"Two phase 3 sister studies assessing the efficacy and safety of the dapivirine vaginal ring for the prevention of HIV-1 will likely be among the most-watched clinical trial results presented here at the Conference on Retroviruses and Opportu"...
Mechanism Of Action
EPZICOM is an antiretroviral agent [see Microbiology].
Pharmacokinetics in Adults
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 per mL (mean ± SD) and AUC∞was 11.95 ± 2.51 mcg•hour per 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 per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour per 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).
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/h/kg)||0.80 ± 0.24||n = 6||0.33 ± 0.06||n = 20|
|Renal clearance (L/h/kg)||0.007 ± 0.008||n = 6||0.22 ± 0.06||n = 20|
|Elimination half-life (h)||1.45 ± 0.32||n = 20||5 to 7b|
|aData presented as mean ±standard deviation except where
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: The effect of renal impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components).
Hepatic Impairment: EPZICOM: The effect of hepatic impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components).
Pregnancy: Abacavir: No data are available on the pharmacokinetics of abacavir during pregnancy.
Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.
Pediatric Patients: Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine following administration of EPZICOM in pediatric subjects weighing 25 kg and above are limited. The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM. Refer to the EPIVIR and ZIAGEN USPI for pharmacokinetic information on the individual products in pediatric patients [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Clinical Studies].
Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age.
Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.
Race: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.
The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with EPZICOM.
Cytochrome P450 Enzymes: 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/or 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.
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 every 12 h).
Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.
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]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.
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].
Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.
The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.
Table 3: Effect of Coadministered Drugs on Abacavir or
|Coadministered Drug and Dose||Drug and Dose||n||Concentrations of Abacavir or Lamivudine||Concentration of Coadministered Drug|
|Ethanol 0.7 g/kg||Abacavir Single 600 mg||24||↑41%||90% CI: 35% to 48%||↔a|
|Nelfinavir 750 mg every 8 h x 7 to 10 days||Lamivudine Single 150 mg||11||↑10%||95% CI: 1% to 20%||↔|
|Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days||Lamivudine 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.
aThe drug-drug interaction was only evaluated in males.
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.
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.
Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM.
Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades AG and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection 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. Neither abacavir, nor lamivudine, were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Ribavirin, used in 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 with amino acid substitutions K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.
Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/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 at a dose of 600 mg. The clinical relevance of this finding has not been determined.
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%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm³ (range: 21 to 918 cells per mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.60 to 6.99 log10 copies per mL).
The outcomes of randomized treatment are provided in Table 4.
Table 4: Outcomes of Randomized Treatment through Week
|Outcome||ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz
(n = 384)
|ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz
(n = 386)
|Respondera||64% (71%)||65% (72%)|
|Virologic failure b||11% (5%)||11% (5%)|
|Discontinued due to adverse reactions||13%||11%|
|Discontinued due to other reasonsc||11%||13%|
|aSubjects achieved and maintained confirmed HIV-1 RNA less
than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche
AMPLICOR Ultrasensitive HIV-1 MONITOR® standard test version 1.0).
bIncludes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response.
cIncludes 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 per mm³ in the group receiving ZIAGEN 600 mg once daily and 200 cells per 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.
ARROW (COL105677) was a 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-na´ve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. At baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared to 71% of subjects in the once-daily cohort.
Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Subjects randomized to receive once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as EPZICOM.
The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 5. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.
Table 5: Virologic Outcome of Randomized Treatment at
Week 96a (ARROW Randomization 3)
|Outcome||Abacavir plus LamivudineTwice-daily Dosing
(n = 333)
|Abacavir plus LamivudineOnce-daily Dosing
(n = 336)
|HIV-1 RNA < 80 copies/mLb||70%||67%|
|HIV-1 RNA ≥ 80 copies/mLc||28%||31%|
|No virologic data|
|Discontinued due to adverse event or death||1%||< 1%|
|Discontinued study for other reasonsd||0%||< 1%|
|Missing data during window but on study||1%||1%|
|aAnalyses were based on the last observed viral load data
within the Week 96 window.
bRisk difference (95% CI) of response rate is -2.4% (-9% to 5%) at Week 96.
cIncludes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.
dOther includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).
Last reviewed on RxList: 10/23/2015
This monograph has been modified to include the generic and brand name in many instances.
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