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
Eloxatin Pharmacology, Pharmacokinetics, Studies, Metabolism - Oxaliplatin
Eloxatin Pharmacology, Pharmacokinetics, Studies, Metabolism - Oxaliplatin
CLINICAL PHARMACOLOGY
Mechanism of Action
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active
derivatives via displacement of the labile oxalate ligand. Several transient
reactive species are formed, including monoaquo and diaquo DACH platinum, which
covalently bind with macromolecules. Both inter- and intra-strand Pt-DNA crosslinks
are formed. Crosslinks are formed between the N7 positions of two adjacent
guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an
intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription.
Cytotoxicity is cell-cycle nonspecific.
Pharmacology
In vivo studies have shown antitumor activity of oxaliplatin against
colon carcinoma. In combination with 5-fluorouracil (5-FU), oxaliplatin exhibits
in vitro and in vivo antiproliferative activity greater than
either compound alone in several tumor models [HT29 (colon), GR (mammary), and
L1210 (leukemia)].
Human Pharmacokinetics
The reactive oxaliplatin derivatives are present as a fraction of the unbound
platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels
following oxaliplatin administration is triphasic, characterized by two relatively
short distribution phases (t1/2
; 0.43 hours and t1/2
; 16.8 hours) and a long terminal elimination
phase
(t1/2
; 391 hours). Pharmacokinetic parameters obtained
after a single 2-hour IV infusion of ELOXATIN at a dose of 85 mg/m2
expressed as ultrafilterable platinum were Cmax of 0.814 µg/mL and
volume of distribution of 440 L.
Interpatient and intrapatient variability in ultrafilterable platinum exposure
(AUC0-48hr) assessed over 3 cycles was moderate to low (23% and 6%,
respectively). A pharmacodynamic relationship between platinum ultrafiltrate
levels and clinical safety and effectiveness has not been established.
Distribution
At the end of a 2-hour infusion of ELOXATIN, approximately 15% of the administered
platinum is present in the systemic circulation. The remaining 85% is rapidly
distributed into tissues or eliminated in the urine. In patients, plasma protein
binding of platinum is irreversible and is greater than 90%. The main binding
proteins are albumin and gamma-globulins. Platinum also binds irreversibly and
accumulates (approximately 2-fold) in erythrocytes, where it appears to have
no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate
following 85 mg/m2 every two weeks.
Metabolism
Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There
is no evidence of cytochrome P450-mediated metabolism in vitro.
Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate
samples from patients, including several cytotoxic species (monochloro DACH
platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and
a number of noncytotoxic, conjugated species.
Elimination
The major route of platinum elimination is renal excretion. At five days after
a single 2-hour infusion of ELOXATIN, urinary elimination accounted for about
54% of the platinum eliminated, with fecal excretion accounting for only about
2%. Platinum was cleared from plasma at a rate (10 – 17 L/h) that was similar
to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h).
There was no significant effect of gender on the clearance of ultrafilterable
platinum. The renal clearance of ultrafilterable platinum is significantly correlated
with GFR. (See ADVERSE REACTIONS.)
Pharmacokinetics in Special Populations
Renal Impairment
The AUC0-48hr of platinum in the plasma ultrafiltrate increases
as renal function decreases. The AUC0-48hr of platinum in patients
with mild (creatinine clearance, CLcr 50 to 80 mL/min), moderate
(CLcr 30 to <50 mL/min) and severe renal (CLcr <30
mL/min) impairment is increased by about 60, 140 and 190%, respectively, compared
to patients with normal renal function (CLcr >80 mL/min). (See
PRECAUTIONS and ADVERSE
REACTIONS.)
Drug - Drug Interactions
No pharmacokinetic interaction between 85 mg/m2 of ELOXATIN and
infusional 5-FU has been observed in patients treated every 2 weeks, but increases
of 5-FU plasma concentrations by approximately 20% have been observed with doses
of 130 mg/m2 of ELOXATIN administered every 3 weeks. In vitro,
platinum was not displaced from plasma proteins by the following medications:
erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In
vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome
P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated
in patients.
Since platinum-containing species are eliminated primarily through the kidney,
clearance of these products may be decreased by co-administration of potentially
nephrotoxic compounds, although this has not been specifically studied.
CLINICAL STUDIES
Combination Therapy With ELOXATIN and Infusional 5-FU/LV in Previously Treated
Patients With Advanced Colorectal Cancer
A multicenter, randomized, three-arm controlled study was conducted in the
US and Canada comparing the efficacy and safety of ELOXATIN in combination with
an infusional schedule of 5-FU/LV to the same dose and schedule of 5-FU/LV alone
and to single agent oxaliplatin in patients with advanced colorectal cancer
who had relapsed/progressed during or within 6 months of first line therapy
with bolus 5-FU/LV and irinotecan. The study was intended to be analyzed for
response rate after 450 patients were enrolled. Survival will be subsequently
assessed in all patients enrolled in the completed study. Accrual to this study
is complete, with 821 patients enrolled. Patients in the study had to be at
least 18 years of age, have unresectable, measurable, histologically proven
colorectal adenocarcinoma, with a Karnofsky performance status >50%. Patients
had to have SGOT(AST) and SGPT(ALT) <2x the institution’s upper limit
of normal (ULN), unless liver metastases were present and documented at baseline
by CT or MRI scan, in which case <5x ULN was permitted. Patients had
to have alkaline phosphatase <2x the institution’s ULN, unless liver
metastases were present and documented at baseline by CT or MRI scan, in which
cases <5x ULN was permitted. Prior radio-therapy was permitted if
it had been completed at least 3 weeks before randomization.
The dosing regimens of the three arms of the study are presented in the table
below.
Table 1 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer
Clinical Trial
| Treatment Arm |
Dose |
Regimen |
ELOXATIN
+ 5-FU/LV
(N=152) |
Day 1: ELOXATIN: 85 mg/m2 (2-hour infusion) + LV 200 mg/m2
(2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus),
600 mg/m2 (22-hour infusion)
Day 2: LV 200 mg/m2 (2-hour infusion), followed by 5-FU:
400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
|
q2w |
5-FU/LV
(N=151) |
Day 1: LV 200 mg/m2 (2-hour infusion), followed by 5-FU:
400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
Day 2: LV 200 mg/m2 (2-hour infusion), followed by 5-FU:
400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
|
q2w |
ELOXATIN
(N=156) |
Day 1: ELOXATIN 85 mg/m2
(2-hour infusion) |
q2w |
Patients entered into the study for evaluation of response must have had at
least one unidimensional lesion measuring >20 mm using conventional
CT or MRI scans, or >10 mm using a spiral CT scan. Tumor response
and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation
Criteria in Solid Tumors (RECIST) until radiological documentation of progression
or for 13 months following the first dose of study drug(s), whichever came first.
Confirmed responses were based on two tumor assessments separated by at least
4 weeks.
The demographics of the patient population entered into this study are shown
in the table below.
Table 2 – Patient Demographics in Refractory and Relapsed Colorectal
Cancer Clinical Trial
| |
5-FU/LV
(N=151) |
ELOXATIN
(N=156) |
ELOXATIN
+ 5-FU/LV
(N=152) |
| Sex: Male (%) |
54.3 |
60.9 |
57.2 |
| Female (%)
|
45.7 |
39.1 |
42.8 |
| Median age (years) |
60.0 |
61.0 |
59.0 |
| Range |
21-80 |
27-79 |
22-88 |
| Race (%) |
| Caucasian |
87.4 |
84.6 |
88.8 |
| Black |
7.9 |
7.1 |
5.9 |
| Asian |
1.3 |
2.6 |
2.6 |
| Other |
3.3 |
5.8 |
2.6 |
| KPS (%) |
| 70 – 100 |
94.7 |
92.3 |
95.4 |
| 50 – 60 |
2.6 |
4.5 |
2.0 |
| Not reported |
2.6 |
3.2 |
2.6 |
| Prior radiotherapy (%) |
25.2 |
19.2 |
25.0 |
| Prior pelvic radiation (%) |
18.5 |
13.5 |
21.1 |
| Number of metastatic sites (%) |
| 1 |
27.2 |
31.4 |
25.7 |
| >2 |
72.2 |
67.9 |
74.3 |
| Liver involvement (%) |
| Liver only |
22.5 |
25.6 |
18.4 |
| Liver + other |
60.3 |
59.0 |
53.3 |
The median number of cycles administered per patient was 6 for the ELOXATIN
and infusional 5-FU/LV combination and 3 each for infusional 5-FU/LV alone and
ELOXATIN alone.
Patients treated with the combination of ELOXATIN and infusional
5-FU/LV had an increased response rate compared to patients given infusional
5-FU/LV or oxaliplatin alone. The efficacy results are summarized in the tables
below.
Table 3 – Response Rates (ITT Analysis)
| Best Response |
5-FU/LV
(N=151) |
ELOXATIN
(N=156) |
ELOXATIN
+ 5-FU/LV
( N=152) |
|
CR
|
0 |
0 |
0 |
|
PR
|
0 |
2 (1%) |
13 (9%) |
|
p-value
|
0.0002 for 5-FU/LV vs. ELOXATIN + 5-FU/LV |
|
95% Cl
|
0-2.4% |
0.2-4.6% |
4.6-14.2% |
Table 4 – Summary of Radiographic Time to Progression*
| Arm |
5-FU/LV
(N=151) |
ELOXATIN
(N=156) |
ELOXATIN
+ 5-FU/LV
( N=152) |
|
No. of progressors
|
74 |
101 |
50 |
|
No. of patients with no radiological evaluation beyond baseline
|
22
(15%) |
16
(10%) |
17
(11%) |
|
Median TTP (months)
|
2.7 |
1.6 |
4.6 |
|
95% Cl
|
1.8-3.0 |
1.4-2.7 |
4.2-6.1 |
*This is not an ITT analysis. Events were limited to radiographic
disease progression documented by independent review of radiographs. Clinical
progression was not included in this analysis, and 18% of patients were excluded
from the analysis based on unavailability of the radiographs for independent
review.
At the time of the interim analysis 49% of the radiographic progression events
had occurred. In this interim analysis an estimated 2-month increase in median
time to radiographic progression was observed compared to infusional 5-FU/LV
alone.
Of the 13 patients who had tumor response to the combination of ELOXATIN and
infusional 5-FU/LV, 5 were female and 8 were male, and responders included patients
<65 years old and >65 years old. The small number of non-Caucasian
participants made efficacy analyses in these populations uninterpretable.
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