3TC Mechanism of Action

Pharmacotherapeutic Group: Nucleoside analogue. ATC Code: J05AF05.
Pharmacology: Pharmacodynamics: Lamivudine is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro. It is also active against zidovudine-resistant clinical isolates of HIV. Lamivudine is metabolized intracellularly to the 5'-triphosphate, the active moiety, which has an intracellular half-life of 16-19 hrs. Lamivudine 5'-triphosphate is a weak inhibitor of the RNA and DNA dependent activities of HIV reverse transcriptase; its main mode of action is as a chain terminator of HIV reverse transcription. Lamivudine has been shown to act additively or synergistically with other anti-HIV agents, particularly zidovudine, inhibiting the replication of HIV in cell culture.
Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content.
In vitro, 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. Lamivudine therefore has, in vitro, a high therapeutic index.
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.
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 less than 4-fold decrease in susceptibility to didanosine and zalcitabine; the clinical significance of these findings is unknown. In vitro susceptibility testing has not been standardised and results may vary according to methodological factors.
In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral load and to increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination with zidovudine alone or in combination with zidovudine containing treatment regimens results in a significant reduction in the risk of disease progression and mortality.
Reduced in vitro sensitivity to lamivudine has been reported for HIV isolates from patients who have received 3TC therapy.
Evidence from clinical studies show that lamivudine plus zidovudine delays the emergence of zidovudine-resistant isolates in individuals with no prior anti-retroviral therapy.
Lamivudine has been widely used as a component of antiretroviral combination therapy with other antiretroviral agents of the same class (nucleoside reverse transcriptase inhibitors) or different classes (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).
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 the clinical response to therapy remain under investigation.
Post-Exposure Prophylaxis (PEP): Internationally recognised guidelines (Centre for Disease Control and Prevention - June 1998), recommend that in the event of accidental exposure to HIV infected blood eg, from a needlestick injury, a combination of zidovudine and lamivudine should be administered promptly (within 1-2 hrs). In cases of higher risk of infection a protease inhibitor should be included in the regimen. It is recommended that antiretroviral prophylaxis be continued for four weeks. No controlled clinical studies have been carried out in post-exposure prophylaxis and supporting data is limited. Seroconversion may still occur despite prompt treatment with antiretroviral agents.
Pharmacokinetics: 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. At therapeutic dose levels ie, 4 mg/kg/day (as two 12-hourly doses), C_max is in the order of 1-1.9 mcg/mL.
Co-administration of lamivudine with food resulted in a delay of t_max and a lower C_max (decreased by up to 47%). However, the extent (based on the AUC) of lamivudine absorbed was not influenced. No dose adjustment is needed when co-administered with food.
Tablets: Administration of two 150-mg tablets is bioequivalent to administration of one 300-mg tablet with respect to AUC_∞, C_max and t_max.
Distribution: From IV studies, the mean volume of distribution is 1.3 L/kg and the mean terminal half-life of elimination is 5-7 hrs.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding to albumin.
Limited data shows lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The mean lamivudine CSF/serum concentration ratio 2-4 hrs after oral administration was approximately 0.12. The true extent of penetration or relationship with any clinical efficacy is unknown.
Metabolism and Elimination: Lamivudine mean systemic clearance is approximately 0.32 L/hr/kg, with predominantly renal clearance (>70%) via the organic cationic transport system and little (<10%) hepatic metabolism.
The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16-19 hrs) compared to the plasma lamivudine half-life (5-7 hrs). 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.
The likelihood of adverse interactions between lamivudine and other medicinal products is low due to limited metabolism and plasma protein binding and almost complete renal elimination of unchanged lamivudine.
Special Patient Populations: Children: In general, lamivudine pharmacokinetics in pediatric patients are similar to adults. However, absolute bioavailability (approximately 55-65%) was reduced in pediatric patients <12 years. In addition, systemic clearance values were greater in younger pediatric patients and decreased with age approaching adult values around 12 years.
There are limited pharmacokinetic data for patients <3 months. In neonates 1 week of age, lamivudine oral clearance was reduced when compared to pediatric patients and is likely to be due to immature renal function and variable absorption. Therefore to achieve similar adult and pediatric exposure, the recommended dose for neonates is 2 mg/kg twice a day. However there is no data available in neonates >1 week old.
Elderly: No pharmacokinetic data are available in patients >65 years.
Renal Impairment: Lamivudine plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. The dosage should therefore be reduced for patients with a creatinine clearance of <50 mL/min (see Dosage & Administration).
Hepatic Impairment: Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.
Pregnancy: The pharmacokinetics of lamivudine are similar to that of non-pregnant adults. In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery.
Toxicology: Carcinogenesis, Mutagenesis: 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 3TC should not represent a genotoxic hazard to patients undergoing treatment.
The results of long term oral carcinogenicity studies with lamivudine in rats and mice did not show any carcinogenic potential.
Reproductive Toxicology: Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect on male or female fertility. Lamivudine produced small increases in early embryonic loss when administered to pregnant 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 35 times the clinical exposure (based on C_max).
Animal Toxicology: Administration of lamivudine in animal toxicity studies at very high doses was not associated with any major organ toxicity. Reductions of erythrocyte and neutrophil counts were identified as the effects most likely to be of clinical relevance.