nucleoside analogue. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of action:
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication in vitro
; it is also active against zidovudine-resistant clinical isolates of HIV. No antagonistic effects in vitro
were seen with lamivudine and other anti retrovirals (tested agents: abacavir, didanosine, nevirapine and zidovudine).
HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral reverse transcriptase (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
. In vitro
studies 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.
data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible NRTI's should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTI's are available.
Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of these findings is unknown. In vitro
susceptibility testing has not been standardised and results may vary according to methodological factors.
Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells in vitro
Clinical efficacy and safety:
In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination with zidovudine, results in a significant reduction in the risk of disease progression and mortality.
Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence of zidovudine resistant isolates in individuals with no prior antiretroviral therapy.
Lamivudine has been widely used as a component of antiretroviral combination therapy with other antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse transcriptase inhibitors).
Clinical trial evidence from paediatric patients receiving lamivudine with other antiretroviral drugs (abacavir, nevirapine/efavirenz or zidovudine) has shown that the resistance profile observed in paediatric patients is similar to that observed in adults, in terms of the genotypic substitutions detected and their relative frequency.
Children receiving lamivudine oral solution concomitantly with other antiretroviral oral solutions in clinical trials developed viral resistance more frequently than children receiving tablets (see the description of the clinical experience in paediatric population (ARROW study) and Pharmacokinetics as follows).
Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V mutations.
The relationship between in vitro
susceptibility of HIV to lamivudine and clinical response to lamivudine-containing therapy remains under investigation.
Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of adult patients with chronic HBV infection (for details of clinical studies, see the prescribing information for Zeffix). However, for the treatment of HIV infection, only a 300 mg daily dose of lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.
Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.
Once daily dosing (300 mg once a day): a clinical study has demonstrated the non inferiority between 3TC once a day and 3TC twice a day containing regimens. These results were obtained in an antiretroviral naïve-population, primarily consisting of asymptomatic HIV infected patients (CDC stage A).
Paediatric population: a randomised 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 96 weeks. Of note, from this study clinical data were not available for children under one year old. The results are summarised in the following table: See Table 1.
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In a pharmacokinetic study (PENTA 15), four virologically controlled subjects less than 12 months of age switched from abacavir plus lamivudine oral solution twice daily to a once daily regimen. Three subjects had undetectable viral load and one had plasmatic HIV-RNA of 900 copies/ml at Week 48. No safety concerns were observed in these subjects.
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.
At the time of randomization to once daily vs twice daily dosing (Week 0), those patients who had received tablet formulations had a higher rate of viral load suppression than those who had received any solution formulations at any time. These differences were observed in each different age group studied. This difference in suppression rates between tablets and solutions remained through Week 96 with once daily dosing. (See Table 2.)
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Genotypic resistance analyses were conducted on samples with plasma HIV-1 RNA >1000 copies/ml. More cases of resistance were detected among patients who had received lamivudine solution, in combination with other antiretroviral solutions, compared with those who received similar doses of tablet formulation. This is consistent with the lower rates of antiviral suppression observed in these patients.
Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time (tmax
) to maximal serum concentrations (Cmax
) is about an hour. Based on data derived from a study in healthy volunteers, at a therapeutic dose of 150 mg twice daily, mean (CV) steady-state Cmax
of lamivudine in plasma are 1.2 μg/ml (24%) and 0.09 μg/ml (27%), respectively. The mean (CV) AUC over a dosing interval of 12 hours is 4.7 μg·h/ml (18%). At a therapeutic dose of 300 mg once daily, the mean (CV) steady-state Cmax
and 24h AUC are 2.0 μg/ml (26%), 0.04 μg/ml (34%) and 8.9 μg·h/ml (21%), respectively.
Co-administration of lamivudine with food results in a delay of tmax
and a lower Cmax
(decreased by 47 %). However, the extent (based on the AUC) of lamivudine absorbed is not influenced.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary.
The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC∞
, and tmax
. Administration of 3TC tablets is bioequivalent to 3TC oral solution with respect to AUC∞
in adults. Absorption differences have been observed between adult and paediatric populations (see Special populations as follows).
From intravenous studies, the mean volume of distribution is 1.3 l/kg. The observed half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (>70 %) via the organic cationic transport system.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (< 16% - 36% to serum albumin in in vitro
Limited data show that lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral administration was approximately 0.12. The true extent of penetration or relationship with any clinical efficacy is unknown.
The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours). In 60 healthy adult volunteers, 3TC 300 mg once daily has been demonstrated to be pharmacokinetically equivalent at steady-state to 3TC 150 mg twice daily with respect to intracellular triphosphate AUC24
Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions of lamivudine with other medicinal products is low due to the small extent of hepatic metabolism (5-10%) and low plasma protein binding.
Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. A recommended dosage regimen for patients with creatinine clearance below 50 ml/min is shown in Dosage & Administration (see Dosage & Administration).
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment (see Interactions and Dosage & Administration). Administration of co-trimoxazole with lamivudine in patients with renal impairment should be carefully assessed.
Children: The absolute bioavailability of lamivudine (approximately 58-66%) was reduced in paediatric patients below 12 years of age. In children, administration of tablets given concomitantly with other antiretroviral tablets delivered higher plasma lamivudine AUC∞
than oral solution given concomitantly with other antiretroviral oral solutions. 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 AUC0-24
to twice daily dosing of the same total daily dose.
There are limited pharmacokinetic data for patients less than three months of age. In neonates one week of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likely to be due to immature renal function and variable absorption. Therefore to achieve similar adult and paediatric exposure, an appropriate dose for neonates is 4 mg/kg/day. Glomerular filtration estimates suggests that to achieve similar adult and paediatric exposure, an appropriate dose for children aged six weeks and older could be 8 mg/kg/day.
Pharmacokinetic data were derived from 3 pharmacokinetic studies (PENTA 13, PENTA 15 and ARROW PK substudy) enrolling children under 12 years of age. The data are displayed in the following table: See Table 3.
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In PENTA 15 study, the geometric mean plasma lamivudine AUC(0-24) (95% CI) of the four subjects under 12 months of age who switch from a twice daily to a once daily regimen (see Pharmacodynamics as previously mentioned) are 10.31 (6.26, 17.0) μg·h/ml in the once-daily dosing and 9.24 (4.66, 18.3) μg·h/mL in the twice-daily dosing.
Pregnancy: Following oral administration, lamivudine pharmacokinetics in late-pregnancy were similar to non-pregnant women.
Toxicology: Preclinical safety data:
Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney function were seen together with occasional reductions in liver weight. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia.
Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity in an in vitro
cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vivo
at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical plasma levels. As the in vitro
mutagenic activity of lamivudine could not be confirmed in in vivo
tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.
A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated that foetuses exposed in utero
to the combination sustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.
The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential relevant for humans.
A fertility study in rats has shown that lamivudine had no effect on male or female fertility.