A dose-escalation study of the safety, tolerability, and pharmacokinetics of intravenous gatifloxacin in healthy adult men.

STUDY OBJECTIVES: To examine single- and multiple-dose safety, tolerability, and pharmacokinetics of gatifloxacin administered as daily 1-hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic beta-cell function, and electrocardiogram (ECG). DESIGN: Randomized, double-blind, placebo-controlled, ascending-dose study. SETTING: Bristol-Myers Squibb, Clinical Pharmacology Unit, Princeton, New Jersey, USA. PATIENTS: Forty healthy male subjects, eight in each of five groups, were enrolled to receive sequential doses of gatifloxacin: 200 mg (10 mg/ml), 200 mg (1 mg/ml), and 400, 600, and 800 mg (2 mg/ml); six subjects per group received active drug and two received placebo. INTERVENTIONS: A single dose of the drug was administered as an intravenous infusion over 1 hour. After a 72-hour washout period, the drug was administered once/day for 14 days by 1-hour intravenous infusion. Physical examinations, ECGs, spirometry, and clinical laboratory tests, including glucose tolerance test (GTT) and assessment of glucose homeostasis, were performed before treatment and on selected dosing days. A safety evaluation was performed before escalating doses. No intrasubject dose escalation was permitted. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of gatifloxacin were dose linear and time independent after intravenous administration over the range of 200-800 mg. After daily repeated administration, a predictable, modest accumulation was observed; steady state was reached by the third dose. Approximately 80% of the dose was recovered as unchanged drug in urine. Mean changes (before the first dose to the last dose) after oral GTT and in fasting serum glucose, insulin, and C-peptide concentrations were comparable among the gatifloxacin and placebo treatment groups. A mild, transient decrease in serum glucose was associated with the end of the 1-hour infusion of gatifloxacin. No clinically important changes in QTc interval or spirometry occurred. The most frequent treatment-related adverse effects were local intravenous site reactions, which were associated with dose and/or concentration of intravenous solution. CONCLUSION: Gatifloxacin was safe and well tolerated at intravenous doses of up to 800 mg/day for 14 days. Gatifloxacin pharmacokinetics were linear and time independent.

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Bioavailability and phase II study of oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer.

PURPOSE: This study was undertaken to address the influence of concurrent administration on the pharmacokinetics of UFT (uracil plus tegafur) and leucovorin (LV), and to measure the antitumor activity of a 28-consecutive-day oral regimen of UFT plus LV in patients with relapsed or refractory colorectal cancer. METHODS: Patients with advanced measurable colorectal cancer who had failed previous therapy with intravenous bolus 5-fluorouracil (5-FU) were eligible. Patients were treated with UFT 300 mg/m2 per day plus LV 90 mg per day in three divided doses every 8 h for 28 days, repeated at 35-day intervals. In addition, a three-treatment by three-period crossover bioavailability comparison of oral LV 30 mg plus UFT 200 mg versus either LV or UFT alone was scheduled for the 8 days preceding the first cycle of therapy. RESULTS: Of 19 patients enrolled, 18 were assessable for pharmacokinetics and response. When LV was coadministered with UFT, there were no statistically significant effects on tegafur, uracil, or 5-FU Cmax, AUC, or Tmax with the exception of a delayed Tmax for tegafur (P=0.03). No statistically significant differences were found in LV and 5-methyltetrahydrofolate plasma levels when LV was administered alone or with UFT. However, wide interpatient variability was observed for all parameters. There were no antitumor responses seen. CONCLUSIONS: Although the Tmax for tegafur is delayed with the concurrent administration of LV, there were no differences (P > 0.05) in any pharmacologic parameters that are of likely clinical significance. However, the great interpatient variability observed in UFT and LV pharmacology may have obscured true bioavailability effects in this small patient population. Daily oral UFT plus LV is inactive as second-line therapy in patients who have failed bolus 5-FU.

Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a common lethal disease in Asia and there is no effective chemotherapy. Identification of new effective drugs in the treatment of inoperable HCC is urgently need. This is a phase II clinical study to investigate the efficacy, toxicity and pharmacokinetics of paclitaxel in HCC patients. Twenty patients with measurable, unresectable HCC, normal serum bilirubin, normal bone marrow and renal functions were studied. Paclitaxel 175 mg m(-2) was given intravenously over 3 h every 3 weeks. No complete or partial responses were observed. Five patients had stable disease. Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paclitaxel is metabolized by the liver and the pharmacokinetics of paclitaxel in cancer patients with liver involvement or impairment may be important clinically. Pharmacokinetic study was completed in 13 HCC patients. The paclitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.

Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer.

PURPOSE: To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients. PATIENTS AND METHODS: Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study. RESULTS: The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models. CONCLUSION: The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found.

Oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer.

Therapeutic options for patients with advanced colorectal cancer who have failed treatment with fluorouracil (5-FU) are limited. Responses have been reported in this setting with a protracted venous infusion of 5-FU. Daily oral therapy with tegafur and uracil (UFT) plus leucovorin (LV) has the potential to mimic the pharmacology of continuous infusion 5-FU. Therefore, we undertook a phase II study of a 28-day schedule of a combination chemotherapy regimen containing oral UFT/leucovorin in patients with measurable metastatic colorectal cancer who had failed treatment with bolus 5-FU. In addition, we sought to determine whether coadministration of UFT and leucovorin alters the bioavailability of these agents. In a pretreatment phase, each patient underwent sequential pharmacokinetic sampling following a single dose of UFT alone, leucovorin alone, and the combination of UFT plus leucovorin. The preliminary results of this trial suggest that tegafur pharmacokinetics are not affected by coadministration of leucovorin and that folate pharmacokinetics are not affected by UFT.