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
Relenza Pharmacology, Pharmacokinetics, Studies, Metabolism - Zanamivir
Relenza Pharmacology, Pharmacokinetics, Studies, Metabolism - Zanamivir
CLINICAL PHARMACOLOGY
Pharmacokinetics: Absorption and Bioavailability: Pharmacokinetic
studies of orally inhaled zanamivir indicate that approximately 4% to 17% of
the inhaled dose is systemically absorbed. The peak serum concentrations ranged
from 17 to 142 ng/mL within 1 to 2 hours following a 10-mg dose. The area under
the serum concentration versus time curve (AUC) ranged from 111 to 1,364
ng· hr/mL.
Distribution: Zanamivir has limited plasma protein
binding (<10%).
Metabolism: Zanamivir is renally excreted as
unchanged drug. No metabolites have been detected in humans.
Elimination: The serum half-life of zanamivir
following administration by oral inhalation ranges from 2.5 to 5.1 hours. It
is excreted unchanged in the urine with excretion of a single dose completed
within 24 hours. Total clearance ranges from 2.5 to 10.9 L/hr. Unabsorbed drug
is excreted in the feces.
Special Populations: Impaired Hepatic Function: The
pharmacokinetics of zanamivir have not been studied in patients with impaired
hepatic function.
Impaired Renal Function: Systemic exposure is
limited after inhalation (see Absorption and Bioavailability). After a single
intravenous dose of 4 mg or 2 mg of zanamivir in volunteers with mild/moderate
or severe renal impairment, respectively, significant decreases in renal clearance
(and hence total clearance: normals 5.3 L/hr, mild/moderate 2.7 L/hr, and severe
0.8 L/hr; median values) and significant increases in half-life (normals 3.1
hr, mild/moderate 4.7 hr, and severe 18.5 hr; median values) and systemic exposure
were observed. Safety and efficacy have not been documented in the presence
of severe renal insufficiency.
Pediatric Patients: The pharmacokinetics of zanamivir
were evaluated in pediatric patients with signs and symptoms of respiratory
illness. Sixteen patients, 6 to 12 years of age, received a single dose of 10-mg
zanamivir dry powder via DISKHALER. Five patients had either undetectable zanamivir
serum concentrations or had
low drug concentrations (8.32 to 10.38 ng/mL) that were not
detectable after 1.5 hours. Eleven patients had Cmax median values
of 43 ng/mL (range 15 to 74) and AUC¥ median values
of 167 ng· hr/mL (range 58 to 279). Low or undetectable
serum concentrations were related to lack of measurable PIFR in individual patients
(see DESCRIPTION, INDICATIONS
AND USAGE: Description of Clinical Studies, and PRECAUTIONS:
Pediatric Use).
Geriatric Patients: The pharmacokinetics of
zanamivir have not been studied in patients over 65 years of age (see PRECAUTIONS:
Geriatric Use).
Gender, Race, and Weight: In a population pharmacokinetic
analysis in patient studies, no clinically significant differences in serum
concentrations and/or pharmacokinetic parameters (V/F, CL/F, ka, AUC0-3,
Cmax, Tmax, CLr, and % excreted in urine) were
observed when demographic variables (gender, age, race, and weight) and indices
of infection (laboratory evidence of infection, overall symptoms, symptoms of
upper respiratory illness, and viral titers) were considered. There were no
significant correlations between measures of systemic exposure and safety parameters.
DRUG INTERACTIONS
No clinically significant pharmacokinetic drug interactions
are predicted based on data from in vitro studies.
Zanamivir is not a substrate nor does it affect cytochrome
P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human
liver microsomes.
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