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CLINICAL PHARMACOLOGY

Mechanism of Action

Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.

Pharmacokinetics

Absorption

The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m² to 115 mg/m² in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m² to 115 mg/m² with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hour, respectively. Mean total body clearance was 21 L/h/m².

Distribution

The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.

Metabolism

In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 [see DRUG INTERACTIONS].

Elimination

A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.

Effect of Age

A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m². Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were not influenced by age.

Effect of Gender

The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.

Hepatic Impairment

The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT > 1.5 times ULN concomitant with alkaline phosphatase > 2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with DOCEFREZ. Patients with severe hepatic impairment have not been studied. [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Effect of Race

Mean total body clearance for Japanese patients dosed at the range of 10 mg/m² to 90 mg/m² was similar to that of European/American populations dosed at 100 mg/m² , suggesting no significant difference in the elimination of docetaxel in the two populations.

Effect of Ketoconazole

The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/mē intravenous) alone or docetaxel (10 mg/mē intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administration with ketoconazole [see DOSAGE AND ADMINISTRATION and Drug-Drug Interactions].

Effect of Combination Therapies

Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone.

Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory metastatic prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone.

Clinical Studies

Locally Advanced or Metastatic Breast Cancer

The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens).

Randomized Trials

In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m² every 3 weeks) or the combination of mitomycin (12 mg/m² every 6 weeks) and vinblastine (6 mg/m² every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results (See Table 7).

Table 7 : Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis)

Efficacy Parameter Docetaxel
(n=203)
Mitomycin/ Vinblastine
(n=189)
p-value
Median Survival 11.4 months 8.7 months p=0.01 Log Rank
Risk Ratio*, Mortality (Docetaxel: Control) 0.73
95% CI (Risk Ratio) 0.58-0.93
Median Time to Progression 4.3 months 2.5 months p=0.01 Log Rank
Risk Ratio*, Progression (Docetaxel: Control) 0.75
95% CI (Risk Ratio) 0.61-0.94
Overall Response Rate Complete Response Rate 28.1% 3.4% 9.5% 1.6% p < 0.0001 Chi Square
*For the risk ratio, a value less than 1.00 favors docetaxel.

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m² ) or doxorubicin (75 mg/m² ) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below (See Table 8).

Table 8 : Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis)

Efficacy Parameter Docetaxel
(n=161)
Doxorubicin
(n=165)
p-value
Median Survival 14.7 months 14.3 months p=0.39 Log Rank
Risk Ratio*, Mortality (Docetaxel: Control) 0.89
95% CI (Risk Ratio) 0.68-1.16
Median Time to Progression 6.5 months 5.3 months p=0.45 Log Rank
Risk Ratio*, Progression (Docetaxel: Control) 0.93
95% CI (Risk Ratio) 0.71-1.16
Overall Response Rate Complete Response Rate 45.3% 6.8% 29.7% 4.2% p=0.004 Chi Square
*For the risk ratio, a value less than 1.00 favors docetaxel.

In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m² (n=151), 75 mg/m² (n=188) or 100 mg/m² (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/m² group compared to 22.3% for the 75 mg/m² and 29.8% for the 100 mg/m² group; pair-wise comparison between the 60 mg/m² and 100 mg/m² groups was statistically significant (p=0.037).

Single Arm Studies

Docetaxel at a dose of 100 mg/m²was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0% to 44.8%) and the complete response rate was 2.1%.

Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m² , in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2% to 55.7%), similar to the response rate in single arm studies of 100 mg/m² .

Non-Small Cell Lung Cancer (NSCLC)

The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy.

Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy

Two randomized, controlled trials established that a docetaxel dose of 75 mg/m² was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m² , however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤ 2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m² or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m² . A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m² or best supportive care.

In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤ 2 were randomized to docetaxel 75 mg/m² , docetaxel 100 mg/m² and a treatment in which the investigator chose either vinorelbine 30 mg/m² days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m² days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m² arm and the comparator arms are summarized in Table 9 and Figures 1 and 2 showing the survival curves for the two studies.

Table 9 : Efficacy of Docetaxel in the Treatment of Non-Small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis)

  TAX317 TAX320
Docetaxel 75 mg/m² n=55 Best Supportive Care n=49 Docetaxel 75 mg/m² n=125 Control (V/I*) n=123
Overall Survival Log-rank Test p=0.01 p=0.13
Risk Ratio††, Mortality (Docetaxel: Control) 0.56 0.82
95% CI (Risk Ratio) (0.35, 0.88) (0.63, 1.06)
Median Survival 95% CI 7.5 months** (5.5, 12.8) 4.6 months (3.7, 6.1) 5.7 months (5.1, 7.1) 5.6 months (4.4, 7.9)
% 1-year Survival 95% CI 37%**† (24, 50) 12% (2, 23) 30%**† (22, 39) 20% (13, 27)
Time to Progression 95% CI 12.3 weeks** (9.0, 18.3) 7.0 weeks (6.0, 9.3) 8.3 weeks (7.0, 11.7) 7.6 weeks (6.7, 10.1)
Response Rate 95% CI 5.5% (1.1, 15.1) Not Applicable 5.7% (2.3, 11.3) 0.8% (0.0, 4.5)
* Vinorelbine/Ifosfamide
**p ≤ 0.05;
† uncorrected for multiple comparisons;
†† a value less than 1.00 favors docetaxel.

Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m².

Figure 1 : TAX317 Survival K-M Curves - Docetaxel 75 mg/m² vs. Best Supportive Care

TAX317 Survival K-M Curves - Illustration

Figure 2 : TAX320 Survival K-M Curves – Docetaxel 75 mg/m² vs. Vinorelbine or Ifosfamide Control

TAX320 Survival K-M Curves -  Illustration

Patients treated with docetaxel at a dose of 75 mg/m² experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

Hormone Refractory Prostate Cancer

The safety and efficacy of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥ 60 were randomized to the following treatment groups:

  • Docetaxel 75 mg/m² every 3 weeks for 10 cycles.
  • Docetaxel 30 mg/m² administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
  • Mitoxantrone 12 mg/m² every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.

In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 10 and Figure 3.

Table 10: Efficacy of Docetaxel in the Treatment of Patients with Androgen Independent (Hormone Refractory) Metastatic Prostate Cancer (Intent-to-Treat Analysis)

  Docetaxel + Prednisone every 3 weeks Mitoxantrone + Prednisone every 3 weeks
Number of patients 335 337
Median survival (months) 18.9 16.5
95% CI (17.0-21.2) (14.4-18.6)
Hazard ratio 0.761 --
95% CI (0.619-0.936) --
p-value* 0.0094 --
*Stratified log rank test. Threshold for statistical significance = 0.0175 because of 3 arms.

Figure 3 : TAX327 Survival K-M Curves

TAX327 Survival K-M Curves - Illustration

Last reviewed on RxList: 8/2/2012
This monograph has been modified to include the generic and brand name in many instances.

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