Chemical formula: C₂₂H₂₉N₉O₄S Molecular mass: 515.591 g/mol
Abacavir and lamivudine are NRTIs, and are potent selective inhibitors of HIV-1 and HIV-2 (LAV2 and EHO) replication. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective 5'-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.
No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents:didanosine, nevirapine and zidovudine). The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, stavudine, tenofovir or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.
Both abacavir and lamivudine have been shown to inhibit replication of laboratory strains and clinical isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines and primary cultures of activated peripheral blood lymphocytes (PBLs) and monocyte/macrophages. The concentration of drug necessary to effect viral replication by 50% (EC50) or 50% inhibitory concentration (IC50) varied according to virus and host cell type.
The mean EC50 for abacavir against laboratory strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to 5.8 μM. The median or mean EC50 values for lamivudine against laboratory strains of HIV-1 ranged from 0.007 to 2.3 μM. The mean EC50 against laboratory strains of HIV-2 (LAV2 and EHO) ranged from 1.57 to 7.5 μM for abacavir and from 0.16 to 0.51 μM for lamivudine.
The EC50 values of abacavir against HIV-1 Group M subtypes (A-G) ranged from 0.002 to 1.179 μM, against Group O from 0.022 to 1.21 μM, and against HIV-2 isolates, from 0.024 to 0.49 μM. For lamivudine, the EC50 values against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 μM, against Group O from 0.030 to 0.160 μM and against HIV-2 isolates from 0.002 to 0.120 μM in peripheral blood mononuclear cells.
Baseline HIV-1 samples from therapy-naive subjects with no amino acid substitutions associated with resistance have been evaluated using either the multi-cycle Virco AntivirogramTM assay (n=92 from COL40263) or the the single cycle Monogram Biosciences PhenoSenseTM assay (n=138 from ESS30009). These resulted in median EC50 values of 0.912 μM (range: 0.493 to 5.017 μM) and 1.26 μM (range 0.72 to 1.91 μM) respectively for abacavir, and median EC50 values of 0.429 μM (range: 0.200 to 2.007 μM) and 2.38 μM (1.37 to 3.68 μM) respectively for lamivudine.
Phenotypic susceptibility analyses of clinical isolates from antiretroviral-naïve patients with HIV-1 Group M non-B subtypes in three studies have each reported that all viruses were fully susceptible to both abacavir and lamivudine; one study of 104 isolates that included subtypes A and A1 (n=26), C (n=1), D (n=66), and the circulating recombinant forms (CRFs) AD (n=9), CD (n=1), and a complex inter-subtype recombinant_cpx (n=1), a second study of 18 isolates including subtype G (n=14) and CRF_AG (n=4) from Nigeria, and a third study of six isolates (n=4 CRF_AG, n=1 A and n=1 undetermined) from Abidjan (Côte d’Ivoire).
HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37 untreated patients in Africa and Asia were susceptible to abacavir (IC50 fold changes <2.5), and lamivudine (IC50 fold changes<3.0), except for two CRF02_AG isolates with fold-changes of 2.9 and 3.4 for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive.
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.
The fixed-dose combination tablet of abacavir/lamivudine (FDC) has been shown to be bioequivalent to lamivudine and abacavir administered separately. This was demonstrated in a single dose, 3-way crossover bioequivalence study of FDC (fasted) versus 2 × 300 mg abacavir tablets plus 2 × 150 mg lamivudine tablets (fasted) versus FDC 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. There was also no clinically significant food effect observed between administration of FDC in the fasted or fed state. These results indicate that FDC can be taken with or without food. The pharmacokinetic properties of lamivudine and abacavir are described below.
Abacavir and lamivudine are rapidly and well absorbed from the gastro-intestinal tract following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and 80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hours and 1.0 hour for abacavir and lamivudine, respectively. Following a single dose of 600 mg of abacavir, the mean (CV) Cmax is 4.26 μg/ml (28%) and the mean (CV) AUC∞ is 11.95 μg.h/ml (21%). Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 μg/ml (26%) and the mean (CV) AUC24 is 8.87 μg.h/ml (21%).
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 limited plasma protein binding in vitro (<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 IC 50 of abacavir of 0.08 μg/ml or 0.26 μM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
Abacavir is primarily metabolised by the liver with approximately 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 by renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%).
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 approximately 0.32 l/h/kg, predominantly by renal clearance (>70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Kivexa is not recommended for use in patients with a creatinine clearance <50 ml/min as necessary dose adjustment cannot be made.
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg 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. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP exposures were higher for the abacavir 600 mg once daily regimen (AUC24,ss + 32%, Cmax24,ss + 99% and Ctrough + 18%) compared to the 300 mg twice daily regimen. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, compared to the plasma lamivudine half-life of 5-7 hours. In a crossover study in 60 healthy volunteers, intracellular lamivudine-TP pharmacokinetic parameters were similar (AUC24,ss and Cmax24,ss) or lower (Ctrough – 24%) for the lamivudine 300 mg once daily regimen compared to the lamivudine 150 mg twice daily regimen. Overall, these data support the use of lamivudine 300 mg and abacavir 600 mg once 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).
Pharmacokinetic data has been obtained for abacavir and lamivudine separately.
Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose; the median (range) AUC value was 24.1 (10.4 to 54.8) ug.h/ml.The results showed that there was a mean (90%CI) increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No definitive recommendation on dose reduction is possible in patients with mild hepatic impairment due to substantial variability of abacavir exposure.
Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.
Based on data obtained for abacavir, abacavir/lamivudine combination is not recommended in patients with moderate or severe hepatic impairment.
Pharmacokinetic data have been obtained for lamivudine and abacavir 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. Abacavir/lamivudine is not recommended for use in patients with a creatinine clearance <50 ml/min as necessary dose adjustment cannot be made.
No pharmacokinetic data are available in patients over 65 years of age.
Abacavir is rapidly and well absorbed from oral formulations when administered to children. 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. However, paediatric pharmacokinetic studies with tablet formulations have demonstrated that once daily dosing provides equivalent AUC24 to twice daily dosing of the same total daily dose.
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.
Neither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleoside analogues, they inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were negative.
Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasma concentrations up to 40-50 times higher than clinical plasma concentrations. Abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high tested concentrations.
The carcinogenic potential of a combination of abacavir and lamivudine has not been tested. In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential. 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 rats in the thyroid gland of males and in the liver, urinary bladder, lymph nodes and the subcutis of females.
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. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 and 7 times the human systemic exposure during therapy. While the clinical relevance of these findings is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.
In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinal products hepatically metabolised has not been observed in man.
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.
In reproductive toxicity studies in animals, lamivudine and abacavir were shown to cross the placenta.
Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure.
Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. These findings included decreased foetal body weight, foetal oedema, and an increase in skeletal variations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn with regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.
A fertility study in rats has shown that abacavir and lamivudine had no effect on male or female fertility.
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