A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Taxol Pharmacology, Pharmacokinetics, Studies, Metabolism - Paclitaxel
Taxol Pharmacology, Pharmacokinetics, Studies, Metabolism - Paclitaxel
CLINICAL PHARMACOLOGY
Paclitaxel is a novel antimicrotubule agent
that promotes the assembly of microtubules from tubulin
dimers and stabilizes microtubules by preventing depolymerization.
This stability results
in the inhibition
of the normal dynamic reorganization of the microtubule
network that is essential
for vital interphase
and mitotic cellular
functions. In addition, paclitaxel
induces abnormal arrays
or "bundles" of microtubules throughout the cell
cycle and multiple
asters of microtubules during mitosis.
Following intravenous
administration
of TAXOL, paclitaxel plasma
concentrations declined in a biphasic
manner. The initial
rapid decline represents
distribution to the peripheral
compartment and elimination
of the drug. The later phase is due, in part, to a relatively slow
efflux of paclitaxel from the peripheral compartment.
Pharmacokinetic parameters of paclitaxel following 3-and 24-hour
infusions of TAXOL at dose
levels of 135 and 175 mg/m2 were determined in a Phase
3 randomized study in ovarian
cancer patients and are
summarized in the following table:
|
Summary of Pharmacokinetic Parameters - Mean Values
|
|
Dose
(mg/m2)
|
Infusion
Duration (h)
|
N
(patients)
|
Cmax
(ng/mL)
|
AUC (0-¥
)
(ng•h/mL)
|
T-HALF
(h)
|
CLT
(L/h/m2)
|
|
135
|
24
|
2
|
195
|
6300
|
52.7
|
21.7
|
|
175
|
24
|
4
|
365
|
7993
|
15.7
|
23.8
|
|
135
|
3
|
7
|
2170
|
7952
|
13.1
|
17.7
|
|
175
|
3
|
5
|
3650
|
15007
|
20.2
|
12.2
|
| Cmax= Maximum
plasma concentration |
| AUC (0-¥
)=Area under the plasma
concentration-time curve
from time 0 to infinity |
| CLT = Total
body clearance |
It appeared that with the 24-hour infusion
of TAXOL, a 30% increase in dose
(135 mg/m2 versus 175 mg/m2 ) increased the
Cmax by 87%, whereas the AUC
(0-¥) remained proportional. However,
with a 3-hour infusion,
for a 30% increase in dose, the Cmax and AUC
(0-¥) were increased by 68% and 89%,
respectively. The mean
apparent volume
of distribution at steady state, with the 24-hour infusion
of TAXOL, ranged from 227 to 688 L/m2 , indicating extensive
extravascular
distribution and/or tissue
binding of paclitaxel.
The pharmacokinetics
of paclitaxel were also evaluated in adult
cancer patients who received single doses of 15-135 mg/m2
given by 1-hour infusions (n=15), 30-275 mg/m2 given
by 6-hour infusions (n=36), and 200-275 mg/m2 given by
24-hour infusions (n=54) in Phase 1 & 2 studies. Values for
CLT and volume
of distribution were consistent with the findings in the Phase 3
study. The pharmacokinetics of TAXOL in patients with AIDS-related
Kaposi’s sarcoma have
not been studied.
In vitro studies of binding to human
serum proteins, using
paclitaxel concentrations ranging from 0.1 to 50 mcg/mL,
indicate that between 89-98% of drug
is bound; the presence of cimetidine, ranitidine, dexamethasone,
or diphenhydramine did not affect
protein binding of paclitaxel.
After intravenous
administration
of 15-275 mg/m2 doses of TAXOL as 1-, 6-, or 24-hour
infusions, mean values
for cumulative urinary
recovery of unchanged drug
ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal
clearance. In five patients
administered a 225 or 250 mg/m2 dose of radiolabeled
TAXOL as a 3-hour infusion,
a mean of 71% of the radioactivity
was excreted in the feces
in 120 hours, and 14% was recovered in the urine. Total recovery
of radioactivity
ranged from 56 to 101% of the dose. Paclitaxel represented a mean
of 5% of the administered radioactivity
recovered in the feces, while metabolites, primarily 6a-hydroxypaclitaxel,
accounted for the balance. In vitro studies with human
liver microsomes and tissue
slices showed that paclitaxel was metabolized primarily to 6a-hydroxypaclitaxel
by the cytochrome
P450 isozyme CYP2C8;
and to two minor metabolites,
3’-p-hydroxypaclitaxel and 6a,
3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the
metabolism of paclitaxel
to 6a- hydroxypaclitaxel
was inhibited by a number
of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone,
cyclosporin, teniposide, etoposide, and vincristine), but the concentrations
used exceeded those found in vivo following normal
therapeutic doses.
Testosterone, 17a-ethinyl
estradiol, retinoic acid,
and quercetin, a specific
inhibitor of CYP2C8,
also inhibited the formation
of 6a-hydroxypaclitaxel
in vitro. The pharmacokinetics
of paclitaxel may also be altered in vivoas a result of interactions
with compounds that are substrates, inducers, or inhibitors of CYP2C8
and or CYP3A4. (See DRUG
INTERACTIONS section.) The effect
of renal or hepatic
dysfunction on the disposition
of paclitaxel has not been investigated.
Possible interactions of paclitaxel with concomitantly administered
medications not been formally investigated.
CLINICAL STUDIES
Ovarian Carcinoma: Data from five Phase 1 and 2 clinical
studies (189 patients), a multicenter, randomized Phase 3 study
(407 patients), as well as an interim analysis
of data from more than 300 patients enrolled in a treatment
referral center
program were used
in support of the
use of TAXOL (paclitaxel) Injection in patients who have failed
initial or subsequent
chemotherapy
for metastatic carcinoma
of the ovary. Two of the Phase 2 studies (92 patients) utilized
an initial dose
of 135 to 170 mg/m2 in most patients ( >90%) administered
over 24 hours by continuous infusion. Response rates in these
two studies were 22% (95% CI = 11-37%) and 30% (95% CI = 18-46%)
with a total of six complete and 18 partial responses in 92 patients.
The median duration
of overall response
in these two studies measured from the first day of treatment
was 7.2 months (range: 3.5-15.8 months) and 7.5 months (range:
5.3-17.4 months), respectively. The median survival was 8.1 months
(range: 0.2-36.7 months) and 15.9 months (range: 1.8- 34.5+ months).
Phase 3 study had a bifactorial design and compared the efficacy
and safety of TAXOL, administered at two different doses (135 or
175 mg/m2 ) and schedules (3- or 24-hour infusion). The
overall response rate
for the 407 patients was 16.2% (95%CI=12.8- 20.2%),with 6 complete
and 60partial responses. Duration of response, measured from the
first day of treatment was 8.3 months (range: 3.2-21.6 months).
Median time to progression
was 3.7 months (range: 0.1+ -25.1+ months). Median survival
was 11.5 months (range: 0.2- 26.3+ months).
Response rates, median
survival and median
time to progression
for the 4 arms are given in the following table.
|
Efficacy in the Phase 3 Ovarian Carcinoma Study
|
| |
175/3
|
175/24
|
135/3
|
135/24
|
| |
(n=96)
|
(n=106)
|
(n=99)
|
(n=106)
|
| •Response |
|
|
|
|
| - rate
(percent) |
14.6
|
21.7
|
15.2
|
13.2
|
| - 95% Confidence
Interval |
(8.5-23.6)
|
(14.5-31.0)
|
(9.0-24.1)
|
(7.7-21.5)
|
| •Time to Progression |
|
|
|
|
| - median
(months) |
4.4
|
4.2
|
3.4
|
2.8
|
| - 95% Confidence
Interval |
(3.0-5.6)
|
(3.5-5.1)
|
(2.8-4.2)
|
(1.9-4.0)
|
| •Survival |
|
|
|
|
| - median
(months) |
11.5
|
11.8
|
13.1
|
10.7
|
| - 95% Confidence
Interval |
(8.4-14.4)
|
(8.9-14.6)
|
(9.1-14.6)
|
(8.1-13.6)
|
Analyses were performed as planned by the study protocol, by comparing
the two doses (135 or 175 mg/m2 ) irrespective of the
schedule (3 or 24 hours) and the two schedules irrespective of dose.
Patients receiving the 175 mg/m2 dose
achieved a higher response
rate than those receiving
the 135 mg/m2 dose: 18 vs. 14% (p= 0.28). No
difference in response
rate was detected when
comparing the 3-hour with the 24-hour infusion: 15 vs. 17% (p= 0.50).
Patients receiving the 175 mg/m2 dose of TAXOL had a
longer time to progression
than those receiving the 135 mg/m2 dose: median
4.2 vs. 3.1 months (p= 0.03). Time to progression was longer for
patients receiving the 3-hour vs. the 24-hour infusion: 4.0 months
vs. 3.7 months (p= 0.08). No
difference in survival according to dose
or schedule was observed.
These statistical
analyses should be viewed with caution because of the multiple
comparisons made.
TAXOL remained active in patients who had developed resistance
to platinum-containing therapy (defined as tumor
progression while
on, or tumor relapse
within 6 months from completion of, a platinum-containing regimen)
with response rates of 14% in the Phase 3 study and 31% in the Phase
1 & 2 clinical studies.
The adverse event profile
in the Phase 3 study was consistent with that seen for a pooled
analysis performed
on 812 patients treated in ten clinical studies (see ADVERSE
REACTIONS section). For the 403 patients who received TAXOL
in the Phase 3 study, the following table shows the incidence
of several important adverse events.
|
Frequency* of Important Adverse Events
in the Phase 3 Ovarian Carcinoma Study
|
| |
|
Percent of Patients
|
| |
|
175/3
|
175/24
|
135/3
|
135/24
|
| |
|
(n=95)
|
(n=105)
|
(n=98)
|
(n=105)
|
| • Bone Marrow |
|
|
|
|
|
| - Neutropenia |
<2,000/mm3 |
78
|
98
|
78
|
98
|
| |
<500/mm3 |
27
|
75
|
14
|
67
|
| - Thrombocytopenia |
<100,000/mm3 |
4
|
18
|
8
|
6
|
| |
<50,000/mm3 |
1
|
7
|
2
|
1
|
| - Anemia |
<11g/dL |
84
|
90
|
68
|
88
|
| |
<8 g/dL |
11
|
12
|
6
|
10
|
| - Infections |
|
26
|
29
|
20
|
18
|
| • Hypersensitivity
Reaction** |
| - All |
|
41
|
45
|
38
|
45
|
| - Severe |
|
2
|
0
|
2
|
1
|
| • Peripheral Neuropathy |
|
|
|
|
|
| - Any symptoms |
|
63
|
60
|
55
|
42
|
| - Severe symptoms |
|
1
|
2
|
0
|
0
|
| • Mucositis |
|
|
|
|
|
| - Any symptoms |
|
17
|
35
|
21
|
25
|
| - Severe symptoms |
|
0
|
3
|
0
|
2
|
| * Based
on worst course analysis
** All patients received premedication
|
Myelosuppression was dose
and schedule related,
with the schedule effect
being more prominent. The development
of severe hypersensitivity
reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses
overall. There was no apparent
dose or schedule
effect seen for the HSRs.
Peripheral neuropathy was clearly dose-related, but schedule
did not appear to affect
the incidence.
- The results of the randomized study support
the use of TAXOL at doses of 135 or 175 mg/m2 , administered
by a 3-hour intravenous
infusion. The same doses administered by 24-hour infusion
were more toxic.
Breast Carcinoma: Data from 83 patients accrued in three
phase 2 open label
studies and from 471 patients enrolled in a phase
3 randomized study were available to support
the use of TAXOL in patients with metastatic breast carcinoma.
The Phase 2 open
label studies -
Two studies were conducted in 53 patients previously treated with
a maximum of one prior
chemotherapeutic regimen. TAXOL was administered in these 2 trials
as a 24-hour infusion at initial
doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2
. The response rates
were 57% (95% CI: 37-75%) and 52% (95% CI: 32-72%), respectively.
The third phase 2 study
was conducted in extensively pretreated patients who had failed
anthracycline
therapy and who had
received a minimum of 2 chemotherapy
regimens for the treatment
of metastatic disease. The dose of TAXOL was 200 mg/m2
as a 24-hour infusion
with G-CSF support. Nine of the 30 patients achieved a partial response,
for a response rate of 30% (95% CI: 15- 50%).
The Phase 3 randomized study - This multicenter trial
was conducted in patients previously treated with one or two regimens
of chemotherapy. Patients were randomized to receive TAXOL at a
dose of either 175 mg/m2
or 135 mg/m2 given as a 3-hour infusion. In the 471 patients
enrolled, 60% had symptomatic
disease with impaired
performance status at
study entry, and 73% had visceral
metastases. These patients had failed prior chemotherapy
either in the adjuvant
setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven
percent of the patients
had been previously exposed to anthracyclines and 23% of them had
disease considered resistant
to this class of agents.
The overall response
rate for the 454 evaluable
patients was 26% (95% CI: 22-30%), with 17 complete and 99 partial
responses. The median
duration of response, measured from the first day of treatment,
was 8.1 months (range: 3.4- 18.1+ months). Overall for the 471 patients,
the median time
to progression was 3.5 months (range: 0.03-17.1 months). Median
survival was 11.7 months
(range: 0-18.9 months).
Response rates, median
survival and median
time to progression
for the 2 arms are given in the following table.
|
Efficacy in the Phase 3 Breast Carcinoma Study
|
| |
175/ 3
|
135/ 3
|
| |
(n=235)
|
(n=236)
|
| • Response |
|
|
| - rate (percent) |
28
|
22
|
| - 95% Confidence
Interval |
(22-34)
|
(17-27)
|
| • Time to Progression |
|
|
| - median (months) |
4.2
|
3.0
|
| - 95% Confidence
Interval |
(3.2-4.6)
|
(2.5-3.8)
|
| • Survival |
|
|
| - median
(months) |
11.7
|
10.5
|
| - 95% Confidence
Interval |
(10.0-13.8)
|
(9.0-12.8)
|
For the 458 patients who received TAXOL (paclitaxel) Injection in
the Phase 3 study, the following table
shows the incidence
of several important adverse events by treatment
arm (each arm
was administered by a 3-hour infusion).
|
Frequency* of Important Adverse Events
in the Phase 3 Breast Carcinoma Study
|
| |
|
Percent of Patients
|
| |
|
175 mg/m2
|
135 mg/m2
|
| |
|
(n=229)
|
(n=229)
|
| • Bone Marrow |
|
|
|
| - Neutropenia |
<2,000/mm3 |
90
|
81
|
| |
<500/mm3 |
28
|
19
|
| - Thrombocytopenia |
<100,000/mm3 |
11
|
7
|
| |
<50,000/mm3 |
3
|
2
|
| - Anemia |
< 11 g/dL |
55
|
47
|
| |
< 8 g/dL |
4
|
2
|
| - Infections |
|
23
|
15
|
| - Febrile Neutropenia |
|
2
|
2
|
| • Hypersensitivity
Reaction** |
|
|
|
| - All |
|
36
|
31
|
| - Severe |
|
0
|
<1
|
| • Peripheral Neuropathy |
|
|
|
| - Any symptoms |
|
70
|
46
|
| - Severe symptoms |
|
7
|
3
|
| • Mucositis |
|
|
|
| - Any symptoms |
|
23
|
17
|
| - Severe symptoms |
|
3
|
<1
|
| * Based
on worst course analysis
** All patients received premedication
|
Myelosuppression and peripheral
neuropathy were dose
related. There was one severe hypersensitivity
reaction (HSR) observed
at the dose of 135 mg/m2
.
AIDS-Related Kaposi’s Sarcoma: Data from two Phase 2 open
label studies support
the use of TAXOL as second-line therapy
in patients with AIDS related Kaposi’s sarcoma. Fifty-nine of the
85 patients enrolled in these studies had previously received systemic
therapy, including interferon
alpha (32%), DaunoXome® (31%),
DOXIL® (2%) and doxorubicin
containing chemotherapy
(42%), with 64% having received prior anthracyclines. Eightyfive
percent of the pretreated
patients had progressed on, or could not tolerate, prior systemic
therapy.
In Study CA139-174 patients received TAXOL at 135 mg/m2
as a 3-hour infusion
every 3 weeks (intended dose
intensity 45 mg/m2/week).
If no dose
limiting toxicity was
observed, patients were to receive 155 mg/m2 and 175
mg/m2 in subsequent courses. Hematopoietic growth factors
were not to be used initially. In
Study CA139-281 patients received TAXOL at 100 mg/m2
as a 3-hour infusion
every 2 weeks (intended dose
intensity 50 mg/m2/week).
In this study patients could
be receiving hematopoietic
growth factors before
the start of TAXOL therapy, or this support
was to be initiated as indicated; the dose
of TAXOL was not increased. The dose
intensity of TAXOL
used in this patient population was lower than the dose
intensity recommended
for other solid tumors.
All patients had widespread and p.o.
risk disease. Applying
the ACTG staging criteria to patients with prior systemic
therapy, 93% were poor
risk for extent of disease
(T1), 88% had a CD4
count <200 cells/mm3
(I1), and 97% had p.o.
risk considering their
systemic illness
(S1).
All patients in Study CA139-174 had a Karnofsky performance
status of 80 or 90 at
baseline; in Study CA139-281, there were 26 (46%) patients with
a Karnofsky performance
status of 70 or worse
at baseline.
|
Extent of Disease at Study Entry
|
| |
Percent of Patients
|
| |
Prior Systemic Therapy
|
| |
(n=59)
|
| Visceral ±
edema ± oral ±
cutaneous |
42
|
| Edema or lymph
nodes ± oral cutaneous |
41
|
| oral ±
cutaneous |
10
|
| Cutaneous only |
7
|
Although the planned dose
intensity in the two
studies was slightly different (45 mg/m2/week in Study
CA139-174 and 50 mg/m2 /week in Study CA139-281), delivered
dose intensity
was 38-39 mg/m2/week in both studies, with a similar
range (20-24 to 51-61).
Efficacy - The efficacy
of TAXOL was evaluated by assessing cutaneous tumor
response according
to the amended ACTG criteria and by seeking evidence
of clinical benefit
in patients in six domains of symptoms and/or conditions that are
commonly related to AIDS-related Kaposi’s sarcoma.
Cutaneous Tumor Response (Amended ACTG Criteria) -
The objective response
rate was 59% (95% CI: 46
to 72%)( 35 of 59 patients) in patients with prior systemic
therapy. Cutaneous responses were primarily defined as flattening
of more than 50% of previously raised
lesions.
|
Overall Best Response (Amended ACTG Criteria)
|
| |
Percent of Patients
|
| |
Prior Systemic Therapy
|
| |
(n=59)
|
| Complete response |
3
|
| Partial response |
56
|
| Stable disease |
29
|
| Progression |
8
|
| Early death/toxicity |
3
|
The median time
to response was 8.1
weeks and the median
duration of response
measured from the first day of treatment
was 10.4 months (95% CI: 7.0 to 11.0 months) for the patients who
had previously received systemic therapy. The median
time to progression
was 6.2 months (95% CI: 4.6 to 8.7 months).
Additional Clinical Benefit - Most data on patient
benefit were assessed retrospectively (plans for such
analyses were not included in the study protocols). Nonetheless,
clinical descriptions
and photographs indicated clear benefit
in some patients, including instances of improved pulmonary function
in patients with pulmonary
involvement, improved ambulation, resolution of ulcers, and decreased
analgesic requirements
in patients with KS involving the feet
and resolution of
facial lesions and edema
in patients with KS involving the face, extremities and genitalia.
Safety- The adverse event profile
of TAXOL (paclitaxel) Injection administered to patients with advanced
HIV disease
and poor-risk AIDS-related Kaposi’s sarcoma
was generally similar to that seen in a pooled analysis of 812 patients
with solid tumors (see
ADVERSE REACTIONS section).
In this immunosuppressed
patient population,
however, a lower dose intensity
of TAXOL and supportive therapy
including hematopoietic growth
factors in patients with severe neutropenia
are recommended. Patients with AIDS-related Kaposi’s sarcoma
may have more severe hematologic toxicities than patients with solid
tumors.
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