Lamivudine Other names: 3TC

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).

Resistance

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.

In vitro 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 lamivudineresistant 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.

Absorption

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 (t_max) to maximal serum concentrations (C_max) 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 C_max and C_min 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 C_max, C_min and 24h AUC are 2.0 μg/ml (26%), 0.04 μg/ml (34%) and 8.9 μg.h/ml (21%), respectively.

The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC_∞, C_max, and t_max. Administration of lamivudine tablets is bioequivalent to lamivudine oral solution with respect to AUC_∞ and C_max in adults. Absorption differences have been observed between adult and paediatric populations (see Special populations).

Co-administration of lamivudine with food results in a delay of t_max and a lower C_max (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.

Distribution

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 studies).

Limited data show that lamivudine penetrates the central nervous system and reaches the cerebro-spinal 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.

Biotransformation

The plasma lamivudine half-life after oral dosing is 18 to 19 hours and the active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 hours). In 60 healthy adult volunteers, lamivudine 300 mg once daily has been demonstrated to be pharmacokinetically equivalent at steady-state to lamivudine 150 mg twice daily with respect to intracellular triphosphate AUC₂₄ and C_max.

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.

Elimination

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 the dosage section.

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. Administration of co-trimoxazole with lamivudine in patients with renal impairment should be carefully assessed.

Special populations

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_∞ and C_max 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. Paediatric pharmacokinetic studies with both oral solution and tablet formulations have demonstrated that once daily dosing provides equivalent AUC_0-24 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 table below:

Summary of Stead-State Plasma Lamivudine AUC_(0-24) (μg.h/ml) and Statistical Comparisons for Once and Twice-Daily Oral Administration Across Studies:

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 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.

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.