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
Xeloda Pharmacology, Pharmacokinetics, Studies, Metabolism - Capecitabine
Xeloda Pharmacology, Pharmacokinetics, Studies, Metabolism - Capecitabine
CLINICAL PHARMACOLOGY
Capecitabine is relatively noncytotoxic in vitro. This drug is
enzymatically converted to 5-fluorouracil (5-FU) in vivo.
Bioactivation
Capecitabine is readily absorbed from the gastrointestinal tract. In
the liver, a 60 kDa carboxyesterase hydrolyzes much of the compound to
5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found
in most tissues, including tumors subsequently converts 5'-DFCR to 5'-deoxy-5-fluorouridine
(5'-DFUR). The enzyme thymidine phosphorylase (dThdPase), then hydrolyzes
5'-DFUR to the active drug 5-FU. Many tissues throughout the body express
thymidine phosphorylase. Some human carcinomas express this enzyme in
higher concentrations than surrounding normal tissues.
Metabolic Pathway of capecitabine to 5-FU
Mechanism of Action
Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine
monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites
cause cell injury by two different mechanisms. First, FdUMP and the folate
cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase
(TS) to form a covalently bound ternary complex. This binding inhibits
the formation of thymidylate from 2'-deaxyuridylate. Thymidylate is the necessary
precursor of thymidine triphosphate, which is essential for the synthesis
of DNA, so that a deficiency of this compound can inhibit cell division.
Second nuclear transcriptional enzymes can mistakenly incorporate FUTP
in place of uridine triphosphate (UTP) during the synthesis of RNA. This
metabolic error can interfere with RNA processing and protein synthesis.
Pharmacokinetics in Colorectal Tumors and Adjacent Healthy Tissue
Following oral administration of capecitabine 7 days before surgery in
patients with colorectal cancer, the median ratio of 5-FU concentration
in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0).
These ratios have not been evaluated in breast cancer patients or compared
to 5-FU infusion.
Human Pharmacokinetics
The pharmacokinetics of XELODA and its metabolites have been evaluated
in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2/day.
Over this range the pharmacokinetics of capecitabine and its metabolite,
5-DFCR were dose proportional and did not change over time. The increases
in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional
to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than
on day 1. The elimination half-life of both parent capecitabine and 5-FU
was about ¾ of an hour. The inter-patient variability in the Cmax
and AUC of 5-FU was greater than 85%.
Absorption, Distribution, Metabolism and Excretion
Capecitabine reached peak blood levels in about 1.5 hours (Tmax)
with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced
both the rate and extent of absorption of capecitabine with mean Cmax
and AUC0-¥
decreased by 60% and 35%, respectively. The Cmax and AUC0-¥
of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed
Tmax of both parent and 5-FU by 1.5 hours (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION).
Plasma protein binding of capecitabine and its metabolites is less than
60% and is not concentration-dependent. Capecitabine was primarily bound
to human albumin (approximately 35%).
Capecitabine is extensively metabolized enzymatically to 5-FU. The enzyme
dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine
metabolism, to the much less toxic 5-fluoro-5,6-dihydro-fluorouracil (FUH2).
Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic
acid (FUPA). Finally b-ureido-propionase
cleaves FUPA to a-fluoro-b-alanine
(FBAL) which is cleared in the urine.
Capecitabine and its metabolites are predominantly excreted in urine;
95.5% of administered capecitabine dose is recovered in urine. Fecal excretion
is minimal (2.6%). The major metabolite excreted in urine is FBAL which
represents 57% of the administered dose. About 3% of the administered
dose is excreted in urine as unchanged drug.
Special Populations
Age, Gender and Ethnicity: No formal studies were conducted
to examine the effect of age or gender or ethnicity on the pharmacokinetics
of capecitabine and its metabolites.
Hepatic Insufficiency: XELODA has been evaluated in 13
patients with mild to moderate hepatic dysfunction due to liver metastases
defined by a composite score including bilirubin, AST/ALT and alkaline
phosphatase following a single 1255 mg/m2 dose of capecitabine.
Both AUC0-¥
and Cmax of capecitabine increased by 60% in patients with
hepatic dysfunction compared to patients with normal hepatic function
(n=14). The AUC0-¥
and Cmax of 5-FU was not affected. In patients with mild to
moderate hepatic dysfunction due to liver metastases, caution should be
exercised when XELODA is administered. The effect of severe hepatic dysfunction
on XELODA is not known (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION).
Renal Insufficiency: No formal pharmacokinetic study was
conducted in patients with renal impairment (see PRECAUTIONS).
Drug-Drug Interactions
Drugs Metabolized by Cytochrome P450 Enzymes: In vitro
enzymatic studies with human liver microsomes indicated that capecitabine
and 5'-DFUR had no inhibitory effects on substrates of cytochrome P450
for the major isoenzymes such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1,
suggesting a low likelihood of interactions with drugs metabolized by
cytochrome P450 enzymes.
Antacid: When Maalox®* (20 mL), an aluminum hydroxide-
and magnesium hydroxide-containing antacid, was administered immediately
after capecitabine (1250 mg/m2, n=12 cancer patients), AUC
and Cmax increased by 16% and 35%, respectively for capecitabine
and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed
on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of capecitabine.
XELODA has a low potential for pharmacokinetic interactions related to
plasma protein binding.
CLINICAL STUDIES
In a phase 1 study with XELODA in patients with solid tumors, the maximum
tolerated dose as a single agent was 3000 mg/m2 when administered
daily for 2 weeks, followed by a 1-week rest period. The dose-limiting
toxicities were diarrhea and leukopenia.
Breast Carcinoma: The antitumor activity of XELODA was
evaluated in an open-label single-arm trial conducted in 24 centers in
the US and Canada. A total of 162 patients with stage IV breast cancer
were enrolled. The primary endpoint was tumor response rate in patients
with measurable disease, with response defined as a ³50%
decrease in sum of the products of the perpendicular diameters of bidimensionally
measurable disease for at least 1 month. XELODA was administered at a
daily dose of 2510 mg/m2 for 2 weeks followed by a 1-week rest
period and given as 3-week cycles. The baseline demographics and clinical
characteristics for all patients (n=162) and those with measurable disease
(n=135) are shown in the table below. Resistance was defined as progressive
disease while on treatment, with or without an initial response, or relapse
within 6 months of completing treatment with an anthracycline-containing
adjuvant chemotherapy regimen.
| Table 1. Baseline Demographics and
Clinical Characteristics |
| |
Patients With
Measurable
Disease (n=
135) |
All Patients
(n=
162) |
| Age (median, years) |
55 |
56 |
| Karnofsky PS |
90 |
90 |
| No. Disease Sites |
|
|
| 1-2 |
43(32%) |
60(37%) |
| 3-4 |
63(46%) |
69(43%) |
| >5 |
29(22%) |
34(21%) |
| Dominant Site of Disease |
|
|
| Visceral¹ |
101(75%) |
110(68%) |
| Soft Tissue |
30(22%) |
35(22%) |
| Bone |
4(3%) |
17(10%) |
| Prior Chemotherapy |
|
|
| Paclitaxel |
135(100%) |
162(100%) |
| Anthracycline² |
122(90%) |
147(91%) |
| 5-FU |
110(81%) |
133(82%) |
| Resistance to Paclitaxel |
103(76%) |
124(77%) |
| Resistance to an Anthracycline² |
55(41%) |
67(41%) |
Resistance to both
Paclitaxel and an Anthracycline² |
43(32%) |
51(31%) |
¹ Lung, pleura, liver, peritoneum
²Includes 2 patients treated with an anthracenedione
Antitumor responses for patients with disease resistant to both paclitaxel
and an anthracycline are shown in the table below.
| Table 2. Response Rates
in Doubly-Resistant Patients |
| |
Resistance to Both Paclitaxel
and an Anthracycline
(n= 43) |
| CR |
0 |
| PR¹ |
11 |
| CR + PR¹ |
11 |
Response Rate¹
(95% C. I.) |
25.6%
(13.5, 41.2) |
Duration of Response,¹
Median in days²
(Range) |
154
(63 to 233) |
¹Includes 2 patients treated with an anthracenedione
²From date of first response
For the subgroup of 43 patients who were doubly resistant, the median
time to progression was 102 days and the median survival was 255 days.
The objective response rate in this population was supported by a response
rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients
with measurable disease, who were less resistant to chemotherapy (see
Table 1). The median time to progression was 90 days and the median survival
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