acid Antagonists/administration & dosage , Folic Acid Antagonists/adverse effects , Folic Acid Antagonists/blood , Humans , Male , Middle Aged , Young Adult
2.
Pharmacotherapy ; 36(2): e8-e11, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26809959

ABSTRACT

Pralatrexate (PDX) is a folate antagonist structurally similar to methotrexate (MTX). Unlike MTX, it is currently not known whether PDX exhibits delayed clearance and heightened toxicity in the setting of fluid overload. A specific serum assay for PDX is not commercially available. To our knowledge, we report the first case using an MTX serum assay as a surrogate for PDX concentrations to avoid a potential drug-drug interaction with pralatrexate. We describe a 76-year-old man with refractory cutaneous T-cell lymphoma who began therapy with weekly PDX 15 mg/m(2) intravenous infusions on days 1, 8, and 15 of a 28-day cycle. He subsequently developed mucositis, a moderate right-sided pleural effusion, and peripheral edema over the next 5 weeks. Aggressive diuresis with furosemide was initiated, which was then withheld the day before his next PDX dose to avoid a potential drug-drug interaction between PDX and furosemide. His baseline MTX/PDX concentration (measured prior to administration of the cycle 2, week 2 PDX dose) was less than 0.20 µmol/L (i.e., undetectable). After PDX administration, his 1-hour peak MTX/PDX concentration increased to 0.58 µmol/L. Aggressive diuresis was withheld until his MTX/PDX concentration was undetectable, 43.5 hours later. PDX is more potent than MTX and displays similar pharmacokinetic properties. PDX concentrations using the serum MTX assay reflect lower values than those reported from PDX-specific assays in clinical studies. Because PDX is approved by the U.S. Food and Drug Administration for the treatment of uncommon malignancies, it is unlikely that a specific assay will be commercially developed. We propose that the MTX serum assay has merit for use in determining when to reinstate possible interacting drug therapies such as loop diuretics.


Subject(s)
Aminopterin/analogs & derivatives , Folic Acid Antagonists/blood , Lymphoma, T-Cell, Cutaneous/blood , Skin Neoplasms/blood , Aged , Aminopterin/administration & dosage , Aminopterin/blood , Aminopterin/pharmacokinetics , Aminopterin/therapeutic use , Drug Interactions , Drug Monitoring , Folic Acid Antagonists/administration & dosage , Folic Acid Antagonists/pharmacokinetics , Folic Acid Antagonists/therapeutic use , Furosemide/administration & dosage , Furosemide/adverse effects , Furosemide/therapeutic use , Humans , Infusions, Intravenous , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/physiopathology , Male , Methotrexate/analysis , Methotrexate/chemistry , Pleural Effusion/drug therapy , Pleural Effusion/etiology , Reagent Kits, Diagnostic , Skin Neoplasms/complications , Skin Neoplasms/drug therapy , Skin Neoplasms/physiopathology , Sodium Potassium Chloride Symporter Inhibitors/administration & dosage , Sodium Potassium Chloride Symporter Inhibitors/adverse effects , Sodium Potassium Chloride Symporter Inhibitors/therapeutic use , Treatment Outcome
3.
Clin Pharmacol Ther ; 86(2): 190-6, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19474785

ABSTRACT

In a pralatrexate phase I study, patients displayed a high incidence of mucositis of grades 3 and 4. Preliminary evaluations of the pharmacokinetics of the drug and its association with mucositis suggested that pralatrexate exposure (area under the concentration-time curve (AUC)) could be controlled with body size (e.g., weight or body surface area)-based dosing and that pretreatment with folic acid and vitamin B(12) might diminish the incidence and severity of mucositis. The study was amended, with revised dosing and vitamin B(12) administration. Data from 47 patients were evaluated using NONMEM. Weight and methylmalonic acid (MMA) level were predictive of pharmacokinetic (PK) variability. AUC and MMA level were positively correlated with the risk of developing mucositis. A lower AUC schedule with vitamin B(12) pretreatment may control mucositis without compromising efficacy. The covariates identified in this study are comparable with other antifolate analogs. The application of modeling was a critical step in the development of pralatrexate, yielding important suggestions for dose, scheduling, and pretreatment modifications.


Subject(s)
Aminopterin/analogs & derivatives , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Body Size , Hodgkin Disease/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Mucositis/prevention & control , Adult , Aged , Aminopterin/administration & dosage , Aminopterin/adverse effects , Aminopterin/blood , Aminopterin/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Area Under Curve , Biomarkers/blood , Drug Administration Schedule , Female , Folic Acid Antagonists/administration & dosage , Folic Acid Antagonists/pharmacology , Humans , Incidence , Male , Methylmalonic Acid , Middle Aged , Models, Statistical , Mucositis/chemically induced , Predictive Value of Tests , Recurrence , Severity of Illness Index , Vitamin B 12/administration & dosage
4.
Transl Res ; 150(6): 367-73, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18022599

ABSTRACT

Aminopterin (AMT), like the related compound methotrexate (MTX), is a drug with anticancer and antiinflammatory efficacy that works by interfering with synthetic reactions dependent on the vitamin folic acid. Red blood cell (RBC) precursors will accumulate antifolates like AMT and MTX through the same mechanism by which they take up folate. Intracellular folate and antifolates are then metabolized to polyglutamates that remain within the mature RBCs. RBC MTX has been correlated with toxicity and/or treatment efficacy among patients with acute lymphoblastic leukemia (ALL) or rheumatoid arthritis. Because AMT may offer clinically relevant advantages over MTX, we are testing whether it can be administered safely in multiagent therapy to children with ALL. Total RBC AMT was measured to monitor compliance with this oral, outpatient regimen, and to estimate AMT exposure to the bone marrow. Here we describe methods for quantifying each AMT-polyglutamate species within the RBCs of patients. The assay was linear over a concentration range of 62.5-500 nmol/L. Recovery of individual AMT-polyglutamates ranged from 85% to 92%, and the intraday coefficients of variation were 1.3% to 3.6%. Long-chain AMT-polyglutamates (triglutamate and tetraglutamate forms) accounted for over 40% of intracellular AMT within the RBCs of patients. Patients with long-chain AMT polyglutamate concentrations above the median tended to have lower mean neutrophil counts during weekly AMT therapy, which suggests that RBC AMT polyglutamate accumulation may correlate with hematologic toxicity. As AMT continues to be tested in clinical trials, the methods described here will be useful to define relationships between clinical response to AMT and RBC accumulation of AMT-polyglutamates.


Subject(s)
Aminopterin/blood , Chromatography, High Pressure Liquid/methods , Erythrocytes/chemistry , Methotrexate/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Administration, Oral , Adolescent , Adult , Aminopterin/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Child , Child, Preschool , Erythrocytes/metabolism , Folic Acid Antagonists/administration & dosage , Folic Acid Antagonists/blood , Humans , Infant , Methotrexate/administration & dosage , Polyglutamic Acid/metabolism , Reference Standards , Tissue Distribution
5.
Clin Cancer Res ; 11(22): 8089-96, 2005 Nov 15.
Article in English | MEDLINE | ID: mdl-16299240

ABSTRACT

PURPOSE: To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro. EXPERIMENTAL DESIGN: Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro. RESULTS: Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. CONCLUSIONS: Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.


Subject(s)
Aminopterin/therapeutic use , Folic Acid Antagonists/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Administration, Oral , Adolescent , Adult , Aged , Aminopterin/blood , Aminopterin/pharmacokinetics , Area Under Curve , Child , Child, Preschool , Drug Resistance, Neoplasm , Female , Folic Acid Antagonists/pharmacokinetics , Hematopoietic Stem Cells/metabolism , Humans , Leukemia, Myeloid, Acute/ethnology , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/ethnology , Treatment Outcome
6.
J Chromatogr B Biomed Sci Appl ; 695(2): 401-8, 1997 Aug 01.
Article in English | MEDLINE | ID: mdl-9300877

ABSTRACT

Gamma-methylene-10-deazaaminopterin (MDAM), a unique dihydrofolate reductase inhibitor, has demonstrated antitumor activity against a broad spectrum of human solid tumors in preclinical studies. A novel reversed-phase, ion-pair high-performance liquid chromatography (HPLC) assay that uses fluorescence detection has been developed to quantitate levels of MDAM and its major metabolite, 7-hydroxy-gamma-methylene-10-deazaaminopterin (7-OH-MDAM), in human plasma. The recovery of MDAM and 7-OH-MDAM from plasma was >97% by a simple one-step deproteinization process using tetrabutylammonium bromide (TBABr) and methanol. MDAM and 7-OH-MDAM remained stable in plasma over a 28-day test period at ambient temperatures, and neither compound was light-sensitive. The limit of quantitation was 0.005 microM for both MDAM and 7-OH-MDAM. This assay has been found to be simple, sensitive and reproducible in determining plasma concentrations of MDAM and 7-OH-MDAM in patients with solid cancers in a phase I trial.


Subject(s)
Aminopterin/analogs & derivatives , Antineoplastic Agents/blood , Neoplasms/blood , Pterins/blood , Aminopterin/blood , Aminopterin/therapeutic use , Antineoplastic Agents/therapeutic use , Chromatography, High Pressure Liquid , Humans , Neoplasms/drug therapy , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Fluorescence
7.
J Pharm Biomed Anal ; 11(10): 939-46, 1993 Oct.
Article in English | MEDLINE | ID: mdl-8305599

ABSTRACT

Aminopterin was studied as a model compound for its analogues which maintain the pteridine ring in their structure. Its adsorptive behaviour on mercury was studied and the DC adsorptive stripping and phase-selective AC adsorptive stripping conditions were optimized. 10-Edam, an aminopterin analogue, was studied and shown to behave similarly to aminopterin. Phase-selective AC voltammetry provided the best signal and gave a detection limit of 4 x 10(-12) M aminopterin in aqueous solution employing an accumulation time of 10 min. The optimized method was applied to the analysis of both aminopterin and 10-Edam respectively in human serum. After extraction with a C18 reversed-phase cartridge the detection limit of the method was 1 x 10(-8) M aminopterin and the overall assay percentage recovery was 73.5% (n = 5) at a concentration of 5 x 10(-7) M aminopterin in serum. The analysis of 10-Edam at the same concentration in serum yielded the higher percentage recovery of 94.46% (n = 5) following the same procedure.


Subject(s)
Aminopterin/analogs & derivatives , Aminopterin/blood , Chemistry Techniques, Analytical/methods , Adsorption , Aminopterin/chemistry , Humans , Mercury
8.
Cancer Chemother Pharmacol ; 31(4): 328-32, 1993.
Article in English | MEDLINE | ID: mdl-8380758

ABSTRACT

We studied the pharmacokinetics of 10-ethyl-10-deaza-aminopterin (10-EdAM), edatrexate and its 7-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m2 was given weekly, with dose reduction being undertaken for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was seen, the mean half-lives being 0.10 +/- 0.07, 0.8 +/- 0.3 and 7 +/- 7 h, respectively. The mean plasma clearance was 25 +/- 14 l/h, with 18% +/- 11% of the dose appearing unchanged in the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) with r2 = 0.976. There was considerable variation of the clearance both within and between patients but there was no evidence of a dependence on time or dose. The 1-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was shown to be related to both the AUC of the drug and that of its 7-OH metabolite.


Subject(s)
Aminopterin/analogs & derivatives , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , Aminopterin/blood , Aminopterin/pharmacokinetics , Aminopterin/therapeutic use , Antineoplastic Agents/blood , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Chromatography, High Pressure Liquid , Creatinine/metabolism , Half-Life , Humans , Lung Neoplasms/drug therapy , Metabolic Clearance Rate
9.
J Chromatogr ; 529(1): 135-43, 1990 Jul 13.
Article in English | MEDLINE | ID: mdl-2211926

ABSTRACT

10-Ethyl-10-deaza-aminopterin (10-EdAM) is a novel folic acid antimetabolite currently being tested in phase II clinical trials. We have developed an isocratic high-performance liquid chromatographic method for the quantification of 10-EdAM and metabolites in plasma. Solid-phase extraction was used for sample clean-up. Adequate accuracy was obtained without the use of an internal standard. Fluorometric detection with excitation at 243 nm and emission at 488 nm was used for accurate quantification of samples containing small amounts of drug or metabolites (2.0-4.0 nM, depending on the compound). Ultraviolet detection at 350 nm was only applicable for the analysis of plasma concentrations of 10-EdAM exceeding 50 nM. The usefulness of the assay was demonstrated by the results obtained in a pharmacokinetic study. The assay could separate the parent compound from seven identified and two unknown products.


Subject(s)
Aminopterin/analogs & derivatives , Folic Acid Antagonists/blood , Aminopterin/blood , Aminopterin/metabolism , Chromatography, High Pressure Liquid/methods , Folic Acid Antagonists/metabolism , Humans
10.
Anal Biochem ; 150(1): 203-13, 1985 Oct.
Article in English | MEDLINE | ID: mdl-2417507

ABSTRACT

The antifolate compounds 10-deazaaminopterin (10-dAM) and 10-ethyl-10-deazaaminopterin (10-EdAM) are therapeutically superior to methotrexate in transplanted murine tumor systems and in human tumor xenografts growing in immunodeficient "nude" mice. The increased therapeutic index of these analogs correlates with their selective uptake, retention, and polyglutamation within neoplastic cells. We have developed a fluorescence high-performance liquid chromatographic assay applicable to 10-dAM, 10-EdAM, their polyglutamate anabolites, and their 7-hydroxy (7-OH) and deglutamate catabolites. The assay is based upon the high native fluorescence of pteridine-containing compounds which contain carbon in the 10 position. The assay employs a reverse-phase C-18 column and an ascending acetonitrile gradient in 50 mM phosphate, pH 7.0. The compounds are extracted from plasma and urine with 95 +/- 7% and 98 +/- 2% recoveries, respectively, using C-18 Sep-Paks. The linear range of the assay is, for 10-dAM, 2-100 nM, and for 10-EdAM, 1-100 nM. Polyglutamated metabolites of [3H]10-EdAM isolated from L1210 cells have been separated by HPLC with identification of five derivatives (Glu 1-5) confirmed by enzymatic peak shift using serum conjugase and by quantitative correlation of fluorescence intensity, radioactivity, and titration inhibition of dihydrofolate reductase. The assay has been used successfully in pharmacokinetic analyses of plasma and urine samples from patients receiving 10-dAM and 10-EdAM. In patients who had received 10-EdAM, 7-OH-10-EdAM, and the deglutamate catabolite were also detected. This HPLC fluorescence assay is superior to the dihydrofolate reductase inhibition and binding assays with regard to specificity and precision; moreover, it can provide a means for simultaneous assay of the physiologically important anabolites and catabolites of these new antifolates.


Subject(s)
Aminopterin/analogs & derivatives , Aminopterin/blood , Aminopterin/metabolism , Aminopterin/urine , Animals , Chromatography, High Pressure Liquid , Humans , Leukemia L1210/metabolism , Mice , Mice, Nude , Neoplasms/blood , Neoplasms/urine , Polyglutamic Acid/metabolism , Spectrometry, Fluorescence
11.
J Clin Chem Clin Biochem ; 18(3): 169-74, 1980 Mar.
Article in English | MEDLINE | ID: mdl-6991631

ABSTRACT

A homogeneous enzyme immunoassay for the determination of methotrexate in serum (EMIT, Syva Corp.) was fully mechanized by the use of an Eppendorf analyzer 5010. Coefficients of variation from day to day were in the range 2--16%. A comparison of the results obtained by EMIT and a radioimmunoassay (Methotrexate 125 I Radioimmunoassay Kit, Diagnostic Biochemistry Inc.) in a series of 50 samples from patients showed a good correlation between both methods. The specificity of the EMIT assay appeared to be adequate. The time required for the determination of about 20 patient samples by this procedure was only about 80 minutes. From our clinical experimence the EMIT assay appears to be well suited for routine monitoring of methotrexate serum concentrations above 0.1 mumol/1 during intrathecal and high dose methotrexate therapy.


Subject(s)
Methotrexate/blood , Adult , Aminopterin/blood , Autoanalysis/methods , Costs and Cost Analysis , Female , Humans , Immunoenzyme Techniques , Kinetics , Methotrexate/therapeutic use , Neoplasms/blood , Neoplasms/drug therapy , Osteosarcoma/blood , Osteosarcoma/drug therapy
12.
Cancer Res ; 39(9): 3707-14, 1979 Sep.
Article in English | MEDLINE | ID: mdl-383286

ABSTRACT

We have conducted a Phase 1 study of aminopterin (AMT) with leucovorin (LV) in 17 patients. AMT was administered by bolus injection every 7 to 14 days in dosages from 25 to 425 mg/sq m. LV rescue was instituted at 24 hr and continued for 48 to 72 hr. At dosages above 50 mg/sq m, we observed nephrotoxicity defined as greater than or equal to a 25% increase in serum creatinine 24 hr after AMT administration, but its incidence was not strictly dose related. Urinary alkalinization and volume expansion appeared to reduce the incidence of nephrotoxicity. Nephrotoxic drug courses were associated with 24-hr plasma AMT levels [3.6 +/- 2.0 (S.D.) X 10(-6) M] which were significantly higher than nonnephrotoxic courses (1.6 +/- 1.0 x 10(-6) M) (p less than 0.05). In nonnephrotoxic courses, serum elimination pharmacokinetics appeared to be biphasic with a t1/2 alpha of 1.08 +/- 0.01 hr and t1/2 beta of 12.31 +/- 0.06 hr. Systemic toxicity (myelosuppression and mucositis) could be prevented in patients with impaired AMT clearance by the administration of LV at an increased dose rate. In several courses, systemic toxicity occurred in spite of apparently normal plasma clearance, suggesting that 24-hr plasma levels may not accurately reflect intracellular drug effects. Cytokinetic studies on bone marrow aspirates allowed determination of the rescue effect of LV and may prove useful in predicting marrow protection.


Subject(s)
Aminopterin/administration & dosage , Leucovorin/administration & dosage , Neoplasms/drug therapy , Aminopterin/adverse effects , Aminopterin/blood , Bone Marrow/drug effects , Bone Marrow/metabolism , Clinical Trials as Topic , Drug Administration Schedule , Humans , Kidney/drug effects , Leukopenia/chemically induced , Methotrexate , Neoplasm Metastasis/drug therapy , Solubility
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