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
Anzemet Pharmacology, Pharmacokinetics, Studies, Metabolism - Dolasetron
Anzemet Pharmacology, Pharmacokinetics, Studies, Metabolism - Dolasetron
CLINICAL PHARMACOLOGY
Dolasetron mesylate and its active metabolite,
hydrodolasetron (MDL 74,156), are selective serotonin
5-HT3 receptor antagonists not shown
to have activity at
other known serotonin receptors and with low affinity
for dopamine receptors. The serotonin
5-HT3 receptors are located on the
nerve terminals of the
vagus in the periphery
and centrally in the chemoreceptor
trigger zone
of the area postrema. It
is thought that chemotherapeutic agents produce nausea
and vomiting by releasing
serotonin from the
enterochromaffin cells of the small intestine, and that the released
serotonin then activates
5-HT3 receptors located on vagal
efferents to initiate the vomiting
reflex.
Acute, usually reversible, ECG
changes (PR and QTc prolongation; QRS widening), caused
by dolasetron mesylate, have been observed in healthy volunteers
and in controlled clinical
trials. The active metabolites of dolasetron may block
sodium channels, a property
unrelated to its ability to block
5-HT3 receptors. QTc
prolongation is primarily due to QRS widening. Dolasetron appears
to prolong both depolarization
and to a lesser extent,
repolarization
time. The magnitude and frequency
of the ECG changes increased
with dose (related to peak
plasma concentrations of hydrodolasetron but not the parent
compound). These ECG interval prolongations usually returned to
baseline within 6 to
8 hours, but in some patients were present
at 24 hour follow up. Dolasetron mesylate administration has little
or no effect
on blood pressure.
In healthy volunteers
(N=64), dolasetron mesylate in single intravenous doses up to 5
mg/kg produced no effect
on pupil size or meaningful
changes in EEG tracings.
Results from neuropsychiatric tests revealed that dolasetron mesylate
did not alter mood or concentration.
Multiple daily doses of dolasetron have had no
effect on colonic transit
in humans. Dolasetron has no
effect on plasma prolactin
concentrations.
Pharmacokinetics in Humans
Oral dolasetron is well absorbed, although
parent drug
is rarely detected in plasma
due to rapid and complete metabolism
to the most clinically relevant species,
hydrodolasetron.
The reduction of dolasetron
to hydrodolasetron is mediated by a ubiquitous enzyme, carbonyl
reductase. Cytochrome P-450 (CYP)IID6 is primarily responsible for
the subsequent hydroxylation of hydrodolasetron and both CYPIIIA
and flavin monooxygenase are responsible for the N-oxidation of
hydrodolasetron.
Hydrodolasetron is excreted in the urine
unchanged (61.0% of administered oral dose). Other urinary
metabolites include hydroxylated glucuronides and N-oxide.
Hydrodolasetron appears rapidly in plasma,
with a maximum concentration
occurring approximately 1 hour after dosing, and is eliminated with
a mean half-life of 8.1 hours (%CV=18%) and an apparent
clearance of 13.4
mL/min/kg (%CV=29%) in 30 adults. The apparent
absolute bioavailability
of oral dolasetron, determined
by the major active metabolite
hydrodolasetron, is approximately 75%. Orally administered dolasetron
intravenous solution
and tablets are bioequivalent. Food does not affect
the bioavailability
of dolasetron taken by mouth.
Hydrodolasetron is eliminated by multiple
routes, including renal
excretion and, after metabolism,
mainly, glucuronidation and hydroxylation. Two thirds of the administered
dose is recovered in the
urine and one third in
the feces. Hydrodolasetron is widely distributed in the body
with a mean apparent volume
of distribution
of 5.8 L/kg (%CV=25%, N=24) in adults.
Sixty-nine to 77% of hydrodolasetron is bound
to plasma protein. In
a study with 14C labeled dolasetron,
the distribution of radioactivity
to blood cells was not
extensive. Approximately 50% of hydrodolasetron is bound
to alpha1-acid glycoprotein. The
pharmacokinetics
of hydrodolasetron are linear
and similar in men and women.
Pediatric Patients
The pharmacokinetics
of ANZEMET Tablets have not been studied in the pediatric
population. However, the following pharmacokinetic data are available
on intravenous ANZEMET
Injection administered orally to children.
Thirty-two pediatric
cancer patients ages
3 to 11 years (N=19) and 12 to 17 years (N=13), received 0.6, 1.2,
or 1.8 mg ANZEMET Injection
diluted with either apple or apple-grape juice
and administered orally. In
this study, the mean apparent
clearances of hydrodolasetron were 3 times greater in the younger
pediatric group
and 1.8 times greater in the older pediatric group than those observed
in healthy adult
volunteers. Across this spectrum of pediatric
patients, maximum plasma
concentrations were 0.6 to 0.7 times those observed in healthy
adults receiving similar doses.
For 12 pediatric patients,
ages 2 to 12 years receiving 1.2 mg/kg ANZEMET Injection diluted
in apple or apple-grape juice
and administered orally, the mean
apparent clearance
was 34% greater and half-life
was 21% shorter than in healthy
adults receiving the same dose. The pharmacokinetics
of hydrodolasetron, in special and targeted patient
populations following oral administration
of dolasetron, are summarized in Table 1. The pharmacokinetics of
hydrodolasetron are similar in adult
healthy volunteers and
in adult cancer patients receiving chemotherapeutic agents. The
apparent clearance
following oral administration
of hydrodolasetron is approximately 1.6- to 3.4-fold higher in children
and adolescents than in adults. The clearance following oral
administration
of hydrodolasetron is not affected by age in adult
cancer patients. The
apparent oral
clearance of hydrodolasetron
decreases 42% with severe hepatic
impairment and 44%
with severe renal impairment. No
dose adjustment
is necessary for elderly patients or for patients with hepatic
or renal impairment.
|
Table
1. Pharmacokinetic Values for Plasma Hydrodolasetron Following
Oral Administration of ANZEMET*
|
| |
Age
(years) |
Dose |
CLapp
(mL/min/kg) |
t1/2
(h) |
Cmax
(ng/mL) |
| Young Healthy
Volunteers (N=30) |
19-45 |
200
mg |
13.4
(29%) |
8.1
(18%) |
556
(28%) |
| Elderly Healthy
Volunteers (N=15) |
65-75 |
2.4
mg/kg |
9.5
(36%) |
7.2
(32%) |
662
(28%) |
Cancer
Patients
Adults (N=61)**
Adolescents (N=13)
Children (N=19) |
24-84
12-17
3-11 |
25-200
mg
0.6-1.8 mg/kg
0.6-1.8 mg/kg |
12.9
(49%)
26.5 (67%)
44.2 (49%) |
7.9
(43%)
6.4 (30%)
5.5 (39%) |
--***
374§ (32%)
217|| (67%) |
| Pediatric
Surgery Patients (N=11) |
2-12 |
1.2
mg/kg |
20.8
(49%) |
5.9
(24%) |
159
(32%) |
Patients
with Severe Renal
Impairment (N=12)
(Creatinine clearance
>10 mL/min) |
28-74 |
200
mg |
7.2
(48%) |
10.7
(29%) |
701
(21%) |
Patients
with Severe Hepatic
Impairment (N=3) |
42-52 |
150
mg |
8.8
(57%) |
11.0
(36%) |
410
(12%) |
CLapp:
*:
**:
***:
§:
||: |
apparent
clearance t1/2: terminal
elimination half-life ( ):
coefficient
of variation
in %
mean values
analyzed by nonlinear mixed
effect modeling
with data pooled across dose strengths
sampling times did not allow calculation
results from adolescents (dose=1.8 mg/kg, N=3)
results from children (dose=1.8 mg/kg, N=7) |
|
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