12.3 Pharmacokinetics
Pharmacokinetics in Adults: Lamivudine and Zidovudine: One lamivudine and zidovudine tablet was bioequivalent to 1 EPIVIR tablet (150 mg) plus 1 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 3. 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 3. 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 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 3. Pharmacokinetic Parameters* for Lamivudine and Zidovudine in Adults
Parameter | Lamivudine | Zidovudine |
* Data presented as mean ± standard deviation except where noted.
† Median [range].
‡ Children.
§ Adults.
║ Approximate range.
|
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‡
| 0.6 [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
| |
Effect of Food on Absorption of Lamivudine and Zidovudine: Lamivudine and Zidovudine may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine with food was similar when compared to fasting healthy subjects (n = 24).
Special Populations:
Pregnancy: See Use in Specific Populations (8.1).
Lamivudine and Zidovudine: 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.
Nursing Mothers: See Use in Specific Populations (8.3).
Pediatric Patients: Lamivudine and Zidovudine should not be administered to pediatric patients weighing less than 30 kg.
Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in zidovudine AUC
∞ or lamivudine AUC
∞ normalized for body weight.
Race: Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.
Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.
Drug Interactions: See Drug Interactions (7).
No drug interaction studies have been conducted using lamivudine and zidovudine tablets. However, Table 4 presents drug interaction information for the individual components of lamivudine and zidovudine.
Lamivudine Plus Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine
(300 mg q l2 hr).
Table 4. 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 Drug |
AUC | Variability |
↑ = 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.
|
Nelfinavir 750 mg q 8 hr x 7 to 10 days
| single 150 mg
| 11
| ↑AUC 10%
| 95% CI: l% to 20%
| ↔
|
Trimethoprim 160 mg/Sulfamethoxazole 800 mg daily x 5 days
| single 300 mg
| 14
| ↑AUC 43%
| 90% CI: 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
|
Atovaquone 750 mg q l2 hr with food
| 200 mg q 8 hr
| 14
| ↑AUC 31%
| Range 23% to 78%†
| ↔
|
Clarithromycin 500 mg daily | 100 mg q 4 hr x 7 days
| 4
| ↓AUC 12%
| Range ↓34% to ↑14%
| Not Reported
|
Fluconazole 400 mg daily
| 200 mg q 8 hr
| 12
| ↑AUC 74%
| 95% CI: 54% to 98%
| Not Reported
|
Methadone 30 to 90 mg daily
| 200 mg q 4 hr
| 9
| ↑AUC 43%
| Range 16% to 64%†
| ↔
|
Nelfinavir 750 mg q 8 hr x 7 to 10 days
| single 200 mg
| 11
| ↓AUC 35%
| Range 28% to 41%
| ↔
|
Probenecid 500 mg q 6 hr x 2 days
| 2 mg/kg q 8 hr x 3 days
| 3
| ↑AUC 106%
| Range 100% to 170%†
| Not Assessed
|
Rifampin 600 mg daily x 14 days
| 200 mg q 8 hr x 14 days
| 8
| ↓AUC 47%
| 90% CI: 41% to 53%
| Not Assessed
|
Ritonavir 300 mg q 6 hr x 4 days
| 200 mg q 8 hr x 4 days
| 9
| ↓ AUC 25%
| 95% CI: 15% to 34%
| ↔
|
Valproic acid 250 mg or 500 mg q 8 hr x 4 days
| 100 mg q 8 hr x 4 days
| 6
| ↑AUC 80%
| Range 64% to l30%†
| Not Assessed
|
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients
[see Warnings and Precautions (5.5)].
12.4 Microbiology
Mechanism of Action: Lamivudine: Intracellularly, lamivudine is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. 3TC-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.
Zidovudine: Intracellularly, zidovudine is phosphorylated to its active 5’-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
Antiviral Activity:
Lamivudine Plus Zidovudine: In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity.
Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC
50 values (50% effective concentrations) were in the range of 0.003 to 15 µM (1 µM = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC
50 values of 0.429 µM (range: 0.2 to 2.007 µM) from Virco (n = 92 baseline samples from COL40263) and 2.35 µM (1.37 to 3.68 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC
50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.12 µM, and against HIV-2 isolates from 0.003 to 0.12 µM in peripheral blood mononuclear cells. Ribavirin (50 µM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells.
Zidovudine: The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC
50 and EC
90 values for zidovudine were 0.01 to 0.49 µM (1 µM = 0.27 mcg/mL) and 0.1 to 9 µM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC
50 values of 0.011 µM (range: 0.005 to 0.11 µM) from Virco (n = 92 baseline samples from COL40263) and 0.0017 µM (0.006 to 0.034 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC
50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from 0.00049 to 0.004 µM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.
Resistance: Lamivudine Plus Zidovudine Administered As Separate Formulations: In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of amino acid substitutions conferring resistance to zidovudine.
HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.
Lamivudine: Lamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from patients treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated patients showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (Ml84V/I).
Zidovudine: HIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from patients treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed substitutions in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions.
Cross-Resistance:Cross-resistance has been observed among NRTIs.
Lamivudine Plus Zidovudine: Cross-resistance between lamivudine and zidovudine has not been reported. In some patients treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a substitution at codon 184, which confers resistance to lamivudine. Cross-resistance to abacavir, didanosine, tenofovir, and zalcitabine has been observed in some patients harboring lamivudine-resistant HIV-1 isolates. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple drugs, including lamivudine, have emerged (see under Zidovudine below).
Lamivudine: See Lamivudine Plus Zidovudine (above).
Zidovudine: In a study of 167 HIV-1-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, Fl16Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.