Abingem Mechanism of Action

Pharmacotherapeutic group: Pyrimidine analogues. ATC code: L01BC05.
Pharmacology: Pharmacodynamics: Cytotoxic Activity in Cell Culture Models: Gemcitabine exhibits significant cytotoxicity activity against a variety of cultured murine and human tumour cells. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells through the G1/S-phase boundary. In vitro the cytotoxic action of gemcitabine is both concentration and time dependent.
Antitumour Activity in Preclinical Models: In animal tumour models, the antitumour activity of gemcitabine is schedule dependent. When gemcitabine is administered daily, high animal mortality but minimal antitumoural activity is seen. If, however, gemcitabine is given every third or fourth day, it can be administered in non-lethal doses with substantial antitumoural activity against a broad spectrum of mouse tumours.
Cellular Metabolism and Mechanisms of Action: Gemcitabine (dFdC), which is a pyrimidine antimetabolite, is metabolised intracellularly by nucleoside kinase to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic action of gemcitabine is due to inhibition of DNA synthesis by two actions of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP causes reduction in the concentrations of deoxynucleosides in general, and especially in that of dCTP. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).
Likewise, a small amount of gemcitabine may also be incorporated into RNA. Thus, the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon is essentially unable to remove gemcitabine and repair the growing DNA strands. After gemcitabine is incorporated into DNA, one additional nucleotide is added to the growing DNA strands. After this addition there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, gemcitabine then appears to induce the programmed cellular death process known as apoptosis.
Pharmacokinetics: The pharmacokinetics of gemcitabine have been examined in 353 patients in seven studies. The 121 women and 232 men ranged in age from 29 to 79 years. Of these patients, approximately 45% had non-small cell lung cancer and 35% were diagnosed with pancreatic cancer. The following pharmacokinetic parameters were obtained for doses ranging from 500 to 2,592 mg/m² that were infused from 0.4 to 1.2 hours.
Peak plasma concentrations (obtained within 5 minutes of the end of the infusion) were 3.2 to 45.5 μg/mL. Plasma concentrations of the parent compound following a dose of 1,000 mg/m²/30-minutes are greater than 5 μg/mL for approximately 30-minutes after the end of the infusion, and greater than 0.4 μg/mL for an additional hour.
Distribution: The volume of distribution in central compartment was 12.4 L/m² for women and 17.5 L/m² for men (inter-individual variability was 91.9%). The volume of distribution of the peripheral compartment was 47.4 L/m². The volume of the peripheral compartment was not sensitive to gender.
The plasma protein binding was considered to be negligible.
Half-life: This ranged from 42 to 94 minutes depending on age and gender. For the recommended dosing schedule, gemcitabine elimination should be virtually complete within 5 to 11 hours of the start of the infusion. Gemcitabine does not accumulate when administered once weekly.
Metabolism: Gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidney, blood, and other tissues.
Intracellular metabolism of gemcitabine produces the gemcitabine mono-, di-, and triphosphates (dFdCMP, dFdCDP, and dFdCTP), of which dFdCDP and dFdCTP are considered active. These intracellular metabolites have not been detected in plasma or urine.
The primary metabolite, 2-deoxy-2',2'-difluorouridine (dFdU), is not active and is found in plasma and urine.
Excretion: Systemic clearance ranged from 29.2 L/hr/m² to 92.2 L/hr/m² depending on gender and age (inter-individual variability was 52.2%). Clearance for women is approximately 25% lower than the values for men. Although rapid, clearance for both men and women appears to decrease with age. For the recommended gemcitabine dose of 1,000 mg/m² given as a 30 minute infusion, lower clearance values for women and men should not necessitate a decrease in the gemcitabine dose.
Urinary excretion: Less than 10% is excreted as unchanged drug.
Renal clearance was 2 to 7 L/hr/m².
During the week following administration, 92 to 98% of the dose of gemcitabine administered is recovered, 99% in the urine, mainly in the form of dFdU and 1% of the dose is excreted in faeces.
dFdCTP Kinetics: This metabolite can be found in peripheral blood mononuclear cells and the information as follows refer to these cells.
Intracellular concentrations increase in proportion to gemcitabine doses of 35-350 mg/m²/30 min, which give steady-state concentrations of 0.4-4.5 μg/mL. At gemcitabine plasma concentrations above 5 μg/mL, dFdCTP level do not increase, suggesting that the formation is saturable in these cells.
Half-life terminal elimination: 0.7-12 hours.
dFdU Kinetics: Peak plasma concentrations (3-15 minutes after end of 30 minute infusion, 1,000 mg/m²): 28-52 μg/mL.
Trough concentration following once weekly dosing: 0.07-1.12 μg/mL, with no apparent accumulation.
Triphasic plasma concentration versus time curve, mean half-life of terminal phase: 65 hours (range 33-84 hours).
Formation of dFdU from parent compound: 91%-98%.
Mean volume of distribution of central compartment: 18 L/m² (range 11-22 L/m²).
Mean steady-state volume of distribution (Vss): 150 L/m² (range 96-228 L/m²).
Tissue distribution: Extensive.
Mean apparent clearance: 2.5 L/hr/m² (range1-4 L/hr/m²).
Urinary excretion: All.
Gemcitabine and Paclitaxel Combination Therapy: Combination therapy did not alter the pharmacokinetics of either gemcitabine or paclitaxel.
Gemcitabine and Carboplatin Combination Therapy: When given in combination with carboplatin the pharmacokinetics of gemcitabine were not altered.
Renal impairment: Mild to moderate renal insufficiency (GFR from 30 mL/min to 80 mL/min) has no consistent, significant effect on gemcitabine pharmacokinetics.