Gemzar

Clinical Pharmacology

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Clinical Pharmacology

Gemzar

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. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose.

The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m² following infusions lasting <70 minutes, indicating that gemcitabine, after short infusions, is not extensively distributed into tissues. For long infusions, the volume of distribution rose to 370 L/m², reflecting slow equilibration of gemcitabine within the tissue compartment.

The maximum plasma concentrations of dFdU (inactive metabolite) were achieved up to 30 minutes after discontinuation of the infusions and the metabolite is excreted in urine without undergoing further biotransformation. The metabolite did not accumulate with weekly dosing, but its elimination is dependent on renal excretion, and could accumulate with decreased renal function.

The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not been assessed.

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.

Drug Interactions — When Gemzar (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 under PRECAUTIONS). Analysis of data from metastatic breast cancer patients shows that, on average, Gemzar 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. Data from NSCLC patients demonstrate that Gemzar and carboplatin given in combination does not alter the pharmacokinetics of Gemzar or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

CLINICAL STUDIES

Ovarian Cancer — Gemzar 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 1000 mg/m² on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar 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 2. The addition of Gemzar to carboplatin resulted in statistically significant improvement in PFS and overall response rate as shown in Table 3 and Figure 1. Approximately 75% of patients in each arm received post-study chemotherapy. Only 13 of 120 patients with documented post-study chemotherapy regimen in the carboplatin arm received Gemzar after progression. There was not a significant difference in overall survival between arms.

Table 2: Gemzar Plus Carboplatin Versus Carboplatin in Ovarian Cancer - Baseline Demographics and Clinical Characteristics

	Gemzar/Carboplatin	Carboplatin
Number of randomized patients	178	178
Median age, years	59	58
Range	36 to 78	21 to 81
Baseline ECOG performance status 0-1^a	94%	95%
Disease Status
Evaluable	7.9%	2.8%
Bidimensionally measurable	91.6%	95.5%
Platinum-free interval^b
6-12 months	39.9%	39.9%
>12 months	59.0%	59.6%
First-line therapy
Platinum-taxane combination	70.2%	71.3%
Platinum-non-taxane combination	28.7%	27.5%
Platinum monotherapy	1.1%	1.1%
^a Nine patients (5 on the Gemzar plus carboplatin arm and 4 on the carboplatin arm) did not have baseline Eastern Cooperative Oncology Group (ECOG) performance status recorded.
^b Three patients (2 on the Gemzar plus carboplatin arm and 1 on the carboplatin arm) had a platinum-free interval of less than 6 months.

Table 3: Gemzar Plus Carboplatin Versus Carboplatin in Ovarian Cancer - Results of Efficacy Analysis

	Gemzar/Carboplatin (N=178)	Carboplatin (N=178)
PFS
Median (95%, C.I.) months	8.6 (8.0, 9.7)	5.8 (5.2, 7.1)	p=0.0038^d
Hazard Ratio (95%, C.I.)	0.72 (0.57,0.90)		p=0.0038^d
Overall Survival
Median (95%, C.I.) months	18.0 (16.2, 20.3)	17.3 (15.2, 19.3)	p=0.8977^d
Hazard Ratio (95%, C.I.)	0.98 (0.78,1.24)
Adjusted^a Hazard Ratio (95%, C.I.)	0.86 (0.67,1.10)
Investigator Reviewed
Overall Response Rate	47.2%	30.9%	p=0.0016^e
CR	14.6%	6.2%
PR+PRNM^b	32.6%	24.7%
Independently Reviewed
Overall Response Rate^c,f	46.3%	35.6%	p=0.11^e
CR	9.1%	4.0%
PR+PRNM	37.2%	31.7%
^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/Carboplatin N=121, Carboplatin N=101