Gemita Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Gemcitabine, a pyrimidine analog, has a wide spectrum of antitumor activity. It is cell-cycle phase specific and kills the cells undergoing DNA synthesis in the S-phase. It also blocks the progression of cells through the G₁/S-phases. Gemcitabine is metabolized intracellularly to two active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). The diphosphate of gemcitabine appears to be an effective inhibitor of ribonucleotide reductase and this may be irreversible. Ribonucleotide reductase inhibition results in depletion of cellular deoxyribonucleotide triphosphate pools. The effect of cellular depletion of deoxycytidine triphosphate is a self-potentiation of the cytotoxicity of gemcitabine as gemcitabine triphosphate (dFdCTP) competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine needs to be activated by deoxycytidine kinase and other kinases to its triphosphate, gemcitabine triphosphate, which can be incorporated into RNA and DNA. The latter effect is considered to be responsible for its antitumor effect and causes masked chain termination and inhibition of DNA repair. This effect may be of importance for combination with DNA interacting agents.
Pharmacokinetics: Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. In a radiolabeled study on gemcitabine in five patients who received a single 1000 mg/m²/30 minute infusion of drug, ninety two to ninety eight percent of the dose was recovered, almost entirely in the urine within one week's time. The inactive uracil metabolite, 2'-deoxy-2', 2'-difluorouridine (dFdU) and gemcitabine accounted for 99% of the excreted dose. The plasma protein binding is negligible for gemcitabine. Pharmacokinetic study of gemcitabine was carried out in 353 patients, with various solid tumors. The total gemcitabine dose varied from 500 to 3600 mg/m². Using the data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusion (<70 minutes) and long infusions (70 to 285 minutes) the pharmacokinetic parameters were derived. Combined single and multiple dose studies showed that duration of infusion, age and gender significantly influenced the volume of distribution and drug clearance of gemcitabine. Base on patient characteristics or the duration of infusion the differences in either clearance or volume of distribution result in changes in half-life and plasma concentrations. The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not been assessed. In mononuclear cells, the half-life of the terminal phase for gemcitabine triphosphate ranges from 1.7 to 19.4 hours. The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells.
Clinical Studies: Non-Small Cell Lung Cancer (NSCLC): The use of gemcitabine in combination with cisplatin as first line treatment was established by two randomized clinical studies in patients with locally advanced or metastatic NSCLC having a sample size of 657 patients.
Sandler AB et al carried out a randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in 522 chemotherapy-naive patients with inoperable Stage IIIA, IIIB, or IV advanced NSCLC who had not received prior chemotherapy. Gemcitabine 1000 mg/m² was administered on days 1, 8, and 15 of a twenty-eight day cycle with cisplatin 100 mg/m² administered on day 1 of each cycle. Single-agent cisplatin 100 mg/m² was administered on day 1 of each 28-day cycle. The primary end point was survival. Gemcitabine plus cisplatin arm had a median survival time of 9.0 months compared to 7.6 months for single-agent cisplatin arm. Gemcitabine plus cisplatin arm had a median time to disease progression of 5.2 months compared to cisplatin arm with 3.7 months. In the gemcitabine plus cisplatin arm the objective response rate was 26% compared to 10% for cisplatin. With regard to duration of response there was no difference observed between treatment arms.
Cardenal F et al conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). In a multicentric study 135 patients with Stage IIIB or IV NSCLC were randomized to gemcitabine 1250 mg/m² on days 1 and 8, and cisplatin 100 mg/m² on day 1 of a 21-day cycle or to etoposide 100 mg/m² I.V. on days 1, 2, and 3 and cisplatin 100 mg/m² on day 1 on a 21-day cycle. There was no significant difference in survival between the two treatment arms. Gemcitabine plus cisplatin arm showed an objective response rate of 33% compared to 14% on the etoposide plus cisplatin arm. Gemcitabine plus cisplatin arm had median time to disease progression of 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm. Gemcitabine plus cisplatin arm had a median survival of 8.7 months versus 7.0 months for the etoposide plus cisplatin arm.
Pancreatic Cancer: A trial compared gemcitabine to 5-fluorouracil (5-FU) in patients who had received no prior chemotherapy. One hundred and twenty six chemo-naive patients with (measurable or evaluable) confirmed advanced or metastatic pancreas cancer were randomized to gemcitabine, 1000 mg/m² over 30 min once weekly for up to 7 weeks, followed by weekly x 3 every 4 weeks thereafter, or to 5-FU 600 mg/m² over 30 min once weekly. Gemcitabine treated patients had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to 5-FU. With either treatment, no confirmed objective tumor responses were observed. A second trial studied the use of gemcitabine in 63 patients (32F, 31M) with 5-FU-refractory pancreas cancer. The first cycle of gemcitabine was administered intravenously at a dose of 1000 mg/m² over 30 minutes once weekly for up to 7 weekly (or until toxicity necessitated holding a dose) followed by a week of rest from treatment with gemcitabine. Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every 4 weeks. The median survival was 3.9 months and the clinical benefit response rate was 27%.
Breast cancer: Data from a multi-national, randomized Phase 3 study of 529 patients support the use of gemcitabine in combination with paclitaxel for treatment of breast cancer patients who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated.
Gemcitabine 1250 mg/m² was administered on Days 1 and 8 of a 21-day cycle with paclitaxel 175 mg/m² administered prior to gemcitabine on Day 1 of each cycle. Single-agent paclitaxel 175 mg/m² was administered on Day 1 of each 21-day cycle as the control arm. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in time to documented disease progression (5.2 months, 2.9 months) and overall response rate (40.8%, 22.1%) compared to monotherapy with Paclitaxel. Further, there was a strong trend toward improved survival for the group given gemcitabine based on an interim survival analysis.