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Epzicom (Abacavir Sulfate / Lamivudine) - Description and Clinical Pharmacology

 
 



EPZICOM™
(abacavir sulfate and lamivudine)
Tablets

DESCRIPTION

EPZICOM

EPZICOM Tablets contain the following 2 synthetic nucleoside analogues: abacavir sulfate (ZIAGEN®, also a component of TRIZIVIR®) and lamivudine (also known as EPIVIR® or 3TC) with inhibitory activity against HIV.

EPZICOM Tablets are for oral administration. Each orange, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (Opadry® orange YS-1-13065-A) that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.

Abacavir Sulfate

The chemical name of abacavir sulfate is ( 1 S,cis)- 4-[2-amino-6-(cyclopropylamino)-9 H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2•H2SO4 and a molecular weight of 670.76 daltons. It has the following structural formula:

Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled water at 25°C.

In vivo, abacavir sulfate dissociates to its free base, abacavir. All dosages for abacavir sulfate are expressed in terms of abacavir.

Lamivudine

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 daltons. 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.

MICROBIOLOGY

Mechanism of Action

Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3′-OH group in the incorporated nucleotide analogue prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.

Lamivudine is a synthetic nucleoside analogue. 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 RT via DNA chain termination after incorporation of the nucleotide analogue. CBV-TP and 3TC-TP are weak inhibitors of cellular DNA polymerases α, β, and γ.

Antiviral Activity

Abacavir

The antiviral activity of abacavir against HIV-1 was evaluated against a T-cell tropic laboratory strain HIV-1IIIB in lymphoblastic cell lines, a monocyte/macrophage tropic laboratory strain HIV - 1BaL in primary monocytes/macrophages, and clinical isolates in peripheral blood mononuclear cells. The concentration of drug necessary to effect viral replication by 50 percent (EC50) ranged from 3.7 to 5.8 μM (1 μM = 0.28 mcg/mL) and 0.07 to 1.0 μM against HIV-1IIIB and HIV-1BaL, respectively, and was 0.26 ± 0.18 μM against 8 clinical isolates. The EC50 values of abacavir against different HIV-1 clades (A-G) ranged from 0.0015 to 1.05 μM, and against HIV-2 isolates, from 0.024 to 0.49 μM. Ribavirin (50 μM) had no effect on the anti−HIV-1 activity of abacavir in cell culture.

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. EC50 values were in the range of 0.003 to 15 μM (1 μM = 0.23 mcg/mL). HIV from therapy-naive subjects with no mutations associated with resistance gave median EC50 values of 0.426 µM (range: 0.200 to 2.007 µM) from Virco (n = 93 baseline samples from COLA40263) and 2.35 µM (1.44 to 4.08 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 µM, and against HIV-2 isolates from 0.003 to 0.120 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.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Abacavir/lamivudine had additive to synergistic activity in cell culture in combination with the nucleoside reverse transcriptase inhibitors (NRTIs: emtricitabine, stavudine, tenofovir, zalcitabine, zidovudine), the non-nucleoside reverse transcriptase inhibitors (NNRTIs: delavirdine, efavirenz, nevirapine), the protease inhibitors (PIs: amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), or the fusion inhibitor, enfuvirtide. Ribavirin, used in combination with interferon for the treatment of HCV infection, decreased the anti-HIV potency of abacavir/lamivudine reproducibly by 2- to 6-fold in cell culture.

Resistance

HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture and have also been obtained from patients failing abacavir/lamivudine-containing regimens. Genotypic characterization of abacavir/lamivudine-resistant viruses selected in cell culture identified amino acid substitutions M184V/I, K65R, L74V, and Y115F in HIV-1 RT.

Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated patients demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT contributed to abacavir resistance. 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 HIV-1 RT at codon 184 changing the methionine to either isoleucine or valine (M184V/I). In a study of therapy-naive adults receiving ZIAGEN 600 mg once daily (n = 384) or 300 mg twice daily (n = 386) in a background regimen of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), the incidence of virologic failure at 48 weeks was similar between the 2 groups (11% in both arms). Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the RT mutations that emerged during abacavir/lamivudine once-daily and twice-daily therapy were K65R, L74V, Y115F, and M184V/I. The abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed mutation in virologic failure isolates from patients receiving abacavir/lamivudine once daily (56%, 10/18) and twice daily (40%, 8/20).

Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a >2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range 0.7 to 13). Fifty-six percent (10/18) of the virologic failure isolates in the once-daily abacavir group compared to 41% (7/17) of the failure isolates in the twice-daily abacavir group had a >2.5-fold decrease in lamivudine susceptibility with median-fold changes of 81 (range 0.79 to >116) and 1.1 (range 0.68 to >116) in the once-daily and twice-daily abacavir arms, respectively.

Cross-Resistance

Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors. Viruses containing abacavir and lamivudine resistance-associated mutations, namely, K65R, L74V, M184V, and Y115F, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in cell culture and in patients. The K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine.

The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the mutations K65R with or without the M184V/I mutation, viruses with L74V plus the M184V/I mutation, and viruses with thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults

EPZICOM

In a single-dose, 3-way crossover bioavailability study of 1 EPZICOM Tablet versus 2 ZIAGEN Tablets (2 x 300 mg) and 2 EPIVIR Tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component.

Abacavir

Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 patients, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC was 11.95 ± 2.51 mcg•hr/mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide.

Lamivudine

Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy volunteers, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hr/mL. 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).

The steady-state pharmacokinetic properties of the EPIVIR 300-mg Tablet once daily for 7 days compared to the EPIVIR 150-mg Tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared to the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared to the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of abacavir and lamivudine in fasting patients are summarized in Table 1.

Table 1. Pharmacokinetic Parameters* for Abacavir and Lamivudine in Adults

Parameter

Abacavir

Lamivudine

Oral bioavailability (%)

86 ± 25

n = 6

86 ± 16

n = 12

Apparent volume of distribution (L/kg)

0.86 ± 0.15

n = 6

1.3 ± 0.4

n = 20

Systemic clearance (L/hr/kg)

0.80 ± 0.24

n = 6

0.33 ± 0.06

n = 20

Renal clearance (L/hr/kg)

.007 ±.008

n = 6

0.22 ± 0.06

n = 20

Elimination half-life (hr)

1.45 ± 0.32

n = 20

5 to 7

*Data presented as mean ± standard deviation except where noted.

Approximate range.

Effect of Food on Absorption of EPZICOM

EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability study resulted in no change in AUClast, AUC∞, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC∞), but the rate of absorption (Cmax) was decreased approximately 24% compared to fasted conditions (n = 25). These results are similar to those from previous studies of the effect of food on abacavir and lamivudine tablets administered separately.

Special Populations

Impaired Renal Function

EPZICOM

Because lamivudine requires dose adjustment in the presence of renal insufficiency, EPZICOM is not recommended for use in patients with creatinine clearance <50 mL/min (see PRECAUTIONS).

Impaired Hepatic Function

EPZICOM

Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment. Because EPZICOM is a fixed-dose combination and cannot be dose adjusted, EPZICOM is contraindicated for patients with hepatic impairment.

Pregnancy

See PRECAUTIONS: Pregnancy.

Abacavir and Lamivudine

No data are available on the pharmacokinetics of abacavir or lamivudine during pregnancy.

Nursing Mothers

See PRECAUTIONS: Nursing Mothers.

Abacavir

No data are available on the pharmacokinetics of abacavir in 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.

Pediatric Patients

EPZICOM

The pharmacokinetics of EPZICOM in pediatric patients are under investigation. There are insufficient data at this time to recommend a dose (see PRECAUTIONS: Pediatric Use).

Geriatric Patients

The pharmacokinetics of abacavir and lamivudine have not been studied in patients over 65 years of age.

Gender

Abacavir

A population pharmacokinetic analysis in HIV-infected male (n = 304) and female (n = 67) patients showed no gender differences in abacavir AUC normalized for lean body weight.

Lamivudine

A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in lamivudine AUC normalized for body weight.

Race

Abacavir

There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.

Lamivudine

There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions

See PRECAUTIONS: Drug Interactions. The drug interactions described are based on studies conducted with the individual nucleoside analogues. In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.

Abacavir

Fifteen HIV-infected patients were enrolled in a crossover-designed drug interaction study evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

Lamivudine

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). Lamivudine pharmacokinetics are not significantly affected by abacavir.

Table 2. Effect of Coadministered Drugs on Abacavir and Lamivudine AUC* Note: ROUTINE DOSE MODIFICATION OF ABACAVIR AND LAMIVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.

Drugs That May Alter Abacavir Blood Concentrations

Coadministered

Abacavir

Abacavir

Concentrations

Concentration of Coadministered

Drug and Dose

Dose

n

AUC

Variability

Drug

Ethanol

0.7 g/kg

Single 600 mg

24

↑41%

90% CI:

35% to 48%

Drugs That May Alter Lamivudine Blood Concentrations

Coadministered

Lamivudine

Lamivudine

Concentrations

Concentration of Coadministered

Drug and Dose

Dose

n

AUC

Variability

Drug

Nelfinavir

750 mg q 8 hr x 7 to 10 days

Single 150 mg

11

↑10%

95% CI:

1% to 20%

Trimethoprim 160 mg/

Sulfamethoxazole 800 mg daily x 5 days

Single 300 mg

14

↑43%

90% CI:

32% to 55%

↑ = Increase; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.

*See PRECAUTIONS: Drug Interactions for additional information on drug interactions.

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/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/HCV co-infected patients (see WARNINGS).

ANIMAL TOXICOLOGY

Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.

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