Pharmacotherapeutic Group: nucleoside reverse transcriptase inhibitor (NRTI).
ATC Code: J05A R02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Abacavir and lamivudine are NRTIs, and are potent, selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which are the active moieties. Lamivudine-TP and carbovir-TP (the active triphosphate form of abacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.
In a study of 20 HIV-infected patients receiving abacavir 300mg twice daily, with only one300mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. The steady state pharmacokinetic properties of abacavir 600 mg once daily was compared to abacavir 300 mg twice daily in acrossover study in 27 HIV-infected patients. Intracellular carbovir triphosphate exposures in peripheral blood mononuclear cells were higher for abacavir 600 mg once daily with respect to AUC24,ss (32%, higher), Cmax24,ss (99% higher) and trough values (18% higher), compared to the 300 mg twice daily regimen. For patients receiving lamivudine 300mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16 to 19hours, compared to the plasma lamivudine half-life of 5 to 7 hours. The steady state pharmacokinetic properties of lamivudine 300 mg once daily for 7 days compared to lamivudine 150 mg twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were 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. These data support the use of lamivudine 300mg and abacavir 600mgonce daily for the treatment of HIV-infected patients. Additionally, the efficacy and safety of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021 - see Clinical Studies as follows).
Pharmacodynamic Effects: The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. No antagonistic effects
in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).
HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral RT. This variant arises both
in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity
in vitro. Studies
in vitro indicate that zidovudine-resistant virus isolates can become zidovudine-sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.
Abacavir-resistant isolates of HIV-1 have been selected
in vitro and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). Viral resistance to abacavir develops relatively slowly
in vitro and
in vivo, requiring multiple mutations to reach an eight-fold increase in IC50over wild-type virus, which may be a clinically relevant level. Isolates resistant to abacavir might also show reduced sensitivity to lamivudine, zalcitabine, tenofovir, emtricitabine and/or didanosine, but remain sensitive to zidovudine and stavudine.
Cross-resistance between abacavir or lamivudine and antiretrovirals from other classes e.g. protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI), is unlikely. Reduced susceptibility to abacavir has been demonstrated in clinical isolates of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to other nucleoside inhibitors.
Clinical isolates with three or more mutations associated with NRTIs are unlikely to be susceptible to abacavir. Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine, stavudine, abacavir and tenofovir maintain their antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation.
Clinical Studies: Abacavir and lamivudine have been used as components of antiretroviral combination therapy in naïve and experienced patients. Combination therapy has included other antiretroviral agents of the same class or different classes, such as PIs and NNRTIs. Abacavir and lamivudine from Abacavir sulfate and Lamivudine tablets tablet have been shown to be bioequivalent to abacavir and lamivudine when given separately (see Pharmacokinetics as follows). The clinical efficacy of antiretroviral combination therapy containing abacavir plus lamivudine, administered once or twice daily has been confirmed in the studies described as follows.
Therapy-naive patients: A once daily regimen of abacavir and lamivudine was investigated in a multicentre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naive adults. They were randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. Patients were stratified at baseline based on plasma HIV-1 RNA less than or equal to 100,000 copies/ml or greater than 100,000 copies/ml. The duration of double-blind treatment was at least 48 weeks. The results are summarised in the table as follows: (See Table 1.)
Click on icon to see table/diagram/image
The abacavir once daily group was demonstrated to be non-inferior when compared to the twice daily group in the overall and base-line viral load sub-groups. The incidence of adverse events reported was similar in the two treatment groups. Genotypic analysis was attempted for all subjects with virologic failure (confirmed HIV RNA greater than 50 copies/ml). There was a low overall incidence of virologic failure in both the once and twice daily treatment groups (10% and 8% respectively). Additionally, for technical reasons, genotyping was restricted to samples with plasma HIV-1 RNA greater than 500 copies/ml. These factors resulted in a small sample size. Therefore, no firm conclusions could be drawn regarding differences in treatment emergent mutations between the two treatment groups. Reverse transcriptase amino acid residue 184 was consistently the most frequent position for NRTI resistance-associated mutations (M184V or M184I). The second most frequent mutation was L74V. Mutations Y115F and K65R were uncommon.
Therapy-experienced patients: In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and received treatment with either Abacavir sulfate and Lamivudine tablets once daily or abacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovir and a PI or an NNRTI for 48 weeks. Results indicate that the Abacavir sulfate and Lamivudine tablets group was non-inferior to the abacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average area under the curve minus baseline (AAUCMB, -1.65 log10 copies/ml versus -1.83 log10 copies/ml respectively, 95% CI -0.13, 0.38). Proportions with HIV-1 RNA < 50 copies/ml (50% versus 47%) and < 400 copies/ml (54% versus 57%) were also similar in each group (ITT population). However, as there were only moderately experienced patients included in this study with an imbalance in baseline viral load between the arms, these results should be interpreted with caution.
In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were randomised to continue this regimen or switch to Abacavir sulfate and Lamivudine tablets plus a PI or NNRTI for 48 weeks. Results indicate that the Abacavir sulfate and Lamivudine tablets group was associated with a similar virologic outcome (non-inferior) compared to the abacavir plus lamivudine group, based on proportions of subjects with HIV-1 RNA < 50 copies/ml (90% and 85% respectively, 95% CI -2.7, 13.5).
Paediatric population: A comparison of a regimen including once daily vs twice daily dosing of abacavir and lamivudine was undertaken within a randomised, multicentre, controlled study of HIV-infected, paediatric patients. 1206 paediatric patients aged 3 months to 17 years enrolled in the ARROW Trial (COL105677) and were dosed according to the weight - band dosing recommendations in the World Health Organisation treatment guidelines (Antiretroviral therapy of HIV infection in infants and children, 2006). After 36 weeks on a regimen including twice daily abacavir and lamivudine, 669 eligible subjects were randomised to either continue twice daily dosing or switch to once daily abacavir and lamivudine for at least an additional 96 weeks. Within this population, 104 patients weighing at least 25 kg received 600 mg abacavir and 300 mg lamivudine as Abacavir sulfate and Lamivudine tablets once daily, with a median duration of exposure of 596 days. The results are summarised in the table as follows: (See Table 2.)
Click on icon to see table/diagram/image
The abacavir/lamivudine once daily dosing group was demonstrated to be non-inferior to the twice daily group according to the pre-specified non-inferiority margin of -12%, for the primary endpoint of <80 c/mL at Week 48 as well as at Week 96 (secondary endpoint) and all other thresholds tested (<200c/mL, <400c/mL, <1000c/mL), which all fell well within this non-inferiority margin. Subgroup analyses testing for heterogeneity of once vs twice daily demonstrated no significant effect of sex, age, or viral load at randomisation. Conclusions supported non-inferiority regardless of analysis method.
Antiretroviral Pregnancy Registry: The Antiretroviral Pregnancy Registry has received prospective reports of over 2,000 exposures to abacavir during pregnancy resulting in live birth. These consist of over 800 exposures during the first trimester, over 1,100 exposures during the second/third trimester and included 27 and 32 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.1% (2.0, 4.4%) and in the second/third trimester, 2.7% (1.9, 3.9%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. There was no association between abacavir and overall birth defects observed in the Antiretroviral Pregnancy Registry.
The Antiretroviral Pregnancy Registry has received reports of over 11,000 exposures to lamivudine during pregnancy resulting in live birth. These consist of over 4,200 exposures during the first trimester, over 6,900 exposures during the second/third trimester and included 135 and 198 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.6, 3.7%) and in the second/third trimester, 2.8% (2.4, 3.2%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. The Antiretroviral Pregnancy Registry does not show an increased risk of major birth defects for lamivudine compared to the background rate.
Pharmacokinetics: The Abacavir sulfate and Lamivudine tablets tablet has been shown to be bioequivalent to abacavir and lamivudine administered separately. This was demonstrated in a single dose, 3-way crossover bioequivalence study of Abacavir sulfate and Lamivudine tablets (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg lamivudine tablets (fasted) versus Abacavir sulfate and Lamivudine tablets administered with a high fat meal, in healthy volunteers (n=30).
In the fasted state there was no significant 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 sulfate and Lamivudine tablets may be administered with or without food. 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. These results were similar to those from previous studies of the effect of food on abacavir and lamivudine tablets administered separately. The pharmacokinetic properties of lamivudine and abacavir are described as follows.
Absorption: Abacavir and lamivudine are rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is 83% and 80 to 85% respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hours and 1.0 hours for abacavir and lamivudine respectively. Following a single oral dose of 600 mg of abacavir, the mean Cmax is 4.26 micrograms/ml and the mean AUC∞ is 11.95 micrograms.h/ml. Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean steady-state Cmax is 2.04 micrograms/ml and the mean AUC24 is 8.87 micrograms.h/ml.
Distribution: Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 l/kg respectively. Plasma protein binding studies
in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%). This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.
Data show that abacavir and lamivudine penetrate the central nervous system (CNS) and reach the cerebrospinal fluid (CSF). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold greater than the IC50 of abacavir of 0.08 micrograms/ml or 0.26 micromolar when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2 to 4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
Metabolism: Abacavir is primarily metabolised by the liver with less than 2% of the administered dose being renally excreted as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (less than 10%).
Elimination: The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day, there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.
The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately0.32 l/h/kg, predominantly by renal clearance (greater than 70%) via the organic cationic transport system.
Special Patient Populations: Children: Abacavir is rapidly and well absorbed from oral solution and tablet formulations administered to children. Plasma abacavir exposure has been shown to be the same for both formulations when administered at the same dose. Children receiving abacavir oral solution according to the recommended dosage regimen achieve plasma abacavir exposure similar to adults. Children receiving abacavir oral tablets according to the recommended dosage regimen achieve higher plasma abacavir exposure than children receiving oral solution because higher mg/kg doses are administered with the tablet formulation. Paediatric pharmacokinetic studies have demonstrated that once daily dosing provides equivalent AUC24 to twice daily dosing of the same total daily dose for both oral solution and tablet formulations.
The absolute bioavailability of lamivudine (approximately 58 to 66%) was lower and more variable in paediatric patients under 12 years of age. In children, administration of tablets delivered higher plasma lamivudine AUC∞ and Cmax than oral solution. Children receiving lamivudine oral solution according to the recommended dosage regimen achieve plasma lamivudine exposure within the range of values observed in adults. Children receiving lamivudine oral tablets according to the recommended dosage regimen achieve higher plasma lamivudine exposure than children receiving oral solution because higher mg/kg doses are administered with the tablet formulation and the tablet formulation has higher bioavailability (see Dosage & Administration). Paediatric pharmacokinetic studies with both oral solution and tablet formulations have demonstrated that once daily dosing provides equivalent AUC24 to twice daily dosing of the same total daily dose.
Hepatically impaired: Pharmacokinetic data has been obtained for abacavir and lamivudine alone. Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5 to 6). The results showed that there was a mean increase of 1.89 fold in the abacavir AUC and 1.58 fold in the half-life of abacavir. The AUCs of the metabolites were not modified by the liver disease. However, the rates of formation and elimination of these were decreased.
Dosage reduction of abacavir is likely to be required in patients with mild hepatic impairment. The separate preparation of abacavir should therefore be used to treat these patients. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to be variable and substantially increased in these patients. Abacavir sulfate and Lamivudine tablets is therefore contraindicated in patients with moderate and severe hepatic impairment.
Data obtained for lamivudine in patients with moderate to severe hepatic impairment show that the pharmacokinetics are not significantly affected by hepatic dysfunction.
Renally impaired: Pharmacokinetic data have been obtained for abacavir and lamivudine alone. Abacavir is primarily metabolised by the liver, with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function. Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Dose reduction is required for patients with creatinine clearance of less than 50 ml/min, therefore the separate preparation of lamivudine (EPIVIR) should be used to treat these patients.
Toxicology: Pre-clinical Safety Data: With the exception of a negative
in vivo rat micronucleus test, there are no data available on the effects of the combination of abacavir and lamivudine in animals.
Mutagenicity and carcinogenicity: Neither abacavir nor lamivudine were mutagenic in bacterial tests, but like many nucleoside analogues they show activity in the
in vitro mammalian tests such as the mouse lymphoma assay. This is consistent with the known activity of other nucleoside analogues. The results of an
in vivo rat micronucleus test with abacavir and lamivudine in combination were negative.
Carcinogenicity: studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver, urinary bladder, lymph nodes and the subcutis of female rats.
The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. These dose levels were equivalent to 24 to 33 times the expected systemic exposure in humans. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg. This is equivalent to six times the expected human systemic exposure. There is no structural counterpart for this gland in humans. While the carcinogenic potential in humans is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.
Lamivudine has not shown any genotoxic activity in the
in vivo studies at doses that gave plasma concentrations up to 30 to 40 times higher than clinical plasma levels. The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential.
Repeat-dose toxicity: Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two 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.
Reproductive toxicology: In reproductive toxicity studies in animals, abacavir and lamivudine were shown to cross the placenta.
Abacavir demonstrated toxicity to the developing embryo and foetus only in rats at maternally toxic doses of 500 mg/kg/day and above. This dose is equivalent to 33 times human therapeutic exposure based on AUC. The findings included foetal oedema, variations and malformations, resorptions, decreased foetal body weight and an increase in still births. The dose at which there were no effects on pre or post-natal development was 160 mg/kg/day. This dose is equivalent to an exposure of about 10 times that in humans. Similar findings were not observed in rabbits.
Lamivudine was not teratogenic in animal studies, but there were indications of an increase in early embryonic deaths in rabbits at exposure levels comparable to those achieved in man. However, there was no evidence of embryonic loss in rats at exposure levels of approximately 33 times the clinical exposure (based on C
max).
Fertility studies in the rat have shown that abacavir and lamivudine had no effect on male or female fertility.