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
Emtriva Pharmacology, Pharmacokinetics, Studies, Metabolism - Emtricitabine
Emtriva Pharmacology, Pharmacokinetics, Studies, Metabolism - Emtricitabine
CLINICAL PHARMACOLOGY
Pharmacodynamics:
The in vivo activity of emtricitabine was evaluated in two
clinical trials in which 101 patients were administered 25 to 400 mg a day of
EMTRIVA as monotherapy for 10 to 14 days. A dose-related antiviral effect was
observed, with a median decrease from baseline in plasma HIV-1 RNA of 1.3 log10
at a dose of 25 mg QD and 1.7 log10 to 1.9 log10 at a dose of 200
mg QD or BID.
Pharmacokinetics:
The pharmacokinetics of emtricitabine were evaluated in healthy
volunteers and HIV-infected individuals. Emtricitabine pharmacokinetics are
similar between these populations.
Figure 1 shows the mean steady-state plasma emtricitabine concentration-time profile in 20 HIV-infected subjucts
receiving EMTRIVA.
Figure 1. Mean (± 95% CI) Steady-State Plasma Emtricitabine
Concentration in HIV-Infected Adults (N=20)
Absorption:
Emtricitabine is rapidly and extensively absorbed following
oral administration with peak plasma concentrations occurring at 1 to 2 hours
post-dose. Following multiple dose oral administration of EMTRIVA to 20 HIV-infected
subjects, the (mean SD) steady-state plasma emtricitabine peak concentration
(Cmax) was 1.8 0.7 µg/mL and the area-under the plasma concentration-time
curve over a 24-hour dosing interval (AUC) was 10.0 3.1 hr*µg/mL. The mean steady
state plasma trough concentration at 24 hours post-dose was 0.09 µg/mL. The
mean absolute bioavailability of EMTRIVA was 93%.
The multiple dose pharmacokinetics of emtricitabine are dose
proportional over a dose range of 25 to 200 mg.
Effects of Food on Oral Absorption:
EMTRIVA may be taken with or without food.
Emtricitabine systemic exposure (AUC) was unaffected while
Cmax decreased by 29% when EMTRIVA was administered with food (an
approximately 1000 kcal high-fat meal).
Distribution:
In vitro binding of emtricitabine to human plasma proteins
was <4% and independent of concentration over the range of 0.02 – 200 µg/mL.
At peak plasma concentration, the mean plasma to blood drug concentration ratio
was ~ 1.0 and the mean semen to plasma drug concentration ratio was ~ 4.0.
Metabolism:
In vitro studies indicate that emtricitabine is not an inhibitor
of human CYP450 enzymes. Following administration of 14C-emtricitabine,
complete recovery of the dose was achieved in urine (~ 86%) and feces (~ 14%).
Thirteen percent (13%) of the dose was recovered in urine as three putative
metabolites. The biotransformation of emtricitabine includes oxidation of the
thiol moiety to form the 3’-sulfoxide diastereomers (~ 9% of dose) and conjugation
with glucuronic acid to form 2’-O-glucuronide (~ 4% of dose). No other metabolites
were identifiable.
Elimination:
The plasma emtricitabine half-life is approximately 10 hours.
The renal clearance of emtricitabine is greater than the estimated
creatinine clearance, suggesting elimination by both glomerular filtration and
active tubular secretion. There may be competition for elimination with other
compounds that are also renally eliminated.
Special Populations:
The pharmacokinetics of emtricitabine were similar in male
and female patients and no pharmacokinetic differences due to race have been
identified.
The pharmacokinetics of emtricitabine have not been fully evaluated
in children or in the elderly.
The pharmacokinetics of emtricitabine have not been studied
in patients with hepatic impairment, however, emtricitabine is not metabolized
by liver enzymes, so the impact of liver impairment should be limited.
The pharmacokinetics of emtricitabine are altered in patients
with renal impairment (See PRECAUTIONS).
In patients with creatinine clearance < 50 mL/min or with end-stage renal
disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine
were increased due to a reduction in renal clearance (Table 1). It is recommended
that the dosing interval for EMTRIVA be modified in patients with creatinine
clearance < 50 mL/min or in patients with ESRD who require dialysis (see
DOSAGE AND ADMINISTRATION).
|
Table 1. Mean ± SD
Pharmacokinetic Parameters in Patients with Varying Degrees of Renal Function
|
|
Creatinine clearance (mL/min)
|
>80 (n=6)
|
50-80 (n=6)
|
30-49 (n=6)
|
<30 (n=5)
|
ESRD* <30(n=5)
|
|
Baseline Creatinine clearance (mL/min)
|
107 ± 21
|
59.8 ± 6.5
|
40.9 ± 5.1
|
22.9 ± 5.3
|
8.8 ± 1.4
|
|
Cmax (m g/mL)
|
2.2 ± 0.6
|
3.8 ± 0.9
|
3.2 ± 0.6
|
2.8 ± 0.7
|
2.8 ± 0.5
|
|
AUC (hr m g/mL)
|
11.8 ± 2.9
|
19.9 ± 1.1
|
25.0 ± 5.7
|
34.0 ± 2.1
|
53.2 ± 9.9
|
|
CL/F (mL/min)
|
302 ± 94
|
168 ± 10
|
138 ± 28
|
99 ± 6
|
64 ± 12
|
|
CLr (mL/min)
|
213.3 ± 89.0
|
121.4 ± 39.0
|
68.6± 32.1
|
29.5±11.4
|
-
|
|
*ESRD patients requiring dialysis
|
|
"-" = not applicable
|
Hemodialysis: Hemodialysis treatment removes approximately
30% of the emtricitabine dose over a 3-hour dialysis period starting within
1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate
flow rate of 600 mL/min). It is not known whether emtricitabine can be removed
by peritoneal dialysis.
DRUG INTERACTIONS
At concentrations up to 14 fold higher than those observed
in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by
any of the following human CYP 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9,
CYP2C19, CYP2D6 and CYP3A4. Emtricitabine did not inhibit the enzyme responsible
for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on
the results of these in vitro experiments and the known elimination pathways
of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine
with other medicinal products is low.
EMTRIVA has been evaluated in healthy volunteers in combination
with tenofovir disoproxil fumarate (DF), indinavir, famciclovir, and stavudine.
Tables 2 and 3 summarize the pharmacokinetic effects of co-administered drug
on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics
of co-administered drug.
|
Table 2. Drug Interactions: Change in Pharmacokinetic
Parameters for Emtricitabine in the Presence of the Co-administered Drug1
|
|
Co-Administered Drug
|
Dose of Co-
Administered Drug (mg)
|
Emtricitabine Dose (mg)
|
N
|
% Change of Co-administered Drug Pharmacokinetic Parameters
2 (90% CI)
|
|
|
|
|
Cmax
|
AUC
|
Cmin
|
|
Tenofovir DF
|
300 once daily x 7 days
|
200 once daily x 7 days
|
17
|
Û
|
Û
|
20 (
12 to 29)
|
|
Indinavir
|
800 x 1
|
200 x 1
|
12
|
Û
|
Û
|
-
|
|
Famciclovir
|
500 x 1
|
200 x 1
|
12
|
Û
|
Û
|
-
|
|
Stavudine
|
40 x 1
|
200 x 1
|
6
|
Û
|
Û
|
-
|
|
1. All interaction studies conducted in healthy volunteers
|
|
2. = Increase; ¯
= Decrease; Û = no effect; "-"
= not applicable
|
|
Table 3. Drug Interactions: Change in Pharmacokinetic
Parameters for Co-administered Drug in the Presence of Emtricitabine1
|
|
Co-Administered Drug
|
Dose of Co-Administered Drug (mg)
|
Emtricitabine Dose (mg)
|
N
|
% Change of Co-administered Drug Pharmacokinetic Parameters
2 (90% CI)
|
|
Cmax
|
AUC
|
Cmin
|
|
Tenofovir DF
|
300 once daily x 7 days
|
200 once daily x 7 days
|
17
|
Û
|
Û
|
Û
|
|
Indinavir
|
800 x 1
|
200 x 1
|
12
|
Û
|
Û
|
-
|
|
Famciclovir
|
500 x 1
|
200 x 1
|
12
|
Û
|
Û
|
-
|
|
Stavudine
|
40 x 1
|
200 x 1
|
6
|
Û
|
Û
|
-
|
|
1. All interaction studies conducted in healthy volunteers
|
|
2. = Increase; ¯
= Decrease; Û = no effect; "-"
= not applicable
|
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