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Mechanism of Action
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the Gl/S-phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine 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 a reduction in the concentrations of deoxynucleotides, including dCTP. Second, gemcitabine 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 gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one 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 gemcitabine nucleotide and repair the growing DNA strands (masked chain termination). In CEM T lymphoblastoid cells, gemcitabine induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death.
Gemcitabine demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect of cisplatin on gemcitabine triphosphate accumulation or DNA double-strand breaks was observed. In vivo, gemcitabine 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 orNCI-H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to gemcitabine 4 hours before cisplatin produced the greatest interaction.
Absorption and Distribution
The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokirietic 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 Gemzar (gemcitabine hcl) dose varied from 500 to 3600 mg/m2.
The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting < 70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.
Gemcitabine 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 gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible.
Gemcitabine 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. Gemcitabine ( < 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.
The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.
Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine 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 9 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.
Table 9: Gemcitabine Clearance and Half-Life for the "Typical"
|Age|| Clearance Men
| Clearance Women
|Half-Lifea Men (min)||Half-Lifea Women (min)|
|a Half-life for patients receiving a short infusion ( < 70 min).|
Gemcitabine 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.
When Gemzar (gemcitabine hcl) (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. The clearance of cisplatin in the same study was reported to be 3.94 mL/min/m2 with a corresponding half-life of 134 hours [see DRUG INTERACTIONS]. Analysis of data from metastatic breast cancer patients shows that, on average, Gemzar (gemcitabine hcl) 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 Gemzar (gemcitabine hcl) . Data from NSCLC patients demonstrate that Gemzar (gemcitabine hcl) and carboplatin given in combination does not alter the pharmacokinetics of Gemzar (gemcitabine hcl) or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.
Gemzar (gemcitabine hcl) was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemzar (gemcitabine hcl) 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar (gemcitabine hcl) on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS).
Patient characteristics are shown in Table 10. The addition of Gemzar (gemcitabine hcl) to carboplatin resulted in statistically significant improvement in PFS and overall response rate as shown in Table 11 and Figure 1. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar (gemcitabine hcl) after progression. There was not a significant difference in overall survival between arms.
Table 10: Gemzar (gemcitabine hcl) Plus Carboplatin Versus Carboplatin in Ovarian
Cancer - Baseline Demographics and Clinical Characteristics
|Number of randomized patients||178||178|
|Median age, years Range||59 36 to 78||58 21 to 81|
|Baseline ECOG performance status 0-la||94%||95%|
|> 12 months||59.0%||59.6%|
| a Nine patients (5 on the Oemzar plus carboplatm
arm and 4 on the carboplatin arm) did not have baseline bastern Cooperative
Oncology Group (ECOG) performance status recorded.
b Three patients (2 on the Gemzar (gemcitabine hcl) plus carboplatin arm and 1 on the carboplatin arm) had a platinum-free interval of less than 6 months.
Table 11: Gemzar (gemcitabine hcl) Plus Carboplatin Versus Carboplatin in Ovarian
Cancer- Results of Efficacy Analysis
|Median (95%, C.I.) months||8.6 (8.0, 9.7)||5.8(5.2,7.1)||p=0.0038d|
|Hazard Ratio (95%, C.I.)||0.72 (0.57, 0.90)|
|Median (95%, C.I.) months||18.0 (16.2,20.3)||17.3(15.2, 19.3)||p=0.8977d|
|Hazard Ratio (95%, C.l.) Ratio||0.98 (0.78, 1.24)|
|Adjusteda Hazard Ratio (95%, C.I.)||0.86 (0.67, 1.10)|
|Overall Response Rate||47.2%||30.9%||p=0.0016e|
|Overall Response Ratec,f||46.3%||35.6%||p=0.11e|
| a Treatment adjusted for performance status, tumor
area, and platinum-free interval.
b Partial response non-measurable disease
c Independent reviewers could not evaluate disease demonstrated by sonography or physical exam.
d Log Rank, unadjusted
e Chi Square
f Independently reviewed cohort - Gemzar (gemcitabine hcl) /Carboplatin N= 121, Carboplatin N= 101
Figure 1: Kaplan-Meier Curve of Progression Free Survival
in Gemzar (gemcitabine hcl) Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356)
Data from a multi-national, randomized Phase 3 study (529 patients) support the use of Gemzar (gemcitabine hcl) in combination with paclitaxel for treatment of breast cancer patients who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Gemzar (gemcitabine hcl) 1250 mg/m2 was administered on Days 1 and 8 of a 21-day cycle with paclitaxel 175 mg/m2 administered prior to Gemzar (gemcitabine hcl) 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 Gemzar (gemcitabine hcl) to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to monotherapy with paclitaxel as shown in Table 12 and Figure 2. Final survival analysis results at 440 events were Hazard Ratio of 0.86 (95%, CI: 0.71 - 1.04) for the ITT population, as shown in Table 12.
Table 12: Gemzar (gemcitabine hcl) Plus Paclitaxel Versus Paclitaxel in Breast
|Number of patients||267||262|
|Median age, years Range||53 26 to 83||52 26 to 75|
|Baseline KPSa ≥ 90||70.4%||74.4%|
|Number of tumor sites|
|Median (95%, CI)||18.6 (16.5,20.7)||15.8 (14.1, 17.3)|
|Hazard Ratio (95%, CI)||0.86 (0.71,1.04)|
|Time to Documented Disease Progressionc|
|Median (95%, C.I.), months||5.2 (4.2, 5.6)||2.9 (2.6, 3.7)||p < 0.000l|
|Hazard Ratio (95%, C.I.)||0.650 (0.524, 0.805)||p < 0.000l|
|Overall Response Rate0 (95%, C.I.)||40.8% (34.9, 46.7)||22.1% (17.1, 27.2)||p < 0.000l|
|a Karnofsky Performance Status.
b Based on the ITT population
c These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
Figure 2: Kaplan-Meier Curve of Time to Documented Disease
Progression in Gemzar (gemcitabine hcl) Plus Paclitaxel Versus Paclitaxel Breast Cancer Study
Non-Small Cell Lung Cancer (NSCLC)
Data from 2 randomized clinical studies (657 patients) support the use of Gemzar (gemcitabine hcl) in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC.
Gemzar (gemcitabine hcl) plus cisplatin versus cisplatin: This study was conducted in Europe, the US, and Canada in 522 patients with inoperable Stage III A, IIIB, or IV NSCLC who had not received prior chemotherapy. Gemzar (gemcitabine hcl) 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 primary endpoint was survival. Patient demographics are shown in Table 13. An imbalance with regard to histology was observed with 48% of patients on the cisplatin arm and 37% of patients on the Gemzar (gemcitabine hcl) plus cisplatin arm having adenocarcinoma.
The Kaplan-Meier survival curve is shown in Figure 3. Median survival time on the Gemzar (gemcitabine hcl) plus cisplatin arm was 9.0 months compared to 7.6 months on the single-agent cisplatin arm (Log rank p=0.008, two-sided). Median time to disease progression was 5.2 months on the Gemzar (gemcitabine hcl) plus cisplatin arm compared to 3.7 months on the cisplatin arm (Log rank p=0.009, two-sided). The objective response rate on the Gemzar (gemcitabine hcl) plus cisplatin arm was 26% compared to 10% with cisplatin (Fisher's Exact p < 0.0001, two-sided). No difference between treatment arms with regard to duration of response was observed.
Gemzar (gemcitabine hcl) plus cisplatin versus etoposide plus cisplatin: A second, multicenter, study in Stage IIIB or IV NSCLC randomized 135 patients to Gemzar (gemcitabine hcl) 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle (Table 13).
There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided). The median survival was 8.7 months for the Gemzar (gemcitabine hcl) plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemzar (gemcitabine hcl) plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemzar (gemcitabine hcl) plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact p=0.01, two-sided).
Figure 3: Kaplan-Meier Survival Curve in Gemzar (gemcitabine hcl) Plus Cisplatin
Versus Cisplatin NSCLC Study (N=522)
Table 13: Randomized Trials of Combination Therapy With
Gemzar (gemcitabine hcl) Plus Cisplatin in NSCLC
|Trial||28-day Schedulea||21-day Scheduleb|
|Number of patients||260||262||69||66|
|Median age, years||62||63||58||60|
|Range||36 to 88||35 to 79||33 to 76||35 to 75|
|Baseline KPSd 70 to 80||41%||44%||45%||52%|
|Baseline KPSd 90 to 100||57%||55%||55%||49%|
|(95%, C.I.) months||8.2, 11.0||6.6, 8.8||7.8, 10.1||6.0, 9.7|
|Time to Disease Progression||p=0.009||p=0.015|
|(95%, C.I.) months||4.2, 5.7||3.0,4.3||4.2, 6.4||2.4, 4.5|
|Tumor Response||26%||10%||p < 0.0001e||33%||14%||p=0.01e|
| a 28-day schedule — Gemzar (gemcitabine hcl) plus Cisplatin: Gemzar (gemcitabine hcl)
1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m on Day
1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2
on Day 1 every 28 days.
b 21-day schedule — Gemzar (gemcitabine hcl) plus cisplatin: Gemzar (gemcitabine hcl) 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 every 21 days.
c N/A Not applicable.
d Karnofsky Performance Status.
e p-value for tumor response was calculated using the two-sided Fisher's Exact test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event.
Data from 2 clinical trials evaluated the use of Gemzar (gemcitabine hcl) in patients with locally advanced or metastatic pancreatic cancer. The first trial compared Gemzar (gemcitabine hcl) to 5-Fluorouracil (5-FU) in patients who had received no prior chemotherapy. A second trial studied the use of Gemzar (gemcitabine hcl) injjapcreatic cancer patients previously treated with 5-FU or a 5-FU-containing regimen. In both studies, the first cycle of Gemzar (gemcitabine hcl) was administered intravenously at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitated holding a dose) followed by a week of rest from treatment with Gemzar (gemcitabine hcl) . Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every 4 weeks.
The primary efficacy parameter in these studies was "clinical benefit response," which is a measure of clinical improvement based on analgesic consumption, pain intensity, performance status, and weight change. Definitions for improvement in these variables were formulated prospectively during the design of the 2 trials. A patient was considered a clinical benefit responder if either:
i) the patient showed a ≥ 50% reduction in pain intensity (Memorial Pain
Assessment Card) or analgesic consumption, or a 20-point or greater improvement
in performance status (Karnofsky Performance Status) for a period of at least
4 consecutive weeks, without showing any sustained worsening in any of the other
parameters. Sustained worsening was defined as 4 consecutive weeks with either
any increase in pain intensity or analgesic consumption or a 20-point decrease
in performance status occurring during the first 12 weeks of therapy.
ii) the patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain ( ≥ 7% increase maintained for ≥ 4 weeks) not due to fluid accumulation.
The first study was a multicenter (17 sites in US and Canada), prospective, single-blinded, two-arm, randomized, comparison of Gemzar (gemcitabine hcl) and 5-FU in patients with locally advanced or metastatic pancreatic cancer who had received no prior treatment with chemotherapy. 5-FU was administered intravenously at a weekly dose of 600 mg/m2 for 30 minutes. The results from this randomized trial are shown in Table 14. Patients treated with Gemzar (gemcitabine hcl) had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to 5-FU. The Kaplan-Meier curve for survival is shown in Figure 4. No confirmed objective tumor responses were observed with either treatment.
Table 14: Gemzar (gemcitabine hcl) Versus 5-FU in Pancreatic Cancer
|Number of patients||63||63|
|Median age||62 years||61 years|
|Range||37 to 79||36 to 77|
|Stage IV disease||71.4%||76.2%|
|Baseline KPSa ≤ 70||69.8%||68.3%|
|Clinical benefit response||22.2% (Nc=14)||4.8% (Nc=3)||p=0.004e|
|Median||5.7 months||4.2 months|
|6-month probabilityb||(N=30) 46%||(N=19)29%|
|9-month probabilityb||(N=14)24%||(N=4) 5%|
|1-year probabilityb||(N=9) 1 8%||(N=2) 2%|
|Range||0.2 to 18.6 months||0.4 to 1 5. l+d months|
|95% C.I. of the median||4.7 to 6.9 months||3.1 to 5.1 months|
|Time to Disease Progression||p=0.0013|
|Median||2.1 months||0.9 months|
|Range||0.1 +d to 9.4 months||0.1 to 12.0+d months|
|95% C.I. of the median||1.9 to 3. 4 months||0.9 to 1.1 months|
|a Karnofsky Performance Status.
b Kaplan-Meier estimates.
c N=number of patients.
d No progression at last visit; remains alive.
e The p-value for clinical benefit response was calculated using the two-sided test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event.
Clinical benefit response was achieved by 14 patients treated with Gemzar (gemcitabine hcl) and 3 patients treated with 5-FU. One patient on the Gemzar (gemcitabine hcl) arm showed improvement in all 3 primary parameters (pain intensity, analgesic consumption, and performance status). Eleven patients on the Gemzar (gemcitabine hcl) arm and 2 patients on the 5-FU arm showed improvement in analgesic consumption and/or pain intensity with stable performance status. Two patients on the Gemzar (gemcitabine hcl) arm showed improvement in analgesic consumption or pain intensity with improvement in performance status. One patient on the 5-FU arm was stable with regard to pain intensity and analgesic consumption with improvement in performance status. No patient on either arm achieved a clinical benefit response based on weight gain.
Figure 4: Kaplan-Meier Survival Curve
The second trial was a multicenter (17 US and Canadian centers), open-label study of Gemzar (gemcitabine hcl) in 63 patients with advanced pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The study showed a clinical benefit response rate of 27% and median survival of 3.9 months.
Other Clinical Studies
When Gemzar (gemcitabine hcl) was administered more frequently than once weekly or with infusions longer than 60 minutes, increased toxicity was observed. Results of a Phase 1 study of Gemzar (gemcitabine hcl) to assess the maximum tolerated dose (MTD) on a daily x 5 schedule showed that patients developed significant hypotension and severe flu-like symptoms that were intolerable at doses above 10 mg/m2. The incidence and severity of these events were dose-related. Other Phase 1 studies using a twice-weekly schedule reached MTDs of only 65 mg/m2 (30-minute infusion) and 150 mg/m2 (5-minute bolus). The dose-limiting toxicities were thrombocytopenia and flu-like symptoms, particularly asthenia. In a Phase 1 study to assess the maximum tolerated infusion time, clinically significant toxicity, defined as myelosuppression, was seen with weekly doses of 300 mg/m2 at or above a 270-minute infusion time. The half-life of gemcitabine is influenced by the length of the infusion and the toxicity appears to be increased if Gemzar (gemcitabine hcl) is administered more frequently than once weekly or with infusions longer than 60 minutes [see WARNINGS AND PRECAUTIONS].
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.ISA, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs: Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich, M., White, J. M, & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
Last reviewed on RxList: 4/4/2011
This monograph has been modified to include the generic and brand name in many instances.
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