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
Temodar Pharmacology, Pharmacokinetics, Studies, Metabolism - Temozolomide
Temodar Pharmacology, Pharmacokinetics, Studies, Metabolism - Temozolomide
CLINICAL PHARMACOLOGY
Mechanism of Action
Temozolomide is not directly active but undergoes rapid non-enzymatic
conversion at physiologic pH
to the reactive compound
MTIC. The cytotoxicity of MTIC is thought to be primarily due to
alkylation of DNA.
Alkylation (methylation) occurs mainly at the O6 and
N7 positions of guanine.
Pharmacokinetics
Temozolomide is rapidly and completely absorbed after oral
administration; peak plasma
concentrations occur in 1 hour. Food reduces the rate
and extent of temozolomide absorption. Mean peak plasma
concentration
and AUC decreased by 32
% and 9 %, respectively, and Tmax increased 2- fold
(from 1.1 to 2.25 hours) when temozolomide was administered after
a modified high fat breakfast. Temozolomide is rapidly eliminated
with a mean elimination
half- life of 1.8 hours and exhibits linear
kinetics over the therapeutic
dosing range. Temozolomide has a mean
apparent volume
of distribution
of 0.4 L/kg (% CV= 13%). It is weakly bound
to human plasma
proteins; the mean percent
bound of drug- related total radioactivity
is 15%.
Metabolism and Elimination
Temozolomide is spontaneously hydrolyzed at physiologic pH
to the active species, 3-methyl-( triazen-1-yl) imidazole-4-carboxamide
(MTIC) and to temozolomide acid
metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide
(AIC) which is known to be an intermediate
in p.r.n. and nucleic
acid biosynthesis and to
methylhydrazine, which is believed to be the active alkylating species.
Cytochrome P450 enzymes play
only a minor role
in the metabolism
of temozolomide and MTIC. Relative to the AUC
of temozolomide, the exposure
to MTIC and AIC is 2.4% and 23%, respectively. About 38% of the
administered temozolomide total radioactive
dose is recovered over
7 days; 37.7% in urine
and 0.8% in feces. The majority of the recovery
of radioactivity
in urine is as unchanged
temozolomide (5.6%), AIC (12%), temozolomide acid
metabolite (2.3%), and unidentified polar
metabolite(s) (17%). Overall clearance
of temozolomide is about 5.5 L/hr/m2 .
Special Populations
Age: Population pharmacokinetic analysis
indicates that age (range 19-78 years) has no
influence on the pharmacokinetics
of temozolomide. In the anaplastic astrocytoma
study population, patients 70 years of age or older had a higher
incidence of Grade
4 neutropenia and
Grade 4 thrombocytopenia in the first cycle
of therapy than patients
under 70 years of age. (See PRECAUTIONS).
In the entire
safety database, however, there did not appear to be a higher incidence
in patients 70 years of age
or older. (See ADVERSE REACTIONS).
Gender: Population pharmacokinetic analysis
indicates that women have an approximately 5% lower clearance
(adjusted for body surface area) for temozolomide than men. Women
have higher incidences of Grade 4 neutropenia
and thrombocytopenia
in the first cycle of
therapy than men. (See ADVERSE REACTIONS).
Race: The effect
of race on the pharmacokinetics
of temozolomide has not been studied.
Tobacco Use: Population pharmacokinetic analysis
indicates that the oral
clearance of temozolomide
is similar in smokers and non-smokers.
Creatinine Clearance: Population pharmacokinetic
analysis indicates that creatinine
clearance over the
range of 36-130 ml/min/m2
has no effect
on the clearance of
temozolomide after oral
administration. The pharmacokinetics
of temozolomide have not been studied in patients with severely
impaired renal function
(CLcr < 36 ml/min/m2 ). Caution should be exercised
when TEMODAR is administered to patients with severe renal
impairment. TEMODAR has not been studied in patients on dialysis.
Hepatically Impaired Patients: In
a pharmacokinetic study, the pharmacokinetics
of temozolomide in patients with mild to moderate hepatic impairment
(Child's-Pugh Class I - II) were similar to those observed in patients
with normal hepatic
function. Caution should be exercised when temozolomide is administered
to patients with severe hepatic
impairment.
Pediatrics: Pediatric patients (3 to 17 years of
age) and adult patients
have similar clearance
and half-life values
for temozolomide. There is no
clinical experience
with the use of TEMODAR in children under the age
of 3 years.
Drug-Drug Interactions
In a multiple-dose study, administration
of TEMODAR with ranitidine did not change the Cmax or AUC
values for temozolomide or MTIC.
Population analysis
indicates that administration
of valproic acid decreases
the clearance of temozolomide
by about 5% (See PRECAUTIONS).
Population analysis
failed to demonstrate any influence of coadministered dexamethasone,
prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor
antagonists, or phenobarbital
on the clearance of
orally administered temozolomide.
Clinical Studies
A single arm, multicenter study was conducted in 162 patients who
had anaplastic astrocytoma
at first relapse and
who had a baseline
Karnofsky performance status
of 70 or greater. Patients had previously received radiation therapy
and may also have previously received a nitrosourea with or without
other chemotherapy. Fifty-four patients had disease
progression on prior
therapy with both a nitrosourea and procarbazine and their malignancy
was considered refractory
to chemotherapy
(refractory anaplastic astrocytoma population). Median age
of this subgroup of 54 patients was 42 years (19-76). Sixty-five
percent were male. Seventy-two
percent of patients
had a KPS of ³80.Sixty-three percent
of patients had surgery
other than a biobsy at the time
of initial diagnosis.
Of those patients undergoing resection, 73% underwent a subtotal
resection and 27%
underwent a gross total
resection. Eighteen percent
of patients had surgery at the time
of first relapse. The median
time from initial
diagnosis to first
relapse was 13.8 months
(4.2-75.4).
TEMODAR was given for the first 5 consecutive days of a 28 day
cycle at a starting dose
of 150 mg/m2/day. If the nadir and day of dosing (Day
29, Day 1 of next cycle) absolute
neutrophil 2 count
was ³1.5 x 109 /L (1,500/µL)
and the nadir and day 29, Day 1 of next cycle, platlet count
was >100 x 109 /L (100,000/µL), the TEMODAR
dose was increased to 200
mg/m2/day for the first 5 consecutive days of a 28 day
cycle.
In the refractory
anaplastic astrocytoma
population the overall
tumor response rate (CR
+ PR) was 22% (12/54 patients) and the complete response rate was
9% (5/54 patients). The median
duration of all responses
was 50 weeks (range of 16 to 114 weeks) and the median
duration of complete
responses was 64 weeks ( range
of 52 to 114 weeks). In this
population, progression-free survival at 6 months was 45% (95% confidence
interval 31-58%) and
progression-free survival at 12 months was 29% (95% confidence interval
16-42%). Median progression-free survival
was 4.4 months. Overall survival
at 6 months was 74% (95% confidence interval
62-86%) and 12 month overall survival was 65% (95% confidence interval
52-78%). Median overall survival
was 15.9 months.
top
