The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacology: Mechanism of Action:Nabigem 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. Nabigem is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effects of Nabigem are attributed to a combination of 2 actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, Nabigem 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, Nabigem 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 Nabigem triphosphate into DNA (self-potentiation). After the Nabigem 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 Nabigem nucleotide and repair the growing DNA strands (masked chain termination). In CEM T lymphoblastoid cells, Nabigem induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death.
Nabigem demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect of cisplatin on Nabigem triphosphate accumulation or DNA double-strand breaks was observed. In vivo, Nabigem 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. Nabigem was synergistic with cisplatin in the Lewis lung murine xenografts. Sequential exposure to Nabigem 4 hrs before cisplatin produced the greatest interaction.
Clinical Studies: Non-Small Cell Lung Cancer: Phase III studies using combination chemotherapy with Nabigem 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) Nabigem+cisplatin vs cisplatin was studied. Nabigem 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 Nabigem/cisplatin arm vs the cisplatin arm were 39% and 28% respectively (p=0.008). Median survival time on the Nabigem/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 Nabigem/cisplatin arm compared to 3.7 months on the cisplatin arm (p=0.009). The objective response rate in Nabigem/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 Nabigem 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 Nabigem+cisplatin arm compared to 14% on the etoposide+cisplatin arm (p=0.01).
The other phase III studies conducted include Nabigem+cisplatin vs mitomycin+ifosfamide+cisplatin and Nabigem+cisplatin vs cisplatin+paclitaxel vs cisplatin+docetaxel vs carboplatin+paclitaxel.
Pancreatic Cancer: Phase II trials of single-agent Nabigem in the treatment of advanced pancreatic malignancy have demonstrated its modest activity, mild toxicity profile and palliation of disease in chemo-naive patients. Nabigem 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 Nabigem 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 Nabigem vs 5-fluorouracil (5-FU) in 126 patients with pancreatic cancer, Nabigem 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: Nabigem 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: Nabigem pharmacokinetics is linear. Following IV administration, Nabigem 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, Nabigem has the elimination half-life of 18.5-57.1 min. Steady-state plasma concentrations of Nabigem are proportional to dose and are achieved in 30 min consistent with its short half-life.
Nabigem 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 Nabigem is 46 L/hr/m2 in females and 67 L/hr/m2 in males. The renal clearance of Nabigem is <10% of the systemic clearance, indicating tissue metabolism in the elimination of Nabigem.
The major metabolite of Nabigem is the inactive, deaminated product, 2'-deoxy-2',2'-difluorouridine (dFdU), maximum plasma concentrations of which occur 0-30 min after the infusion of Nabigem. 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 Nabigem 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 Nabigem 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 Nabigem for any given dose. In general, in single agent studies of Nabigem, 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 Nabigem?
Your doctor will prescribe your exact dose and tell you how often it should be given. Nabigem is given through a needle placed into one of your veins.
Nabigem 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 Nabigem 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 Nabigem. 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.
Nabigem administration
Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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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
Nabigem pharmacology
Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
Mechanism of Action
Nabigem kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Nabigem is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Nabigem diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Nabigem 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 Nabigem triphosphate into DNA (self-potentiation). After the Nabigem nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death.
Pharmacokinetics
The pharmacokinetics of Nabigem were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Nabigem dose varied from 500 to 3600 mg/m2.
Distribution
The volume of distribution was increased with infusion length. Volume of distribution of Nabigem was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.
Nabigem pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of Nabigem was significantly influenced by duration of infusion and gender. Nabigem plasma protein binding is negligible.
Elimination
Metabolism
The active metabolite, Nabigem triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for Nabigem triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.
Excretion
Nabigem disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Nabigem (<10%) and the inactive uracil metabolite, 2´-deoxy-2´,2´-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.
Specific Populations
Geriatric Patients
Clearance of Nabigem was affected by age. The lower clearance in the elderly results in higher concentrations of Nabigem for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 17 shows plasma clearance and half-life of Nabigem following short infusions for typical patients by age and gender.
Table 17: Nabigem Clearance and Half-Life for the “Typical” Patient
Age
Clearance Men (L/hr/m2)
Clearance Women (L/hr/m2)
Half-Lifea Men
(min)
Half-Lifea Women
(min)
29
92.2
69.4
42
49
45
75.7
57
48
57
65
55.1
41.5
61
73
79
40.7
30.7
79
94
a Half-life for patients receiving <70 minute infusion.
Nabigem half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.
Male and Female Patients
Clearance of Nabigem was affected by gender. Female patients have lower clearance and longer half-lives than male patients as described in Table 17.
Patients with Renal Impairment
No clinical studies have been conducted with Nabigem in patients with decreased renal function.
Patients with Hepatic Impairment
No clinical studies have been conducted with Nabigem in patients with decreased hepatic function.
Drug Interactions
When Nabigem (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of Nabigem on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on average, Nabigem has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of Nabigem. Data from NSCLC patients demonstrate that Nabigem and carboplatin given in combination does not alter the pharmacokinetics of Nabigem or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.
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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).
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