Phase II study of E7070 in patients with metastatic melanoma.

E7070 is a synthetic chloro-indolyl sulphonamide that is being developed as an anti cancer agent. In this phase II study, 28 patients with metastatic melanoma received 700 mg/m(2) of E7070 as a 60-min infusion repeated every 3 weeks. Although therapy was well tolerated, with one patient receiving 14 courses of treatment, there were only minor responses on independent radiological review. E7070 does not warrant further development as a single agent for the treatment of metastatic melanoma.

In vitro pharmacokinetic study of the novel anticancer agent E7070: red blood cell and plasma protein binding in human blood.

E7070 is a novel sulfonamide anticancer agent that arrests the G(1)/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics (PK) of the drug. A population PK analysis revealed that the human plasma concentration-time data were best described by a three-compartment model with non-linear distribution. We have studied the in vitro interaction of 14C-radiolabeled E7070 with red blood cells (RBC) and its binding to plasma proteins in the concentration range where non-linearity in disposition was observed in humans to get more insight into the behavior of the drug. After the addition of E7070 to whole blood at 37 degrees C, the drug is taken up or binds to RBC in a concentration-dependent manner. The addition of sodium azide, however, did not result in a decrease of drug uptake by RBC, indicating passive diffusion processes. A non-linear increase in drug uptake was observed at incubation concentrations above 4 microg/ml E7070 in whole blood. This non-linearity was confirmed by lower partition coefficients between RBC and plasma at higher incubation concentrations (from 2.37 at 4 microg/ml to 0.31 at 200 microg/ml). The plasma protein binding of E7070 was high (98-99%) and linear in the concentration range studied (20-200 microg/ml). In conclusion, E7070 in whole blood is preferentially bound to RBC and exhibits high plasma protein binding. The non-linear distribution of E7070 in humans can be caused, in part at least, by saturable binding of E7070 to RBC.

Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors.

BACKGROUND: Rapid and consistent acid suppression on the first day of dosing may be important in treating acid-related disorders. AIM: To compare the antisecretory activity and onset of action of single doses of rabeprazole, lansoprazole, pantoprazole, omeprazole capsule, omeprazole multiple unit pellet system (MUPS) tablet and placebo in healthy Helicobacter pylori-negative subjects. METHODS: This cross-over, double-blind, randomized study was performed in 18 H. pylori-negative subjects. Twenty-four-hour intragastric pH monitoring was performed on the day of treatment (once-daily dose of rabeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, omeprazole capsule 20 mg, omeprazole MUPS tablet 20 mg or placebo). RESULTS: The intragastric pH (3.4) and time at pH > 4 during the 24 h post-dose (8.0 h) were significantly greater with rabeprazole than with lansoprazole, pantoprazole, omeprazole capsule, omeprazole MUPS tablet or placebo (P

Phase I clinical and pharmacokinetic study of E7070, a novel sulfonamide given as a 5-day continuous infusion repeated every 3 weeks in patients with solid tumours. A study by the EORTC Early Clinical Study Group (ECSG).

A single-agent dose-escalating phase I study on the novel sulfonamide E7070 was performed to determine the toxicity profile and the recommended dose for phase II studies. The pharmacokinetic profile of E7070 was also determined. E7070 was administered as a continuous infusion over 5 days repeated every 3 weeks. 27 patients were treated at doses ranging from 6 to 200 mg/m(2)/day. As with other administration schedules, the dose-limiting toxicities were dose-dependent, reversible neutropenia and thrombocytopenia. Although no objective responses were observed, seven patients had stable disease. E7070 displayed a non-linear pharmacokinetic profile, especially at dose-levels greater than 24 mg/m(2)/day, with a reduction in clearance and an increase in the half-life at the higher dose levels. The risk of myelosuppression became significant with an AUC greater than 4000 microg h/ml. The recommended dose of E7070 for further studies is 96 mg/m(2)/day when administered on a 5-day continuous infusion schedule every 3 weeks.

Safety and efficacy of 7-day rabeprazole- and omeprazole-based triple therapy regimens for the eradication of Helicobacter pylori in patients with documented peptic ulcer disease.

AIM: A double-blind, randomized study was designed to determine whether rabeprazole- and omeprazole-based triple therapy regimens are therapeutically equivalent in the eradication of Helicobacter pylori. METHODS: Three hundred and forty-five patients with current or previously active peptic ulcer and a positive H. pylori urease test were randomly assigned to receive RCA, OCA, RCM or OCM twice daily for 7 days (R, rabeprazole 20 mg; O, omeprazole 20 mg; C, clarithromycin 500 mg; A, amoxicillin 1000 mg; M, metronidazole 400 mg). H. pylori eradication was documented by negative 13C-urea breath tests at 4 and 12 weeks, and was evaluated using a 2 x 2 factorial design with proton pump inhibitor and antibiotic as factors. RESULTS: Overall eradication rates (per protocol/intention-to-treat) were 87%/77% and 85%/75% with rabeprazole and omeprazole, respectively (not significant). However, a statistical interaction between proton pump inhibitor and antibiotic was identified. RCA produced a somewhat higher eradication rate than OCA (94% vs. 84%; difference, 9.8%; 95% confidence interval, - 0.7% to + 20.4%), whereas RCM produced a lower eradication rate than OCM (79% vs. 86%; difference, 8.1%; 95% confidence interval, - 21.4% to + 5.1%). Ulcer healing rates were > 90% with H. pylori eradication. Each regimen was well tolerated. CONCLUSIONS: Rabeprazole- and omeprazole-based triple therapy regimens are therapeutically equivalent in the eradication of H. pylori and well tolerated. The statistical interaction observed between the proton pump inhibitor and supplementary antibiotic may be due to chance.

Development and validation of limited sampling strategies for prediction of the systemic exposure to the novel anticancer agent E7070 (N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide).

AIMS: E7070 is a novel, sulphonamide anticancer agent currently under clinical development for the treatment of solid tumours. The aim of this study was to develop and validate limited sampling strategies for the prediction of E7070 exposure in two different treatment schedules for phase II studies using the Bayesian estimation approach. METHODS: Data from two phase I dose finding studies were used in which E7070 was administered either as a single 1 h infusion or as a daily 1 h infusion for 5 days. Plasma concentration-time data from 75 patients were randomly divided into an index data set, used for the development of the strategies, and a validation data set. Population pharmacokinetic parameters were derived on the basis of the index data set. The D-optimality algorithm was used for the selection of optimal time points for both treatment schedules. The developed strategies were compared by assessment of their predictive performance of exposure, expressed as AUC (area under the plasma concentration vs time curve), in the validation data set. RESULTS: The developed population pharmacokinetic model comprised three compartments, with saturable distribution to one peripheral compartment and both linear and saturable elimination from the central compartment. For the 1 h infusion, a four sample strategy was selected which resulted in unbiased and accurate predictions of AUC (bias 0.74%, precision 13%). A five sample strategy was generated for the daily times five schedule yielding unbiased (bias 3.2%) and precise (12% precision) predictions of AUC. CONCLUSIONS: Optimal sampling strategies were developed and validated for estimation of E7070 exposure in two different treatment schedules. Both schedules enabled accurate and unbiased predictions of AUC.

Population pharmacokinetics of the novel anticancer agent E7070 during four phase I studies: model building and validation.

PURPOSE: N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters. PATIENTS AND METHODS: Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model. RESULTS: The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model. CONCLUSION: A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.

Phase I and pharmacokinetic study of E7070, a novel chloroindolyl sulfonamide cell-cycle inhibitor, administered as a one-hour infusion every three weeks in patients with advanced cancer.

PURPOSE: The objectives were to determine the maximum-tolerated dose, the recommended dose, the dose-limiting toxicity, the pharmacokinetics, and the activity of E7070, a novel cell-cycle inhibitor. PATIENTS AND METHODS: E7070 was given as a 1-hour intravenous infusion every 3 weeks in two groups of patients with advanced solid tumors who met prespecified eligibility criteria (group A) or who met the same eligibility criteria but in addition were less heavily pretreated and had more favorable liver functions (group B). RESULTS: Forty patients (31 patients in group A and nine patients in group B) were entered. Dose escalation proceeded through eight levels (range, 50 to 1,000 mg/m(2)). In group A, neutropenia and thrombocytopenia were dose-limiting toxicities occurring during the first cycle in two of seven patients treated at the doses of 700 mg/m(2) and two of four patients treated at 800 mg/m(2). Identical dose-limiting toxicities were observed in zero of six and two of three patients from group B at doses of 800 and 1,000 mg/m(2), respectively. Other toxicities included acne-like skin eruption, mucositis, conjunctivitis, nausea, fatigue, and alopecia. At doses greater than 400 mg/m(2), the area under the concentration-time curve increased disproportionately to the administered dose. Tumor stabilization lasting > or = 6 months was observed in six assessable patients. CONCLUSION: The recommended doses of E7070 in this schedule were 700 mg/m(2) (group A) and 800 mg/m(2) in patients who were less heavily pretreated (group B) with a moderate tumor burden. Prolonged disease stabilization observed in this study might warrant further investigation of E7070 in selected tumor types.

Phase I and pharmacokinetic study of E7070, a novel sulfonamide, given at a daily times five schedule in patients with solid tumors. A study by the EORTC-early clinical studies group (ECSG).

BACKGROUND: E7070 is a novel antitumor sulfonamide which blocks the cell in G1 phase. A phase I study was initiated to investigate the toxicity, maximum tolerated dose (MTD), and pharmacokinetics of this compound when administered intravenously at a daily times five schedule once every three weeks. PATIENTS AND METHODS: Patients with solid tumors not amenable to standard forms of therapy were eligible. E7070 was administered to cohorts of 3-6 patients per dose level, the starting dose was 10 mg/m2/day. Dose escalation was performed according to a Fibonacci-like scheme. RESULTS: Thirty-three patients entered the study. At E7070 doses of 200 and 160 mg/m2/day dose-limiting toxicities occurred, which consisted of febrile neutropenia, thrombocytopenia. diarrhea, skin folliculitis, asthenia, and stomatitis. The pharmacokinetic profile of E7070 at this schedule is non-linear with increasing dose. A partial response was observed in a patient with heavily pretreated breast cancer. Disease stabilizations and some minor responses were also documented. CONCLUSIONS: Myelosuppression is the predominant toxicity of E7070. Clinical efficacy with E7070 was observed. The recommended dose for further studies at this daily times five schedule is 130 mg/m2/day.

A pharmacokinetic interaction between cimetidine or ranitidine and lornoxicam.

Cimetidine 400 mg twice daily significantly increased serum concentrations and reduced apparent oral clearance of lornoxicam 8 mg twice daily in 12 healthy volunteers. Ranitidine 150 mg twice daily produced no significant changes in lornoxicam pharmacokinetics.

Renal and general tolerability of repeated doses of nimesulide in normal subjects.

The renal and general tolerability of nimesulide was studied in 16 healthy men, randomised to 4 groups of 4 subjects. The groups all underwent 2 treatment periods of 7 days each, separated by a washout period of 14 days. The second treatment period was always at a higher dosage level than the first. There were 4 dosage regimens: placebo, and nimesulide 200, 300 and 400mg, all given twice daily by mouth according to a double-blind design. The tolerability of nimesulide was assessed by regular clinical examination, nondirected questions about adverse events, haematological and biochemical screening, and daily urine testing. Plasma and urinary concentrations of Tamm-Horsfall glycoprotein (THG), urinary retinol-binding protein (RBP) and beta-N-acetyl glucosaminidase (NAG) on days 1, 3, 7, and 10 of each period were used as selective indicators of nephrotoxicity. The highest dose of nimesulide (800mg daily) was associated with abdominal pain and indigestion in 5 of 8 recipients. The 400 and 600mg daily dosages were well tolerated. There were no clinically significant alterations in the haematological or biochemical screening tests during the study, and daily urinalysis remained normal throughout. The renal toxicity tests showed no evidence of nephrotoxicity associated with the administration of nimesulide in 14 subjects. The other 2 subjects each had modest increases in either urinary THG or NAG concentrations during treatment with nimesulide 800mg daily, but the results of their other tests remained normal. The study, therefore, showed only equivocal evidence of minor renal toxicity with nimesulide 800mg daily. Nimesulide 400 and 600mg daily were well tolerated in all respects, even though these dosages are higher than those recommended for clinical use.

The effect of repeated oral doses of lornoxicam on antipyrine elimination in normal human volunteers.

Treatment with lornoxicam 4 mg twice daily for 14 d did not produce any change in salivary antipyrine elimination in 11 of 12 healthy volunteers. Anomalous results in one subject are presented and discussed.

Renal and gastrointestinal tolerability of lornoxicam, and effects on haemostasis and hepatic microsomal oxidation.

Three separate studies were carried out to assess the renal and gastrointestinal tolerability of lornoxicam, and its effects on haemostasis and hepatic microsomal oxidation. Haemostasis and hepatic microsomal oxidation. Six men and 6 women had salivary antipyrine half-life determined before and on the last day of 14 days' treatment with lornoxicam 4 mg twice daily. Haemostasis, coagulation and thrombolysis were assessed ex vivo using a haemostatometer before and on Day 14 of lornoxicam treatment. Lornoxicam 4 mg twice daily for 14 days had no significant influence on antipyrine elimination half-life or haemostasis, coagulation and thrombolysis. Renal tolerability. Three groups of 8 healthy young men received respectively 4, 6 and 8 mg lornoxicam twice daily by mouth for 22 days. Nephrotoxicity studies on serum and urine were done repeatedly before, during and after lornoxicam treatment. Serum and urine creatinine, serum Tamm-Horsfall glycoprotein (THG), and urine n-acetylglucosaminidase (NAG), THG and retinol binding protein (RBP) concentrations showed sporadic values outside the laboratory reference range, but these were not in any subject temporally related to drug treatment and were unrelated to dose. Urine microscopy was unremarkable. Thus this study yielded no evidence that lornoxicam has any nephrotoxic effects in healthy young men receiving doses up to 8 mg twice daily for 22 days. Gastrointestinal blood loss and endoscopy. The gastrointestinal effects of lornoxicam 4 mg, indomethacin 50 mg or placebo twice daily for 29 days were evaluated in 45 healthy men. After an initial endoscopic examination, subjects underwent 51Cr red cell labelling. Complete daily faecal collections were then made from Days 6-12, 20-26 and 34-40. Treatments were given from Days 13-41. Endoscopy was repeated 4-8 h after the last dose of medication. Faecal blood loss during lornoxicam treatment was greater than placebo and less than indomethacin, but within- and between-subject variability was such that the differences were not statistically significant. Endoscopic findings were normal in most subjects before and after all 3 treatments.

Clinical pharmacological studies of some possible interactions of lornoxicam with other drugs.

A series of studies in human subjects of potential interactions of lornoxicam with some other drugs is reviewed. No evidence of kinetic interaction was found with the antacids Maalox or Solugastrol, nor was there evidence of influence on antipyrine clearance. Lornoxicam reduced warfarin clearance and enhanced its hypoprothrombinaemic effect. It did not influence glibenclamide kinetics, but plasma insulin concentrations were significantly higher and plasma glucose concentrations significantly lower when lornoxicam and glibenclamide were co-administered. Lornoxicam produced a modest reduction in digoxin clearance, but no other clear evidence of interaction was seen. Lornoxicam significantly antagonized the diuretic and natriuretic actions of frusemide.

Minaprine and imipramine in the treatment of major depressive disorders. A comparative double-blind study.

Minaprine dihydrochloride is an aminopyridazine derivative which is chemically unrelated to other known psychotropic drugs. In rodents minaprine is active in most models of depression and is thought to exert this activity by enhancing serotonergic and dopaminergic transmission. In humans minaprine has been shown to be more effective than placebo in the treatment of major depressive episodes as defined by the DSM-III. In the present study, the efficacy and safety of minaprine (100 mg b.i.d.) in the treatment of major depressive disorders (DSM-III) were compared with those of imipramine (50 b.i.d.) in 104 patients, in a 4-week randomized, double-blind, multicentre trial. The two drugs were comparable in efficacy as judged by the Hamilton Depression Rating Scale, a Clinical Global impression and a Zung Self-Rating Scale. The onset of activity appeared to be significantly more rapid with minaprine. The incidence and intensity of unwanted effects was significantly higher in the imipramine treatment group.