"Entry Inhibitors (including Fusion Inhibitors) and CCR5 Co-receptor Antagonist
Entry inhibitors block HIV entry into CD4+ cells.
The only drug in this class "...
Mechanism of Action
EPZICOM is an antiviral agent.
Pharmacokinetics in Adults
EPZICOM: In a single-dose, 3-way crossover bioavailability trial 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 subjects, 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 subjects, 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 with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. 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 with 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 with 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 subjects are summarized in Table 2.
Table 2: Pharmacokinetic Parametersa for Abacavir and
Lamivudine in Adults
|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 7b|
|a Data presented as mean ± standard deviation
except where noted.
b 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 trial 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 with fasted conditions (n = 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately.
Renal Impairment: 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 DOSAGE AND ADMINISTRATION].
Hepatic Impairment: EPZICOM: EPZICOM is contraindicated for patients with hepatic impairment because EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. Abacavir is contraindicated in patients with moderate to severe hepatic impairment, and dose reduction is required in patients with mild hepatic impairment.
Pregnancy: See Use In Specific Populations.
Abacavir and Lamivudine: No data are available on the pharmacokinetics of abacavir or lamivudine during pregnancy.
Nursing Mothers: See Use In Specific Populations.
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 subjects are under investigation. There are insufficient data at this time to recommend a dose.
Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age.
Gender: Abacavir: A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.
Lamivudine: A pharmacokinetic trial 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.
The drug interactions described are based on trials 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: Lamivudine and Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial 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.
Methadone: In a trial of 11 HIV-1-infected subjects 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%) [see DRUG INTERACTIONS].
Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).
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 subjects [see WARNINGS AND PRECAUTIONS].
The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.
Table 3: Effect of Coadministered Drugs on Abacavir and
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 Drug and Dose||Abacavir Dose||n||Abacavir Concentrations||Concentration of Coadministered Drug|
|Ethanol 0.7 g/kg||Single 600 mg||24||↑ 41%||90% CI: 35% to 48%||↔|
|Drugs That May Alter Lamivudine Blood Concentrations|
|Coadministered Drug and Dose||Lamivudine Dose||n||Lamivudine Concentrations||Concentration of Coadministered 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.|
Mechanism of Action
Abacavir: 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 a, b, and g.
Lamivudine: 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 a, b, and g.
Abacavir: The antiviral activity of abacavir against HIV-1 was evaluated against a T-cell tropic laboratory strain HIV-1mB 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 然 (1 然 = 0.28 mcg/mL) and 0.07 to 1.0 然 against HIV-1iiib and HIV-1 BaL, respectively, and was 0.26 ± 0.18然 against 8 clinical isolates. The EC50 values of abacavir against different HIV-1 clades (A-G) ranged from 0.0015 to 1.05 然, and against HIV-2 isolates, from 0.024 to 0.49 然. Ribavirin (50 然) 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 然 (1然 = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 然 (range: 0.200 to 2.007 然) from Virco (n = 92 baseline samples from COLA40263) and 2.35 然 (1.37 to 3.68 然) 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 然, and against HIV-2 isolates from 0.003 to 0.120 然 in peripheral blood mononuclear cells. Ribavirin (50 然) 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-1 potency of abacavir/lamivudine reproducibly by 2- to 6-fold in cell culture.
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 subjects 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 subjects 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 subjects 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 trial 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 (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 trial showed that the RT substitutions that emerged during abacavir/lamivudine once-daily and twice-daily therapy were K65R, L74V, Y115F, and M184V/I. The abacavir- and lamivudine-associated resistance substitution M184V/I was the most commonly observed substitution in virologic failure isolates from subjects receiving abacavir/lamivudine once daily (56%, 10/18) and twice daily (40%, 8/20).
Thirty-nine percent (7/18) of the isolates from subjects 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 with 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 has been observed among NRTIs. Viruses containing abacavir and lamivudine resistance-associated amino acid substitutions, namely, K65R, L74V, M184V, and Y115F, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in cell culture and in subjects. The K65R substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V substitution can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine.
The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitutions K65R with or without the M184V/I substitution, viruses with L74V plus the M184V/I substitution, 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.
Animal Toxicology and/or Pharmacology
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.
There have been no clinical trials conducted with EPZICOM. One EPZICOM Tablet given once daily is an alternative regimen to EPIVIR Tablets 300 mg once daily plus ZIAGEN Tablets 2 x 300 mg once daily as a component of antiretroviral therapy.
The following trial was conducted with the individual components of EPZICOM.
CNA30021 was an international, multi-center, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), Caucasian (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells/mm³ (range: 21 to 918 cells/mm³) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies/mL (range: 2.60 to 6.99 log10 copies/mL).
The outcomes of randomized treatment are provided in Table 4.
Table 4: Outcomes of Randomized Treatment Through Week 48
|Outcome||ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz
|ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz
(n = 386)
|Respondera||64% (71%)||65% (72%)|
|Virologic failureb||11% (5%)||11% (5%)|
|Discontinued due to adverse reactions||13%||11%|
|Discontinued due to other reasonsc||11%||13%|
|a Subjects achieved and maintained confirmed
HIV-1 RNA < 50 copies/mL ( < 400 copies/mL) through Week 48 (Roche AMPLICOR
Ultrasensitive HIV-1 MONITOR® standard test version 1.0).
b Includes viral rebound, failure to achieve confirmed < 50 copies/mL ( < 400 copies/mL) by Week 48, and insufficient viral load response.
c Includes consent withdrawn, lost to follow-up, protocol violations, clinical progression, and other.
After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm³ in the group receiving ZIAGEN 600 mg once daily and 200 cells/mm³ in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.
Last reviewed on RxList: 6/4/2012
This monograph has been modified to include the generic and brand name in many instances.
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