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
Combivir Pharmacology, Pharmacokinetics, Studies, Metabolism - Lamivudine and zidovudine
Combivir Pharmacology, Pharmacokinetics, Studies, Metabolism - Lamivudine and zidovudine
CLINICAL PHARMACOLOGY
Pharmacokinetics in Adults
COMBIVIR: One COMBIVIR Tablet was bioequivalent
to one EPIVIR Tablet (150 mg) plus one RETROVIR Tablet (300 mg) following single-dose
administration to fasting healthy subjects (n = 24).
Lamivudine: The pharmacokinetic properties of
lamivudine in fasting patients are summarized in Table 1. Following oral administration,
lamivudine is rapidly absorbed and extensively distributed. Binding to plasma
protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered
as unchanged drug in the urine. Metabolism of lamivudine is a minor route of
elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite
(approximately 5% of an oral dose after 12 hours).
Zidovudine: The pharmacokinetic properties of
zidovudine in fasting patients are summarized in Table 1. Following oral administration,
zidovudine is rapidly absorbed and extensively distributed.
Binding to plasma protein is low. Zidovudine is eliminated
primarily by hepatic metabolism. The major metabolite of zidovudine is 3¢-azido-3¢-deoxy-5¢-O-b-D-glucopyranuronosylthymidine
(GZDV). GZDV area under the curve (AUC) is about 3- fold greater than the zidovudine
AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the
dose following oral administration, respectively. A second metabolite, 3¢-amino-3¢-deoxythymidine
(AMT), has been identified in plasma. The AMT AUC was one fifth of the zidovudine
AUC.
|
Table 1. Pharmacokinetic Parameters* for Lamivudine and
Zidovudine in Adults
|
|
Parameter
|
Lamivudine
|
|
Zidovudine
|
|
|
Oral bioavailability (%)
|
86 ± 16
|
n = 12
|
64 ± 10
|
n = 5
|
|
Apparent volume of distribution (L/kg)
|
1.3 ± 0.4
|
n = 20
|
1.6 ± 0.6
|
n = 8
|
|
Plasma protein binding (%)
|
<36
|
|
<38
|
|
|
CSF:plasma ratio†
|
0.12 [0.04 to 0.47]
|
n = 38‡
|
0.60 [0.04 to 2.62]
|
n = 39§
|
|
Systemic clearance (L/hr/kg)
|
0.33 ± 0.06
|
n = 20
|
1.6 ± 0.6
|
n = 6
|
|
Renal clearance (L/hr/kg)
|
0.22 ± 0.06
|
n = 20
|
0.34 ± 0.05
|
n = 9
|
|
Elimination half- life (hr) ||
|
5 to 7
|
|
0.5 to 3
|
|
|
* Data presented as mean ± standard deviation
except where noted.
|
|
† Median [range].
|
|
‡ Children.
|
|
§ Adults.
|
|
|| Approximate range.
|
Effect of Food on Absorption of COMBIVIR
COMBIVIR may be administered with or without food. The extent
of lamivudine and zidovudine absorption (AUC) following administration of COMBIVIR
with food was similar when compared to fasting healthy subjects (n = 24).
Special Populations
Impaired Renal Function: COMBIVIR: Because lamivudine
and zidovudine require dose adjustment in the presence of renal insufficiency,
COMBIVIR is not recommended for patients with impaired renal function (see PRECAUTIONS).
Impaired Hepatic Function: COMBIVIR:
A reduction in the daily dose of zidovudine may be necessary in patients with
mild to moderate impaired hepatic function or liver cirrhosis. Because COMBIVIR
is a fixed-dose combination that cannot be adjusted for this patient population,
COMBIVIR is not recommended for patients with impaired hepatic function.
Pregnancy: See PRECAUTIONS:
Pregnancy.
COMBIVIR: No data are available.
Zidovudine: Zidovudine pharmacokinetics has been
studied in a Phase 1 study of 8 women during the last trimester of pregnancy.
As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics
of zidovudine was similar to that of nonpregnant adults. Consistent with passive
transmission of the drug across the placenta, zidovudine concentrations in neonatal
plasma at birth were essentially equal to those in maternal plasma at delivery.
Although data are limited, methadone maintenance therapy in 5 pregnant women
did not appear to alter zidovudine pharmacokinetics. In a nonpregnant adult
population, a potential for interaction has been identified (see CLINICAL
PHARMACOLOGY: Drug Interactions).
Nursing Mothers: See PRECAUTIONS:
Nursing Mothers.
Lamivudine: Samples of breast milk obtained from
20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination
therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had
measurable concentrations of lamivudine.
COMBIVIR: No data are available.
Zidovudine: After administration of a single
dose of 200 mg zidovudine to 13 HIV- infected women, the mean concentration
of zidovudine was similar in human milk and serum.
Pediatric Patients: COMBIVIR: COMBIVIR
should not be administered to pediatric patients less than 12 years of age because
it is a fixed-dose combination that cannot be adjusted for this patient population.
Gender: COMBIVIR: A pharmacokinetic study in
healthy male (n = 12) and female (n = 12) subjects showed no gender differences
in zidovudine exposure (AUC) or lamivudine AUC
normalized for body weight.
Race: Lamivudine: There are no significant racial
differences in lamivudine pharmacokinetics.
DRUG INTERACTIONS
See PRECAUTIONS: Drug
Interactions.
COMBIVIR: No drug interaction studies have been
conducted using COMBIVIR Tablets.
Lamivudine Plus Zidovudine: No clinically significant
alterations in lamivudine or zidovudine pharmacokinetics were observed in 12
asymptomatic HIV-infected adult patients given a single dose of zidovudine (200
mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).
|
Table 2. Effect of Coadministered Drugs on Lamivudine
and Zidovudine AUC* Note: ROUTINE DOSE MODIFICATION OF LAMIVUDINE AND
ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
|
|
Drugs That May Alter Lamivudine Blood Concentrations
|
|
Coadministered Drug and Dose
|
Lamivudine Dose
|
n
|
Lamivudine Concentrations
|
Concentration of Coadministered
|
|
AUC
|
Variability
|
Drug
|
|
Nelfinavir
|
single
|
11
|
AUC
|
95% CI:
|
«
|
|
750 mg q 8 hr x 7 to10 days
|
150 mg
|
|
10%
|
1% to 20%
|
|
|
Trimethoprim 160 mg/
|
single
|
14
|
AUC
|
90% CI:
|
«
|
|
Sulfamethoxazole800 mg daily x 5 days
|
300 mg
|
|
43%
|
32% to 55%
|
|
|
Drugs That May Alter Zidovudine Blood Concentrations
|
|
Coadministered Drug and Dose
|
Zidovudine Dose
|
n
|
Zidovudine Concentrations
|
Concentration of Coadministered Drug
|
|
|
AUC
|
Variability
|
|
Atovaquone750 mg q 12 hr
|
200 mg q 8 hr
|
14
|
AUC
|
Range
|
«
|
|
with food
|
|
|
31%
|
23% to 78%†
|
|
| |
|
|
|
|
|
|
Fluconazole
|
200 mg q 8 hr
|
12
|
AUC
|
95% CI:
|
Not Reported
|
|
400 mg daily
|
|
|
74%
|
54% to 98%
|
|
|
Methadone
|
200 mg q 4 hr
|
9
|
AUC
|
Range
|
«
|
|
30 to 90 mg daily
|
|
|
43%
|
16% to 64%†
|
|
|
Nelfinavir
|
single 200 mg
|
11
|
¯ AUC
|
Range
|
«
|
|
750 mg q 8 hr x 7 to 10 days
|
|
|
35%
|
28% to 41%
|
|
|
Probenecid
|
2 mg/kg q 8 hr
|
3
|
AUC
|
Range
|
Not Assessed
|
|
500 mg q 6 hr x
|
x 3 days
|
|
106%
|
100% to
|
|
|
2 days
|
|
|
|
170%†
|
|
|
Ritonavir
|
200 mg q 8 hr
|
9
|
¯ AUC
|
95% CI:
|
«
|
|
300 mg q 6 hr x
|
x 4 days
|
|
25%
|
15% to 34%
|
|
|
4 days
|
|
|
|
|
|
|
Valproic acid
|
100 mg q 8 hr
|
6
|
AUC
|
Range
|
Not Assessed
|
|
250 mg or 500 mg
|
x 4 days
|
|
80%
|
64% to 130%†
|
|
|
q 8 hr x 4 days
|
|
|
|
|
|
|
= Increase;
¯ = Decrease; «
= no significant change; AUC = area under the concentration versus time
curve; CI = confidence interval.
|
|
* This table is not all inclusive.
|
|
†Estimated range of percent difference.
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