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
Tamiflu Pharmacology, Pharmacokinetics, Studies, Metabolism - Oseltamivir Phosphate
Tamiflu Pharmacology, Pharmacokinetics, Studies, Metabolism - Oseltamivir Phosphate
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption and Bioavailability
Oseltamivir is readily absorbed from the gastrointestinal tract
after oral administration of oseltamivir phosphate and is extensively converted
predominantly by hepatic esterases to oseltamivir carboxylate. At least 75%
of an oral dose reaches the systemic circulation as oseltamivir carboxylate.
Exposure to oseltamivir is less than 5% of the total exposure after oral dosing
(Table 1).
|
Table 1. Mean (%CV) Pharmacokinetic Parameters of Oseltamivir
and Oseltamivir Carboxylate After a Multiple 75 mg Capsule Twice Daily
Oral Dose (n=20)
|
|
Parameter
|
Oseltamivir
|
Oseltamivir Carboxylate
|
|
Cmax (ng/mL)
|
65.2 (26)
|
348 (18)
|
|
AUC0-12h (ng·h/mL)
|
112 (25)
|
2719 (20)
|
Plasma concentrations of oseltamivir carboxylate are proportional
to doses up to 500 mg given twice daily (see DOSAGE
AND ADMINISTRATION).
Coadministration with food has no significant effect on the
peak plasma concentration (551 ng/mL under fasted conditions and 441 ng/mL under
fed conditions) and the area under the plasma concentration time curve (6218
ng·h/mL under fasted conditions and 6069 ng·h/mL under fed conditions) of oseltamivir
carboxylate.
Distribution
The volume of distribution (Vss) of oseltamivir
carboxylate, following intravenous administration in 24 subjects, ranged between
23 and 26 liters.
The binding of oseltamivir carboxylate to human plasma protein
is low (3%). The binding of oseltamivir to human plasma protein is 42%, which
is insufficient to cause significant displacement-based drug interactions.
Metabolism
Oseltamivir is extensively converted to oseltamivir carboxylate
by esterases located predominantly in the liver. Neither oseltamivir nor oseltamivir
carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms.
Elimination
Absorbed oseltamivir is primarily (>90%) eliminated by conversion
to oseltamivir carboxylate. Plasma concentrations of oseltamivir declined with
a half-life of 1 to 3 hours in most subjects after oral administration. Oseltamivir
carboxylate is not further metabolized and is eliminated in the urine. Plasma
concentrations of oseltamivir carboxylate declined with a half-life of 6 to
10 hours in most subjects after oral administration. Oseltamivir carboxylate
is eliminated entirely (>99%) by renal excretion. Renal clearance (18.8 L/h)
exceeds glomerular filtration rate (7.5 L/h) indicating that tubular secretion
occurs, in addition to glomerular filtration. Less than 20% of an oral radiolabeled
dose is eliminated in feces.
Special Populations
Renal Impairment
Administration of 100 mg of oseltamivir phosphate twice daily
for 5 days to patients with various degrees of renal impairment showed that
exposure to oseltamivir carboxylate is inversely proportional to declining renal
function. Oseltamivir carboxylate exposures in patients with normal and abnormal
renal function administered various dose regimens of oseltamivir are described
in Table 2.
|
Table 2. Oseltamivir Carboxylate Exposures in Patients
With Normal and Reduced Serum Creatinine Clearance
|
|
Parameter
|
NormalRenalFunction
|
Impaired Renal Function
|
| |
75 mg qd
|
75 mg bid
|
150 mg bid
|
Creatinine Clearance<10 mL/min
|
Creatinine Clearance >10 and <30 mL/min
|
| |
|
|
|
CAPD
|
Hemodialysis
|
75 mg daily
|
75 mg alternate days
|
30 mg daily
|
|
30mg weekly
|
30 mg alternate HD cycle
|
|
Cmax
|
259*
|
348*
|
705*
|
766
|
850
|
1638
|
1175
|
655
|
|
Cmin
|
39*
|
138*
|
288*
|
62
|
48
|
864
|
209
|
346
|
|
AUC48
|
7476*
|
10876*
|
21864*
|
17381
|
12429
|
62636
|
21999
|
25054
|
|
*Observed values. All other values are predicted.
|
|
AUC normalized to 48 hours.
|
Pediatric Patients
The pharmacokinetics of oseltamivir and oseltamivir carboxylate
have been evaluated in a single dose pharmacokinetic study in pediatric patients
aged 5 to 16 years (n=18) and in a small number of pediatric patients aged 3
to 12 years (n=5) enrolled in a clinical trial. Younger pediatric patients cleared
both the prodrug and the active metabolite faster than adult patients resulting
in a lower exposure for a given mg/kg dose. For oseltamivir carboxylate, apparent
total clearance decreases linearly with increasing age (up to 12 years). The
pharmacokinetics of oseltamivir in pediatric patients over 12 years of age are
similar to those in adult patients.
Geriatric Patients
Exposure to oseltamivir carboxylate at steady-state was 25%
to 35% higher in geriatric patients (age range 65 to 78 years) compared to young
adults given comparable doses of oseltamivir. Half-lives observed in the geriatric
patients were similar to those seen in young adults. Based on drug exposure
and tolerability, dose adjustments are not required for geriatric patients for
either treatment or prophylaxis (see DOSAGE AND ADMINISTRATION:
Special Dosage Instructions).
CLINICAL STUDIES
Description of Clinical Studies : Studies in Naturally Occurring
Influenza
Treatment of Influenza
Adult Patients
Two phase III placebo-controlled and double-blind clinical
trials were conducted: one in the USA and one outside the USA. Patients were
eligible for these trials if they had fever >100ºF, accompanied by at least
one respiratory symptom (cough, nasal symptoms or sore throat) and at least
one systemic symptom (myalgia, chills/sweats, malaise, fatigue or headache)
and influenza virus was known to be circulating in the community. In addition,
all patients enrolled in the trials were allowed to take fever-reducing medications.
Of 1355 patients enrolled in these two trials, 849 (63%) patients
were influenza-infected (age range 18 to 65 years; median age 34 years; 52%
male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected patients, 95%
were infected with influenza A, 3% with influenza B, and 2% with influenza of
unknown type.
TAMIFLU was started within 40 hours of onset of symptoms. Subjects
participating in the trials were required to self-assess the influenza-associated
symptoms as "none", "mild", "moderate" or "severe".
Time to improvement was calculated from the time of treatment initiation to
the time when all symptoms (nasal congestion, sore throat, cough, aches, fatigue,
headaches, and chills/sweats) were assessed as "none" or "mild".
In both studie s, at the recommended dose of TAMIFLU 75 mg twice daily for 5
days, there was a 1.3 day reduction in the median time to improvement in influenza-infected
subjects receiving TAMIFLU compared to subjects receiving placebo. Subgroup
analyses of these studies by gender showed no differences in the treatment effect
of TAMIFLU in men and women.
In the treatment of influenza, no increased efficacy was demonstrated
in subjects receiving treatment of 150 mg TAMIFLU twice daily for 5 days.
Geriatric Patients
Three double-blind placebo-controlled treatment trials were
conducted in patients ³ 65 years of age in three
consecutive seasons. The enrollment criteria were similar to that of adult trials
with the exception of fever being defined as >97.5°
F. Of 741 patients enrolled, 476 (65%) patients were influenza-infected. Of
the 476 influenza-infected patients, 95% were infected with influenza type A
and 5% with influenza type B.
In the pooled analysis, at the recommended dose of TAMIFLU
75 mg twice daily for 5 days, there was a 1 day reduction in the median time
to improvement in influenza-infected subjects receiving TAMIFLU compared to
those receiving placebo (p = NS). However, the magnitude of treatment effect
varied between studies.
Pediatric Patients
One double-blind placebo-controlled treatment trial was conducted
in pediatric patients aged 1 to 12 years (median age 5 years), who had fever
(>100ºF) plus one respiratory symptom (cough or coryza) when influenza virus
was known to be circulating in the community. Of 698 patients enrolled in this
trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian). Of the 452
influenza-infected patients, 67% were infected with influenza A and 33% with
influenza B.
The primary endpoint in this study was the time to freedom
from illness, a composite endpoint which required 4 individual conditions to
be met. These were: alleviation of cough, alleviation of coryza, resolution
of fever, and parental opinion of a return to normal health and activity. TAMIFLU
treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms,
significantly reduced the total composite time to freedom from illness by 1.5
days compared to placebo. Subgroup analyses of this study by gender showed no
differences in the treatment effect of TAMIFLU in males and females.
Prophylaxis of Influenza
The efficacy of TAMIFLU in preventing naturally occurring influenza
illness has been demonstrated in three seasonal prophylaxis studies and a postexposure
prophylaxis study in households. The primary efficacy parameter for all these
studies was the incidence of laboratory confirmed clinical influenza. Laboratory
confirmed clinical influenza was defined as oral temperature ³
99.0ºF/37.2ºC plus at least one respiratory symptom (cough, sore throat, nasal
congestion) and at least one constitutional symptom (aches and pain, fatigue,
headache, chills/sweats), all recorded within 24 hours, plus either a positive
virus isolation or a fourfold increase in virus antibody titers from baseline.
In a pooled analysis of two seasonal prophylaxis studies in
healthy unvaccinated adults (aged 13 to 65 years), TAMIFLU 75 mg once daily
taken for 42 days during a community outbreak reduced the incidence of laboratory
confirmed clinical influenza from 4.8% (25/519) for the placebo group to 1.2%
(6/520) for the TAMIFLU group.
In a seasonal prophylaxis study in elderly residents of skilled
nursing homes, TAMIFLU 75 mg once daily taken for 42 days reduced the incidence
of laboratory confirmed clinical influenza from 4.4% (12/272) for the placebo
group to 0.4% (1/276) for the TAMIFLU group. About 80% of this elderly population
were vaccinated, 14% of subjects had chronic airway obstructive disorders, and
43% had cardiac disorders.
In a study of postexposure prophylaxis in household contacts
(aged t13 years) of an index case, TAMIFLU 75 mg once daily administered within
2 days of onset of symptoms in the index case and continued for 7 days reduced
the incidence of laboratory confirmed clinical influenza from 12% (24/200) in
the placebo group to 1% (2/205) for the TAMIFLU group. Index cases did not receive
TAMIFLU in the study.
ANIMAL TOXICOLOGY
In a 2-week study in unweaned rats, administration of a single
dose of 1000 mg/kg oseltamivir phosphate to 7-day-old rats resulted in deaths
associated with unusually high exposure to the prodrug. However, at 2000 mg/kg,
there were no deaths or other significant effects in 14-day-old unweaned rats.
Further follow-up investigations of the unexpected deaths of 7-day-old rats
at 1000 mg/kg revealed that the concentrations of the prodrug in the brains
were approximately 1500-fold those of the brains of adult rats administered
the same oral dose of 1000 mg/kg, and those of the active metabolite were approximately
3-fold higher. Plasma levels of the prodrug were 10-fold higher in 7-day-old
rats as compared with adult rats. These observations suggest that the levels
of oseltamivir in the brains of rats decrease with increasing age and most likely
reflect the maturation stage of the blood-brain barrier. No adverse effects
occurred at 500 mg/kg/day administered to 7- to 21-day-old rats. At this dosage,
the exposure to prodrug was approximately 800-fold the exposure expected in
a 1-year-old child.
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