Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Acetylshikonin isolated from Lithospermum erythrorhizon roots inhibits dihydrofolate reductase and hampers autochthonous mammary carcinogenesis in Δ16HER2 transgenic mice.

Breast cancer (BC) is the most common cancer in women and, among different BC subtypes, triple negative (TN) and human epidermal growth factor receptor 2 (HER2)-positive BCs have the worst prognosis. In this study, we investigated the anticancer activity of the root ethanolic and hexane extracts from Lithospermum erythrorhizon, a traditional Chinese herbal medicine known also as tzu ts'ao or tzu-ken, against in vitro and in vivo models of TNBC and HER2-positive BC. Treatment with L. erythrorhizon root extracts resulted in a dose-dependent inhibition of BC cell viability and in a significant reduction of the growth of TNBC cells transplanted in syngeneic mice. Acetylshikonin, a naphthoquinone, was identified as the main bioactive component in extracts and was responsible for the observed antitumor activity, being able to decrease BC cell viability and to interfere with autochthonous mammary carcinogenesis in Δ16HER2 transgenic mice. Acetylshikonin anticancer effect depends on its ability to act as a potent inhibitor of dihydrofolate reductase (DHFR), to down-regulate key mediators governing cancer growth and progression, such as HER2, Src and STAT3, and to induce apoptosis by caspase-3 activation. The accumulation of acetylshikonin in blood samples as well as in brain, kidney, liver and tumor tissues was also investigated by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) highlighting that L. erythrorhizon treatment is effective in delivering the active compound into the target tissues. These results provide evidence that L. erythrorhizon extract and in particular its main component acetylshikonin are effective against aggressive BC subtypes and reveal new acetylshikonin mechanisms of action.

Red blood cell folate concentrations and polyglutamate distribution in juvenile arthritis: predictors of folate variability.

OBJECTIVE: Methotrexate (MTX) has several enzymatic targets in the folate pathway. To better understand the variability in response to MTX, we characterized the interindividual variability of intracellular folate pools in children with juvenile arthritis (JA) and determined clinical and genetic contributors to this variability. STUDY DESIGN: This exploratory single-center cross-sectional study evaluated 93 patients with JA not currently receiving MTX. Whole blood, plasma, and erythrocyte folate concentrations were determined after deconjugation and analyzed through reversed-phase separation and stable isotope dilution tandem mass spectrometry. Folate polyglutamates were measured in red blood cell lysates using an ion-pair reversed phase chromatography tandem mass spectrometry method. RESULTS: Intracellular concentrations of 5-methyl-tetrahydrofolate (5-CH3-THF) and 5,10-methenyl-tetrahydrofolate varied approximately 20-fold and 80-fold, respectively. The polyglutamated forms of 5-CH3-THF as a percentage of total 5-CH3-THF (5-CH3-THFGlun) were also measured. Hierarchical clustering of 5-CH3-THFGlun revealed two groups, each with two distinct clusters. There was an inverse relationship between 5-CH3-THFGlun chain length and plasma 5-CH3-THF concentrations. A subgroup of patients with a historical intolerance to MTX had significantly lower cellular folate concentrations (P<0.0001). In univariate analyses, clinical variables including sex, age, and folate supplementation in addition to variations in MTHFR, MTR, and SLC25A32 were associated with differential intracellular folate redox concentrations. Multivariate analysis further supported the association of single nucleotide polymorphisms in SLC25A32, MTHFR, and MTR with variability in intracellular 5-CH3-THF and 5,10-methenyl-tetrahydrofolate concentrations, respectively. CONCLUSION: Measurement of intracellular folate isoforms may contribute toward a better understanding of individual MTX effects in JA. Clinical variables in addition to genotypic differences beyond MTHFR may additionally explain differential intracellular folate concentrations and variable responses to MTX.

Pralatrexate: a novel synthetic antifolate for relapsed or refractory peripheral T-cell lymphoma and other potential uses.

PURPOSE: The pharmacology, pharmacokinetics, clinical trials, adverse effects, dosage, and economic considerations of pralatrexate (PDX) are reviewed. SUMMARY: Peripheral T-cell lymphoma (PTCL) comprises approximately 15-20% of all aggressive lymphomas and 5-10% of all non-Hodgkin's lymphomas. Advanced PTCL is often refractory to traditional first-line chemotherapy regimens. PDX was developed as a synthetic folate analog antimetabolite that competitively inhibits dihydrofolate reductase (DHFR). This results in the depletion of thymidine, leading to interference with deoxyribonucleic acid synthesis and cancer cell death. PDX has a higher potency than methotrexate and edatrexate (EDX). The efficacy and safety of PDX have been demonstrated in the PROPEL trial, a prospective phase II trial in patients with relapsed or refractory PTCL. Patients with prior stem cell transplantation receiving PDX also had similar response rates (RRs). PDX was investigated on the treatment of relapsed or refractory cutaneous T-cell lymphoma, previously treated advanced non-small cell lung cancer and other solid malignancies. PDX has similar side effects to other DHFR inhibitors. The most common side effect of PDX is mucositis. The recommended dose of PDX is 30 mg/m(2) weekly once for 6 weeks in 7-week cycle until disease progresses or unacceptable toxicity for PTCL and may require dose reduction or discontinuation. Patients should be supplemented with oral folic acid and intramuscular vitamin B(12) injections. CONCLUSION: PDX provides clinical benefit to patients with relapsed or refractory PTCL with durable complete and partial responses in patients who had not responded to multiple prior treatment regimens.

Pralatrexate with vitamin supplementation in patients with previously treated, advanced non-small cell lung cancer: safety and efficacy in a phase 1 trial.

INTRODUCTION: Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities. METHODS: Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response. RESULTS: Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2). CONCLUSIONS: Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.

Evaluation of the pharmacokinetics, preclinical and clinical efficacy of pralatrexate for the treatment of T-cell lymphoma.

INTRODUCTION: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of T-cell neoplasms. Most patients with PTCL have a poor outcome with conventional therapies and are not cured without stem-cell transplantation. Pralatrexate, a novel antifolate chemotherapeutic agent, was rationally designed to impede folate metabolism by inhibiting dihydrofolate reductase (DHFR) and to be more efficiently internalized into tumor cells. Pralatrexate is the first drug that is FDA approved for patients with relapsed and refractory PTCL. AREAS COVERED: Pralatrexate has been used as a single agent and in combination with other agents in clinical trials for non-Hodgkin's lymphoma and Hodgkin's disease as well as in solid tumors. This review will cover the development of pralatrexate, the pharmacokinetics of pralatrexate, preclinical findings with pralatrexate and clinical studies of pralatrexate in hematologic malignancies. EXPERT OPINION: Pralatrexate has significant activity in vitro, and in early Phase I/II trials, responses were noted in patients with aggressive T-cell lymphomas. The Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma trial demonstrated the activity of pralatrexate across a spectrum of heavily pretreated patients with different aggressive T-cell lymphoma subtypes, and studies in cutaneous T-cell lymphoma have shown efficacy at different doses and schedules. The most frequent adverse events in these trials were mucositis, reversible thrombocytopenia and fatigue.

Pharmacokinetic evaluation of pemetrexed.

INTRODUCTION: Pemetrexed is a multi-targeted antifolate cytotoxic agent that has demonstrated activity in a number of very common cancer types including NSCLC in both first- and second-line settings and in the treatment of malignant mesothelioma. AREAS COVERED: This article focuses on all of the currently published pharmacokinetic data of pemetrexed reviewing a number of different scenarios and patient populations. All the articles reviewed in this manuscript are from peer-reviewed English-spoken literature without any limitations to the time of publication. EXPERT OPINION: Pemetrexed's clearance correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic or targeted agents. It is the author's opinion that pemetrexed is already a valuable cytotoxic agent which has proved useful in several malignancies. However, future trials might expand on the combined use of pemetrexed with other targeted agents that could be beneficial to other selected patients harboring relevant mutations or other biological features.

Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate.

INTRODUCTION: Folate receptor (FR)-expressing macrophages have been shown to accumulate at sites of inflammation, where they promote development of inflammatory symptoms. To target such a macrophage population, we designed and evaluated the biologic activity of EC0746, a novel folic acid conjugate of the highly potent antifolate, aminopterin. METHODS: Using a FR-positive subclone of murine macrophage-derived RAW264.7 cells and rat thioglycollate-elicited macrophages, we studied the effect of EC0746 on dihydrofolate reductase activity, cell proliferation, and cellular response towards bacterial lipopolysaccharide as well as IFNγ activation. The EC0746 anti-inflammatory activity, pharmacokinetics, and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis; that is, a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans. RESULTS: EC0746 suppresses the proliferation of RAW264.7 cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model, brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly, EC0746 therapy is also shown to be ~40-fold less toxic than unmodified aminopterin, with fewer bone marrow and gastrointestinal problems. CONCLUSIONS: EC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory activities both in vitro and in vivo. Our data reveal that a relatively toxic anti-inflammatory drug, such as aminopterin, can be targeted with folic acid to inflammatory macrophages and thereby relieve inflammatory symptoms with greatly reduced toxicity.

Liposomal M-V-05: formulation development and activity testing of a novel dihydrofolate reductase inhibitor for breast cancer therapy.

In the management of metastatic breast cancer, fewer recognized therapeutic standards are available as compared to the early stages of the disease. Thus, it is pertinent to search for new, effective therapy to improve survival, tolerability and quality of life of patients. In this study, a liposomal formulation was developed for a novel dihydrofolate reductase (DHFR) inhibitor, M-V-05. Drug encapsulation into liposomes was achieved by the citrate-based, pH gradient loading technique, with a final drug-to-lipid weight ratio of 0.1:1. The liposome formulation exhibited a sustained release profile of the encapsulated drug that followed first order release kinetics. Liposomal M-V-05 was found to be more effective than the standard DHFR inhibitor, methotrexate, and its activity was comparable to liposomal doxorubicin, with IC50 values of 37 and 59 microM achieved in MDA-MB-231 and JIMT-1 cells, respectively. Similar cytotoxicity was observed in primary patient samples of invasive ductal carcinoma of the breast. The combination of liposomal M-V-05 and liposomal doxorubicin in fixed molar ratio of 3:1 was additive in cytotoxicity, allowing the concentrations of liposomal doxorubicin and liposomal M-V-05 to be reduced by 62 and 46%, respectively. Taken together, liposomal M-V-05 represents a promising agent and offers a potential new adjuvant therapy for breast cancer treatment.

The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission-induction period of treatment for moderate-to-severe plaque psoriasis.

OBJECTIVE: We assessed the effect of folic acid (FA) on the pharmacokinetics and pharmacodynamics of low-dose oral methotrexate (MTX) during the remission-induction phase of psoriasis treatment. METHODS: In a 32-week, open-label, two-way cross-over study, patients (n=20, seven men, aged 35-70 years) with moderate-to-severe plaque psoriasis were randomly assigned to receive MTX plus FA (20 mg/week) for 16 weeks followed by MTX monotherapy (three doses of MTX separated by 12-h intervals once a week) for an additional 16 weeks (treatment arm A, n=10) or to receive the opposite sequence of treatments (arm B, n=10). Dosing of MTX was individualised with the help of pre-study evaluation of plasma MTX pharmacokinetics. The Psoriasis Area and Severity Index (PASI), biochemistry and haematology tests and erythrocyte concentration of MTX polyglutamates (MTXPG) were evaluated throughout the study. RESULTS: In arms A and B, the mean (range) concentrations of MTXPG (nmol/L) were comparable [week 16: 96.2 (32.0-157) vs. 111 (73.7-175), P=0.32; week 32: 103 (55.8-173) vs. 83.6 (27.4-129), P=0.24]. After 16 weeks, the mean+/-SEM PASI decreased from 20.1+/-2.1 to 8.8+/-1.3 in arm A, while a greater reduction from 27.2+/-2.1 to 5.1+/-1.0 occurred in arm B (P<0.001). Positive correlations were found between the percent improvement in PASI at week 16 and the ratios of the concentration of MTXPG to plasma folate (rho=0.59, P=0.008) or RBC folate concentration (rho=0.56, P=0.013). Due to an accelerated decline in PASI in arm A and a trend to its worsening in arm B after crossing over of treatments, the mean absolute PASI scores in both arms were comparable at week 32. CONCLUSION: The antipsoriatic effect of MTX during the remission-induction phase of treatment is influenced by folate status and may be significantly less if combined treatment with FA is used, irrespective of pre-treatment folate levels. The individual tailoring of MTX dosing needs further attention because the mean percent PASI improvement from baseline was 83% and the inter-patient variability in response was low after 16 weeks of monotherapy with MTX.

[Pemetrexed: from preclinic to clinic]. / Pemetrexed: de la préclinique à la clinique.

The pemetrexed (Alimta) is a new generation antifolate prescribed in the treatment of mesothelioma in association with cisplatin and in the 2nd line treatment of locally advanced or metastatic non-small lung cancer. Pemetrexed is an original molecule, different from the other antifolates. On the opposite methotrexate, pemetrexed inhibits several enzymes involved in the synthesis of purines and pyrimidines, in particular thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase. Pemetrexed is transported in cells by three receptors, which make easier its cellular penetration. On the other hand, the polyglutamation of the product by the folylpolyglutamate synthetase increases considerably its activity notably towards the thymidylate synthase. Finally, unlike methotrexate, pemetrexed presents an atypical effect on cellular synchronisation. The wide spectre of activity of pemetrexed confers it a therapeutic advantage with regard to the other antifolates specific of one or other one enzymes. The clinical results show an anti-tumoral activity against non-small lung cancer and in mesothelioma and recently towards other solid tumours, in particular in head an neck, colon and mammary cancers.

Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability.

Pemetrexed is a novel antifolate recently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. In clinical regimens, pemetrexed is administered in conjunction with folic acid to minimize toxicity. However, excessive folate supplementation may also diminish the activity of this agent. The current study demonstrates, in several human solid tumor cell lines, that when extracellular 5-formyltetrahydrofolate levels are increased in vitro, within the range of normal human blood levels, there is a substantial decrease in pemetrexed activity upon continuous exposure to the drug. This was accompanied by a comparable lower level of trimetrexate activity consistent with an expansion of tumor cell folate pools. Likewise, when cells were exposed to pemetrexed with a schedule that simulates in vivo pharmacokinetics, there was markedly less cell killing with higher extracellular folate levels. Data are provided to indicate that 5-formyltetrahydrofolate is an acceptable surrogate for 5-methyltetrahydrofolate, the major blood folate, for this type of in vitro study. These observations and other reports suggest that, in view of the rise in serum folate and fall in serum homocysteine that has accompanied folic acid supplementation of food in the U.S., the addition of folic acid to regimens with pemetrexed should be limited to the lowest recommended level that provides optimal protection from pemetrexed toxicity.

Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: the Children's Oncology Group.

PURPOSE: We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. PATIENTS AND METHODS: Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. RESULTS: Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. CONCLUSION: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

Resistance to sulphadrug-based antifolate therapy in malaria: are we looking in the right place?

Sulphadrug treatment failure in malaria therapy cannot solely be ascribed to the build-up of genetic resistance within the parasitic genome. Although numerous in vitro studies have tried to determine the exact genetic markers that could predict treatment outcome in patients, this research has not been conclusive. Sulphadrugs work by competitive inhibition with pABA at one point of the pathway to de novo folate synthesis. However, evidence suggests that the malaria parasite is capable of overcoming this competitive inhibition by switching over to other metabolic pathways, like direct folate salvage from a person's bloodstream. In other words, increased folic acid administration, via diet or supplementation, may have reduced the effectiveness of sulphadrugs more than genetic mutations. Although in vitro studies are valuable for understanding disease mechanisms, we should not forget that the human being is infinitely more complex than any laboratory model.

Pemetrexed, a novel antifolate therapeutic alternative for cancer chemotherapy.

Pemetrexed is a newly approved antifolate agent for the treatment of malignant pleural mesothelioma (MPM) and metastatic non-small cell lung cancer (NSCLC). We performed a PubMed/MEDLINE database search to identify relevant literature from January 1966-April 2005. Bibliographies from identified references were searched as well, as were abstracts from the 2004 and 2005 proceedings of the American Society of Clinical Oncology. We discuss the pharmacology of pemetrexed, describing its mechanism of action and comparing it with methotrexate. The pharmacokinetics and pharmacodynamics of pemetrexed are described to provide a better understanding of the properties of this drug. Therapeutic uses are assessed, beginning with the approved indications of MPM and NSCLC. However, pemetrexed has been studied in numerous phase II trials for other types of solid malignancies, and completed trials are reviewed. Data on adverse effects and drug interactions are also provided. Finally, dosing and administration are reviewed, including appropriate premedication. Premedication, including administration of steroids and vitamin supplements, has been shown to decrease the frequency and severity of pemetrexed toxicities. Pemetrexed should be used as a standard of care for unresectable MPM and recurrent metastatic NSCLC.

Pemetrexed: a multitargeted antifolate.

BACKGROUND: The US Food and Drug Administration approved pemetrexed in February 2004 for the treatment of malignant pleural mesothelioma (MPM) in combination with cisplatin in patients with unresectable disease or for whom curative surgery is not an option. Pemetrexed is the first agent approved for the treatment of MPM. In August 2004, pemetrexed was approved as a second-line, single-agent treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). OBJECTIVES: The goals of this article were to summarize the pharmacology, pharmacokinetics, efficacy, and safety of pemetrexed, and to review its current and potential roles in therapy for MPM, NSCLC, and other oncologic conditions. METHODS: Relevant English-language literature was identified through searches of PubMed (1966-December 2004), International Pharmaceutical Abstracts, and the Proceedings of the American Society of Clinical Oncology (January 1995-December 2004). Search terms included pemetrexed, Alimta, MTA, multitargeted antifolate, LY231514, mesothelioma, MPM, non-small cell lung cancer, NSCLC, breast cancer, and pancreatic cancer. In addition to published literature, abstracts and posters presented at national and international scientific meetings were reviewed. RESULTS: Myelosuppression was the predominant dose-limiting toxicity of pemetrexed reported in Phase I studies. Identification of the correlation between poor folate status and increased pemetrexed toxicity in a multivariate analysis led to the requirement of folic acid and vitamin B12 supplementation for patients in all pemetrexed studies, with a resulting noted decrease in pemetrexed toxicity. A single, multicenter, randomized Phase III trial compared the efficacy of pemetrexed in combination with cisplatin versus cisplatin alone in the treatment of MPM. Response rates were 41.3% in the pemetrexed/cisplatin combination and 16.7% with single-agent cisplatin (P < 0.001). The median survival time for the pemetrexed/cisplatin combination was significantly longer at 12.1 months versus 9.3 months for cisplatin alone (P = 0.02). One international, multicenter, randomized Phase III trial in patients with NSCLC compared single-agent pemetrexed versus docetaxel in patients previously treated with chemotherapy. Overall response rates (9.1% and 8.8%) and median survival (8.3 months and 7.9 months) did not differ between pemetrexed and docetaxel (P = 0.105 and P = 0.226, respectively). Hematologic adverse effects-grade 3/4 neutropenia (40.2% vs 5.3%; P < 0.001), febrile neutropenia (12.7% vs 1.9%; P < 0.001), and neutropenic infections (3.3% vs 0%; P = 0.004)-were significantly greater in the docetaxel-treated patients than in the pemetrexed-treated patients, as was alopecia (37.7% vs 6.4%; P < 0.001). Results of an international, multicenter Phase III trial of pemetrexed in combination with gemcitabine conducted in patients with pancreatic cancer indicate that the combination is no more efficacious than single-agent gemcitabine. Results in other disease states are still preliminary. CONCLUSIONS: Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in various tumor types as a single agent and in combination with other chemotherapeutic agents. Efficacy for the treatment of MPM in combination with cisplatin has been demonstrated, and approval as a second-line agent in NSCLC was based on response rate as a surrogate end point for survival. The addition of folic acid and vitamin B12 supplementation markedly reduced.

High-dose methotrexate in acute lymphoblastic leukemia: where is the evidence for its continued use?

High-dose intravenous methotrexate is an important component of many effective chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL). Its use has a strong pharmacologic rationale: to overcome mechanisms of resistance of the malignant cells and to achieve cytotoxic concentrations in sanctuary sites for lymphoblasts. Although therapeutic progress in ALL during the past 4 decades has been closely associated with more widespread use of intravenous methotrexate and in progressively larger doses, little data exist to clearly support the use of high-dose intravenous methotrexate over a regimen of prolonged administration of low-dose methotrexate. The implied superiority of intravenous methotrexate mainly stems from studies that used identical leucovorin rescue with low-dose methotrexate or from studies of upfront window therapy in untreated children with ALL in which single standard doses of oral methotrexate were compared with high-dose intravenous methotrexate with leucovorin rescue. The evidence favoring administration of intravenous methotrexate for children with ALL is critically reviewed. Despite its extensive use, high-dose intravenous methotrexate has not been proved conclusively to be more effective than less toxic, less labor intensive, and less costly methods of methotrexate administration.

Biochemical pharmacology of pemetrexed.

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated activity in clinical trials in a variety of tumor types, including lung, breast, colon, mesothelioma, pancreatic, gastric, bladder, head and neck, and cervix. Pemetrexed is rapidly metabolized into active polyglutamate forms that are potent inhibitors of several tetrahydrofolate cofactor-requiring enzymes critical to the synthesis of purines and thymidine. Functionally, pemetrexed acts as a prodrug for its polyglutamate forms. Two different transporters are known to take extracellular folates, and some antifolates, into the cell. These are the reduced folate carrier and the folate receptor. One of the many attributes that make pemetrexed unique is that methodology has been developed to eliminate and control the many of its associated clinical toxicities. Multivariate analyses demonstrated that pretreatment total plasma homocysteine levels significantly predicted severe thrombocytopenia and neutropenia, with or without associated grade 3/4 diarrhea, mucositis, or infection. Routine vitamin B12 and folic acid supplementation have resulted in decreased frequency/severity of toxicities associated with pemetrexed without affecting efficacy, making this novel antifolate a safe and efficacious anticancer agent.

Pemetrexed (Alimta): a novel multitargeted antifolate agent.

Pemetrexed (Alimta) is a novel, multitargeted antifolate that inhibits at least three of the enzymes involved in folate metabolism, and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated broad antitumor activity in Phase II trials in a wide variety of solid tumors, including mesothelioma, non-small cell lung, breast, cervical, colorectal, head and neck, and bladder cancers. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine (Gemzar). A pivotal Phase III study in mesothelioma has been presented. This study indicates the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. The most significant toxicities of pemetrexed, myelosuppression and mucositis have been significantly ameliorated by folate and vitamin B12 supplementation. More importantly, vitamin supplementation has not demonstrated any adverse efficacy. This review discusses the biochemistry and clinical activity of pemetrexed.

A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate, pemetrexed.

Pemetrexed is a novel antifolate effective in the treatment of mesothelioma. Studies were undertaken to characterize the transport of this antifolate in this tumor. We report the presence of a novel, concentrative high-affinity transport activity in three human mesothelioma cell lines, characterized in detail in the NCI-H28 line, with a pemetrexed influx K(t) of 30 nM and V(max) of 10 nmol/g protein/min. This route is highly specific for pemetrexed, with a substrate specificity pattern quite different from that of the reduced folate carrier and folate receptors. In particular, there is an apparent relatively low affinity for other antifolate inhibitors of dihydrofolate-reductase (MTX, aminopterin, PT523) and thymidylate synthase (ZD1694, ZD9331). Besides its impact on the transport of pemetrexed, this high-affinity route may represent another pathway by which physiological folates are transported into human cells.