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Epivir-HBV (Lamivudine) - Description and Clinical Pharmacology

 
 



EPIVIR-HBV®
(lamivudine)
Tablets
EPIVIR-HBV®
(lamivudine)
Oral Solution

DESCRIPTION

EPIVIR-HBV is a brand name for lamivudine, a synthetic nucleoside analogue with activity against hepatitis B virus (HBV) and HIV. Lamivudine was initially developed for the treatment of HIV infection as EPIVIR. Please see the complete prescribing information for EPIVIR Tablets and Oral Solution for additional information. The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.

EPIVIR-HBV Tablets are for oral administration. Each tablet contains 100 mg of lamivudine and the inactive ingredients hypromellose, macrogol 400, magnesium stearate, microcrystalline cellulose, polysorbate 80, red iron oxide, sodium starch glycolate, titanium dioxide, and yellow iron oxide.

EPIVIR-HBV Oral Solution is for oral administration. One milliliter (1 mL) of EPIVIR-HBV Oral Solution contains 5 mg of lamivudine (5 mg/mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg).

MICROBIOLOGY

Mechanism of Action

Lamivudine is a synthetic nucleoside analogue. Lamivudine is phosphorylated intracellularly to lamivudine triphosphate, L-TP. Incorporation of the monophosphate form into viral DNA by HBV polymerase results in DNA chain termination. L-TP also inhibits the RNA- and DNA-dependent DNA polymerase activities of HIV-1 reverse transcriptase (RT). L-TP is a weak inhibitor of mammalian alpha-, beta-, and gamma-DNA polymerases.

Antiviral Activity In Vitro

In vitro activity of lamivudine against HBV was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. IC50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 μM (2.3 ng/mL) to 5.6 μM (1.3 mcg/mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used . See the EPIVIR package insert for information regarding activity of lamivudine against HIV.

Drug Resistance

HBV

Genotypic analysis of viral isolates obtained from patients who show renewed evidence of replication of HBV while receiving lamivudine suggests that a reduction in sensitivity of HBV to lamivudine is associated with mutations resulting in a methionine to valine or isoleucine substitution in the YMDD motif of the catalytic domain of HBV polymerase (position 552) and a leucine to methionine substitution at position 528. It is not known whether other HBV mutations may be associated with reduced lamivudine susceptibility in vitro.

In 4 controlled clinical trials in adults, YMDD-mutant HBV were detected in 81 of 335 patients receiving lamivudine 100 mg once daily for 52 weeks. The prevalence of YMDD mutations was less than 10% in each of these trials for patients studied at 24 weeks and increased to an average of 24% (range in 4 studies: 16% to 32%) at 52 weeks. In limited data from a long-term follow-up trial in patients who continued 100 mg/day lamivudine after one of these studies, YMDD mutations further increased from 16% at 1 year to 42% at 2 years. In small numbers of patients receiving lamivudine for longer periods, further increases in the appearance of YMDD mutations were observed.

In a controlled trial in pediatric patients, YMDD-mutant HBV were detected in 31 of 166 (19%) patients receiving lamivudine for 52 weeks. For a subgroup who remained on lamivudine therapy in a follow-up study, YMDD mutations increased from 24% at 12 months to 45% (53 of 118) at 18 months of lamivudine treatment.

Mutant viruses were associated with evidence of diminished treatment response at 52 weeks relative to lamivudine-treated patients without evidence of YMDD mutations in both adult and pediatric studies (see PRECAUTIONS). The long-term clinical significance of YMDD-mutant HBV is not known.

HIV

In studies of HIV-1-infected patients who received lamivudine monotherapy or combination therapy with lamivudine plus zidovudine for at least 12 weeks, HIV-1 isolates with reduced in vitro susceptibility to lamivudine were detected in most patients (see WARNINGS).

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults

The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from 5 to 600 mg per day administered to HBV-infected patients.

The pharmacokinetic properties of lamivudine have also been studied in asymptomatic, HIV-infected adult patients after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.

Absorption and Bioavailability

Lamivudine was rapidly absorbed after oral administration in HBV-infected patients and in healthy subjects. Following single oral doses of 100 mg, the peak serum lamivudine concentration (Cmax) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 ± 0.56 mcg/mL and 1.05 ± 0.32 mcg/mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC[0-24 hr]) following 100 mg lamivudine oral single and repeated daily doses to steady state was 4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 mcg•hr/mL, respectively. The relative bioavailability of the tablet and solution were then demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (Cmax), there was no significant difference in systemic exposure (AUC∞) between the solution and the tablet. Therefore, the solution and the tablet may be used interchangeably.

After oral administration of lamivudine once daily to HBV-infected adults, the AUC and Cmax increased in proportion to dose over the range from 5 mg to 600 mg once daily.

The 100-mg tablet was administered orally to 24 healthy subjects on 2 occasions, once in the fasted stateand once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states; therefore, EPIVIR-HBV Tablets and Oral Solution may be administered with or without food.

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the 10-mg/mL oral solution.

Distribution

The apparent volume of distribution after IV administration of lamivudine to 20 asymptomatic HIV-infected patients was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.

Binding of lamivudine to human plasma proteins is low (<36%) and independent of dose. In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Metabolism

Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. In 9 healthy subjects receiving 300 mg of lamivudine as single oral doses, a total of 4.2% (range 1.5% to 7.5%) of the dose was excreted as the trans-sulfoxide metabolite in the urine, the majority of which was excreted in the first 12 hours.

Serum concentrations of the trans-sulfoxide metabolite have not been determined.

Elimination

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD). In 20 HIV-infected patients given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.

In most single-dose studies in HIV- or HBV-infected patients or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10 mg/kg.

Special Populations

Adults With Impaired Renal Function

The pharmacokinetic properties of lamivudine have been determined in healthy subjects and in subjects with impaired renal function, with and without hemodialysis (Table 1):

Table 1. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Oral Dose of Lamivudine in Patients With Varying Degrees of Renal Function

Creatinine Clearance Criterion

(Number of Subjects)

Parameter

≥80 mL/min (n = 9)

20-59 mL/min (n = 8)

<20 mL/min (n = 6)

Creatinine clearance (mL/min)

97 (range 82-117)

39 (range 25-49)

15 (range 13-19)

Cmax (mcg/mL)

1.31 ± 0.35

1.85 ± 0.40

1.55 ± 0.31

AUC∞ (mcg•hr/mL)

5.28 ± 1.01

14.67 ± 3.74

27.33 ± 6.56

Cl/F (mL/min)

326.4 ± 63.8

120.1 ± 29.5

64.5 ± 18.3

Exposure (AUC∞), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Hemodialysis increases lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.

It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.

The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B is not known.

Adults With Impaired Hepatic Function

The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function (Table 2). Patients were stratified by severity of hepatic functional impairment.

Table 2. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Dose of Lamivudine in 3 Groups of Subjects With Normal or Impaired Hepatic Function

Impairment*

Normal

Moderate

Severe

Parameter

(n = 8)

(n = 8)

(n = 8)

Cmax (mcg/mL)

0.92 ± 0.31

1.06 ± 0.58

1.08 ± 0.27

AUC∞ (mcg•hr/mL)

3.96 ± 0.58

3.97 ± 1.36

4.30 ± 0.63

Tmax (hr)

1.3 ± 0.8

1.4 ± 0.8

1.4 ± 1.2

Cl/F (mL/min)

424.7 ± 61.9

456.9 ± 129.8

395.2 ± 51.8

Clr (mL/min)

279.2 ± 79.2

323.5 ± 100.9

216.1 ± 58.0

*Hepatic impairment assessed by aminopyrine breath test.

Pharmacokinetic parameters were not altered by diminishing hepatic function. Therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of EPIVIR-HBV have not been established in the presence of decompensated liver disease (see PRECAUTIONS).

Post-Hepatic Transplant

Fourteen HBV-infected patients received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, 2 weeks after 100-mg once-daily dosing (pre-transplant), and 3 months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal dysfunction; consequently, transplant patients with reduced renal function had generally higher exposure than patients with normal renal function. Safety and efficacy of EPIVIR-HBV have not been established in this population (see PRECAUTIONS).

Pediatric Patients

Lamivudine pharmacokinetics were evaluated in a 28-day dose-ranging study in 53 pediatric patients with chronic hepatitis B. Patients aged 2 to 12 years were randomized to receive lamivudine 0.35 mg/kg twice daily, 3 mg/kg once daily, 1.5 mg/kg twice daily, or 4 mg/kg twice daily. Patients aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine was rapidly absorbed (Tmax 0.5 to 1 hour). In general, both Cmax and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age 2 and declined from 2 to 12 years, where values were then similar to those seen in adults. A dose of 3 mg/kg given once daily produced a steady-state lamivudine AUC (mean 5,953 ng•hr/mL ± 1,562 SD) similar to that associated with a dose of 100 mg/day in adults.

Gender

There are no significant gender differences in lamivudine pharmacokinetics.

Race

There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions

Multiple doses of lamivudine and a single dose of interferon were coadministered to 19 healthy male subjects in a pharmacokinetics study. Results indicated a small (10%) reduction in lamivudine AUC, but no change in interferon pharmacokinetic parameters when the 2 drugs were given in combination. All other pharmacokinetic parameters (Cmax, Tmax, and t½) were unchanged. There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in this study.

Lamivudine and zidovudine were coadministered to 12 asymptomatic HIV-positive adult patients in a single-center, open-label, randomized, crossover study. No significant differences were observed in AUC∞ or total clearance for lamivudine or zidovudine when the 2 drugs were administered together. Coadministration of lamivudine with zidovudine resulted in an increase of 39% ± 62% (mean ± SD) in Cmax of zidovudine.

Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-positive patients in a single-center, open-label, randomized, crossover study. Each patient received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 44% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine (see PRECAUTIONS: Drug Interactions).

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.

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