Actions of Gezt 1 in details
Pharmacology: Mechanism of Action: Gezt 1 exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (5-phase) and also blocking the progression of cells through the G1/S-phase boundary. Gezt 1 is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effects of Gezt 1 are attributed to a combination of 2 actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, Gezt 1 diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes reduction in the concentrations of deoxynucleotides including dCTP. Second, Gezt 1 triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances the incorporation of Gezt 1 triphosphate into DNA (self-potentiation). After the Gezt 1 nucleotide is incorporated into DNA, only the additional nucleotide is added to the growing DNA strands. After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to remove the Gezt 1 nucleotide and repair the growing DNA strands (masked chain termination). In CEM T lymphoblastoid cells, Gezt 1 induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death.
Gezt 1 demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect of cisplatin on Gezt 1 triphosphate accumulation or DNA double-strand breaks was observed. In vivo, Gezt 1 showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Gezt 1 was synergistic with cisplatin in the Lewis lung murine xenografts. Sequential exposure to Gezt 1 4 hrs before cisplatin produced the greatest interaction.
Clinical Studies: Non-Small Cell Lung Cancer: Phase III studies using combination chemotherapy with Gezt 1 and cisplatin have been initiated in NSCLC. The rationale for these combination trials is based in part on the previously observed response rates of 29-54%, 1-year survival probabilities of 35-61% with a manageable toxicity profile.
In one international phase III study in chemo-naive patients with inoperable Stage IIIA, IIIB or IV NSCLC (N=522) Gezt 1+cisplatin vs cisplatin was studied. Gezt 1 1000 mg/m2 was administered on days 1, 8 and 15 of a 28-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 1-year survival of probabilities for the Gezt 1/cisplatin arm vs the cisplatin arm were 39% and 28% respectively (p=0.008). Median survival time on the Gezt 1/cisplatin arm was 9 months compared to 7.6 months in the cisplatin arm (p=0.008). Median time to disease progression was 5.2 months in the Gezt 1/cisplatin arm compared to 3.7 months on the cisplatin arm (p=0.009). The objective response rate in Gezt 1/cisplatin arm was 26% compared to 10% with cisplatin (p<0.0001). No difference between treatment arms in duration of response was observed.
In another randomized multicenter study in 135 patients with stage IIIB or IV NSCLC, treatment with Gezt 1 1250 mg/m2 on day 1 and 8, and cisplatin 100 mg/m2 was administered on day 1 of a 21-day cycle or etoposide 100 mg/m2 IV on days 1, 2 and 3 and cisplatin 100 mg/m2 on day 1 of a 21-day cycle produced objective response rate in 33% on the Gezt 1+cisplatin arm compared to 14% on the etoposide+cisplatin arm (p=0.01).
The other phase III studies conducted include Gezt 1+cisplatin vs mitomycin+ifosfamide+cisplatin and Gezt 1+cisplatin vs cisplatin+paclitaxel vs cisplatin+docetaxel vs carboplatin+paclitaxel.
Pancreatic Cancer: Phase II trials of single-agent Gezt 1 in the treatment of advanced pancreatic malignancy have demonstrated its modest activity, mild toxicity profile and palliation of disease in chemo-naive patients. Gezt 1 has been shown to be more effective than 5-FU in the alleviation of symptoms in patients with advanced symptomatic cancer.
In a phase II study, treatment with Gezt 1 800 mg/m2 weekly for 3 weeks in 44 patients with adenocarcinoma of the pancreas produced an objective tumor response rate in 11% of patients (95% Cl 2-20%) with a median duration of 13 months. Fourteen patients had stable disease for 17 months.
In another randomized trial of Gezt 1 vs 5-fluorouracil (5-FU) in 126 patients with pancreatic cancer, Gezt 1 at a dose of 1000 mg/m2 weekly every 3 weeks with the course repeated monthly produced significantly longer survival when compared to 5-FU 600 mg/m2 weekly (5.65 vs 4.41 months).
Other Tumors: Gezt 1 has been used in several preliminary studies as a single agent or in combination with other agents in the treatment of bladder cancer, breast cancer, ovarian cancer and head and neck cancer.
Pharmacokinetics: Gezt 1 pharmacokinetics is linear. Following IV administration, Gezt 1 is rapidly distributed throughout the body, with negligible binding to plasma proteins. It has a low volume of distribution 15.6 L/m2 in males and 11.3 L/m2 in females. Elimination from the plasma at infusion of <2500 mg/m2 for <70 min is very rapid, with a half-life of 11-26 min. At higher infusion rates for longer intervals, 2500-3600 mg/m2 for 3.6-4.3 hrs, Gezt 1 has the elimination half-life of 18.5-57.1 min. Steady-state plasma concentrations of Gezt 1 are proportional to dose and are achieved in 30 min consistent with its short half-life.
Gezt 1 is eliminated primarily by metabolism in the liver and other tissues. The majority of a dose is excreted as metabolites in the urine (92-98%), with only trace amounts in the feces (<5%). Only traces of the drug are excreted unchanged. The average total body clearance of Gezt 1 is 46 L/hr/m2 in females and 67 L/hr/m2 in males. The renal clearance of Gezt 1 is <10% of the systemic clearance, indicating tissue metabolism in the elimination of Gezt 1.
The major metabolite of Gezt 1 is the inactive, deaminated product, 2'-deoxy-2',2'-difluorouridine (dFdU), maximum plasma concentrations of which occur 0-30 min after the infusion of Gezt 1. The mean volume of distribution of inactive metabolites is 150 L/m2 indicating extensive tissue distribution. The metabolite is eliminated from plasma biphasically, with a terminal elimination half-life of 14 hr. It is excreted in the urine and its elimination is dependent on renal excretion; therefore, could accumulate with decreased renal function.
Studies in animals have shown that Gezt 1 can cross the placenta and accumulate in fetal tissue. It is also excreted in the milk of lactating rats.
Effects of Age and Gender: The half-life of Gezt 1 is not affected by age and gender. Clearance was affected by age and gender. Clearance in women and the elderly is reduced resulting in higher concentrations of Gezt 1 for any given dose. In general, in single agent studies of Gezt 1, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience grade 3/4 neutropenia and thrombocytopenia.
How should I take Gezt 1?
Your doctor will prescribe your exact dose and tell you how often it should be given. Gezt 1 is given through a needle placed into one of your veins.
Gezt 1 often causes nausea and vomiting. It can also cause flu-like symptoms such as chills, fever, general feeling of illness, headache, muscle pain, and weakness. It is very important that you continue to receive the medicine even if it makes you feel ill. Ask your health care professional for ways to lessen these effects.
Dosing
The dose of Gezt 1 will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Gezt 1. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
Gezt 1 administration
IV: For labeled indications, infuse over 30 minutes; if utilizing premixed infusion bags and 2 premixed bags are required, infuse the total volume of both bags over 30 minutes (follow manufacturer
Gezt 1 pharmacology
Gezt 1 is a pyrimidine antimetabolite that inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase, cell cycle-specific for the S-phase of the cycle (also blocks cellular progression at G1/S-phase). Gezt 1 is phosphorylated intracellularly by deoxycytidine kinase to Gezt 1 monophosphate, which is further phosphorylated to active metabolites Gezt 1 diphosphate and Gezt 1 triphosphate. Gezt 1 diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase; Gezt 1 triphosphate incorporates into DNA and inhibits DNA polymerase.
Distribution
Widely distributed into tissues; present in ascitic fluid; V: Infusions <70 minutes: 50 L/m
Metabolism
Metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside metabolites
Excretion
Urine (92% to 98%; primarily as inactive uracil metabolite); feces (<1%)
Time to Peak
30 minutes after completion of infusion
Half-Life Elimination
Gezt 1: Infusion time ≤70 minutes: 42 to 94 minutes; infusion time 3 to 4 hours: 4 to 10.5 hours (affected by age and gender)
Metabolite (Gezt 1 triphosphate), terminal phase: 1.7 to 19.4 hours
Protein Binding
Negligible
References
- NCIt. "Gemcitabine: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Gemcitabine: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
- NCI Cancer Drugs. "gemcitabinehydrochloride". https://www.cancer.gov/about-cancer/... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
