Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: pyrimidine analogues, ATC code: L01BC05

Cytotoxic activity in cell cultures
Gemcitabine shows significant cytotoxic effects against a variety of cultured murine and human tumour cells. Its action is phase-specific such that gemcitabine primarily kills cells that are undergoing DNA synthesis (S-phase) and, under certain circumstances, blocks the progression of cells at the junction of the G1/S phase boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration and time.

Antitumoural activity in preclinical models
In animal tumour models, antitumoural activity of gemcitabine is schedule-dependent. When gemcitabine is administered daily, high mortality among the animals, but minimal antitumoural activity, 

is observed. 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.

Mechanism of action
Cellular metabolism and mechanism 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 effect of gemcitabine is due to inhibition of DNA synthesis by two mechanisms of action by dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalysing the reactions that produce deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP reduces the concentration of deoxynucleosides in general and, in particular, 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 reduced intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to 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 appears to induce the programmed cell death process known as apoptosis.

Clinical efficacy and safety
Bladder cancer
A randomised phase III study of 405 patients with advanced or metastatic urothelial transitional cell carcinoma showed no difference between the two treatment arms, gemcitabine/cisplatin versus methotrexate/vinblastine/adriamycin/cisplatin    (MVAC),         in     terms  of median     survival (12.8 and 14.8 months, respectively, p = 0.547), time to disease progression (7.4 and 7.6 months, respectively, p = 0.842) and response rate (49.4% and 45.7 %, respectively, p = 0.512). However, the combination of gemcitabine and cisplatin had a better toxicity profile than MVAC.

Pancreatic cancer
In a randomised phase III study of 126 patients with advanced or metastatic pancreatic cancer, gemcitabine showed a statistically significant higher clinical benefit response rate than 5-fluorouracil (23.8% and 4.8%, respectively, p = 0.0022). Also, a statistically significant prolongation of the time to progression from 0.9 to 2.3 months (log-rank p < 0.0002) and a statistically significant prolongation of median survival from 4.4 to 5.7 months (log-rank p < 0.0024) was observed in patients treated with gemcitabine compared to patients treated with 5-fluorouracil.

Non-small cell lung cancer
In a randomised phase III study of 522 patients with inoperable, locally advanced or metastatic NSCLC, gemcitabine in combination with cisplatin showed a statistically significant higher response rate than cisplatin alone (31.0% and 12.0%, respectively, p < 0.0001). A statistically significant prolongation of the time to progression, from 3.7 to 5.6 months (log-rank p < 0.0012) and a statistically significant prolongation of median survival from 7.6 months to 9.1 months (log-rank p < 0.004) was observed in patients treated with gemcitabine/cisplatin compared to patients treated with cisplatin.
In another randomised phase III study of 135 patients with stage IIIB or IV NSCLC, a combination of gemcitabine and cisplatin showed a statistically significant higher response rate than a combination of cisplatin and etoposide (40.6% and 21.2%, respectively, p = 0.025). A statistically significant prolongation of the time to progression, from 4.3 to 6.9 months (p = 0.014) was observed in patients treated with gemcitabine/cisplatin compared to patients treated with etoposide/cisplatin.
In both studies it was found that tolerability was similar in the two treatment arms.

Ovarian carcinoma
In a randomised phase III study, 356 patients with advanced epithelial ovarian carcinoma who had relapsed at least 6 months after completing platinum based therapy were randomised to therapy with gemcitabine and carboplatin (GCb), or carboplatin (Cb). A statistically significant prolongation of the time to progression of disease, from 5.8 to 8.6 months (log-rank p = 0.0038) was observed in the patients treated with GCb compared to patients treated with Cb. Differences in response rate of 47.2% in the GCb arm versus 30.9% in the Cb arm (p = 0.0016) and median survival 18 months (GCb) versus 17.3 (Cb) (p = 0.73) favoured the GCb arm.

Breast cancer
In a randomised phase III study of 529 patients with inoperable, locally recurrent or metastatic breast cancer with relapse after adjuvant/neoadjuvant chemotherapy, gemcitabine in combination with paclitaxel showed a statistically significant prolongation of time to documented disease progression from 3.98 to 6.14 months (log-rank p = 0.0002) in patients treated with gemcitabine/paclitaxel compared to patients treated with paclitaxel. After 377 deaths, the overall survival was 18.6 months versus 15.8 months (log-rank p = 0.0489, HR 0.82) in patients treated with gemcitabine/paclitaxel compared to patients treated with paclitaxel and the overall response rate was 41.4% and 26.2% respectively (p = 0.0002).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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 of the 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.

Biotransformation
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.

Elimination
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 substance.
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 below refers to these cells. Intracellular concentrations increase in proportion to gemcitabine doses of 35 - 350 mg/m²/30 minutes, which give steady-state concentrations of 0.4 - 5 µg/ml. At gemcitabine plasma concentrations above 5 µg/ml, dFdCTP levels do not increase, suggesting that the formation is saturable in these cells.
Half-life of 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 hr).
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 (range 1 - 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.