Source: Health Products and Food Branch (CA) Revision Year: 2022
Lamivudine is a synthetic nucleoside analogue, an (-) enantiomer of a dideoxy analogue of cytidine. The sugar ring of lamivudine is novel in that it contains a sulphur at the 3´ position as a second heteroatom. Lamivudine is metabolized by intracellular kinases to its triphosphate (TP), which is the active moiety (lamivudine triphosphate or L-TP). Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI), and is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro. In vitro L-TP has an intracellular half-life of approximately 10.5 to 15.5 hours. L-TP is a substrate for and a competitive inhibitor of HIV reverse transcriptase (RT). Inhibition of RT is via viral DNA chain termination after nucleoside analogue incorporation. L-TP shows significantly less affinity for host cell DNA polymerases and is a weak inhibitor of mammalian α, β, and γ DNA polymerases.
The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-infected adult patients after administration of single oral, multiple oral and intravenous (IV) doses ranging from 0.25 to 10 mg/kg. After oral administration of 2 mg/kg, the peak plasma lamivudine concentration (Cmax) was 1.5 ± 0.5 µg/mL (mean ± S.D.) and half-life was 2.6 ± 0.5 hours. There were no significant differences in half-life across the range of single doses (0.25 to 8 mg/kg). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to dose over the range from 0.25 to 10 mg/kg.
The steady-state pharmacokinetic properties of the 3TC 300 mg tablet once daily for 7 days compared to the 3TC 150 mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. 3TC 300 mg once daily resulted in lamivudine exposures that were similar to 3TC 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared to the 150 mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared to the 150 mg twice-daily regimen.
The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.
Lamivudine is well absorbed from the gut, 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. The administration of tablets is bioequivalent to oral solution with respect to AUC and Cmax in adults. Absorption differences have been observed between adult and pediatric populations (see 10.3 Pharmacokinetics, Special Populations and Conditions, Pediatrics).
No dose adjustment is needed when coadministered with food as lamivudine bioavailability is not altered, although a delay in tmax and reduction in Cmax have been observed. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin.
Coadministration of zidovudine results in a 13% increase in AUC∞ for zidovudine 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.
Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. After oral administration of 2 mg/kg to nine adults with HIV, the peak plasma lamivudine concentration (Cmax) was 1.5 ± 0.5 µg/mL (mean ± S.D.). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to dose over the range from 0.25 to 10 mg/kg. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± S.D.) for the 150 mg tablet and 87% ± 13% for the oral solution.
The steady-state pharmacokinetic properties of the 3TC 300 mg tablet once daily for 7 days compared to the 3TC 150 mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. 3TC 300 mg once daily was pharmacokinetically equivalent to 3TC 150 mg twice daily with respect to plasma AUC24,SS. Intracellular lamivudine triphosphate concentrations in peripheral blood mononuclear cells were also pharmacokinetically equivalent with respect to AUC24,SS and Cmax24,SS.
3TC tablets were administered orally to 12 asymptomatic, HIV-infected patients on two occasions, once in the fasted state and once with food. There was no significant difference in systemic exposure (AUC) in the fed and fasted states; therefore, lamivudine tablets and oral solution may be administered with or without food. Absorption was slower in the fed state as shown by a 47% reduction in mean Cmax from fasted values and a prolonged time to peak concentration.
The apparent volume of distribution after IV administration of lamivudine was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.
Binding of lamivudine to human plasma proteins is concentration-dependent, with 36% bound at 0.1 µg /mL and less than 10% bound at concentrations ≥1 mcg/mL. The distribution of lamivudine in whole human blood was studied in vitro. Over the concentration range of 0.1 to 100 µg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.
Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite which accounts for less than 5% of an oral 150 mg dose of lamivudine. Glucuronide conjugation has not been observed as a metabolic pathway for lamivudine in man.
The majority of lamivudine is eliminated unchanged in urine. Within 4 hours after a single oral dose, 71% ± 16% (mean ± S.D.) of the dose is excreted unchanged in urine. Total clearance and terminal elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10.0mg/kg.
The plasma lamivudine half-life after oral dosing is 18 to 19 h and the active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 h).
Pediatrics: The pharmacokinetics of lamivudine have been studied after either single or repeat doses of 3TC in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution according to the recommended dosage regimen achieved approximately 25% lower plasma concentrations of lamivudine compared with HIV-1 infected adults. Pediatric subjects receiving lamivudine oral tablets according to the recommended dosage regimen achieved plasma concentrations of lamivudine similar to adults. Subjects receiving lamivudine oral tablets achieved higher plasma concentrations of lamivudine than subjects receiving oral solution because the weight-band–based dosing for the tablet formulation results in administration of higher mg/kg doses due to higher bioavailability of the tablets. The absolute bioavailability of both 3TC tablet and oral solution are lower in children than adults.
The pharmacokinetics of lamivudine dosed once daily in HIV-1-infected pediatric patients aged 3 months through 12 years was evaluated in 3 studies (PENTA-15 [n=17], PENTA-13 [n=19], and ARROW PK [n=35]). These 3 studies were designed as 2-period, crossover, open-label pharmacokinetic studies of twice-versus once-daily dosing of abacavir and lamivudine. These 3 studies demonstrated that oncedaily dosing provides equivalent AUC0-24 to twice-daily dosing of lamivudine at the same total daily dose for both the oral solution and tablet formulations. The mean Cmax was approximately 80% to 90% higher with lamivudine once-daily dosing compared with twice-daily dosing.
Table 12. Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials:
| Trial (Number of Subjects) | ||||||
|---|---|---|---|---|---|---|
| ARROW PK (n = 35) | PENTA-13 (n = 19) | PENTA-15 (n = 17)a | ||||
| Age Range | 3-12 years | 2-12 years | 3-36 months | |||
| Formulation | Tablet | Solution and Tabletb | Solution | |||
| Parameter | Once Daily | Twice Daily | Once Daily | Twice Daily | Once Daily | Twice Daily |
| Cmax (mcg/mL) | 3.17 (2.76, 3.64) | 1.80 (1.59, 2.04) | 2.09 (1.80, 2.42) | 1.11 (0.96, 1.29) | 1.87 (1.65, 2.13) | 1.05 (0.88, 1.26) |
| AUC(0-24) (mcgh/mL) | 13.0 (11.4, 14.9) | 12.0 (10.7, 13.4) | 9.80 (8.64, 11.1) | 8.88 (7.67, 10.3) | 8.66 (7.46, 10.1) | 9.48 (7.89, 11.4) |
a N = 16 for PENTA-15 Cmax.
b Five subjects in PENTA-13 received lamivudine tablets.
Distribution of lamivudine into cerebrospinal fluid was assessed in 38 pediatric patients. Cerebrospinal fluid concentrations were 3% to 47% of the concentration in a simultaneous serum sample. The true extent of penetration of relationship with any clinical efficacy is unknown.
Pregnancy and Breast-feeding: Following oral administration, lamivudine pharmacokinetics in late pregnancy were similar to non-pregnant adults.
Renal Insufficiency: The pharmacokinetic properties of lamivudine were determined in a small group of HIV-infected adults with impaired renal function, and are summarized in Table 13.
Table 13. Pharmacokinetic Parameters (Mean ± S.D.) After a Single 300 mg Oral Dose of Lamivudine in Three Groups of Adults With Varying Degrees of Renal Function (CrCl >60 mL/min, CrCl = 10-30 mL/min, and CrCl <10 mL/min):
| Number of subjects | 6 | 4 | 6 |
| Creatinine clearance criterion | >60 mL/min | 10-30 mL/min | <10 mL/min |
| Creatinine clearance (mL/min) | 111 ± 14 | 28 ± 8 | 6 ± 2 |
| Cmax (μg/mL) | 2.6 ± 0.5 | 3.6 ± 0.8 | 5.8 ± 1.2 |
| AUC∞ (μg·h/mL) | 11.0 ± 1.7 | 48.0 ± 19 | 157 ± 74 |
| Cl/F (mL/min) | 464 ± 76 | 114 ± 34 | 36 ± 11 |
These results show increases in Cmax and half-life with diminishing creatinine clearance. Apparent total clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with reduced creatinine clearance (see 4.2 Recommended Dose and Dosage Adjustment).
Lamivudine is a potent inhibitor of HIV-1 and HIV-2 in vitro. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite (lamivudine triphosphate or L-TP), which has an intracellular half-life of approximately 10.5 to 15.5 hours. The principal mode of action of lamivudine is inhibition of HIV reverse transcription via viral DNA chain termination. In addition, L-TP inhibits both the RNA- and DNA-dependent DNA polymerase activities of reverse transcriptase (RT), and is a weak inhibitor of mammalian α, β, and γ DNA polymerases. Lamivudine does not act as a chain terminator of mitochondrial DNA synthesis. Lamivudine has little effect on mammalian cell mitochondrial DNA content and does not interfere with normal cellular deoxynucleotide metabolism (in vitro).
The relationships between in vitro susceptibility of HIV to lamivudine and the inhibition of HIV replication in humans or clinical response are still being investigated. The anti-HIV activity of nucleoside analogues in vitro can vary depending on the viral strain, cell type, and assay used to measure such activity. To assess the activity of lamivudine, a number of virus/cell combinations were used, and inhibitory activity was measured in different assays by determination of IC50 and IC90 values. Lamivudine demonstrated anti-HIV-1 and anti-HIV-2 activities in all virus/cell combinations tested.
The antiviral activity of lamivudine has been studied in combination with other antiretroviral compounds using HIV-1-infected MT-4 cells as the test system. No antagonistic effects were seen in vitro with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).
In nonclinical studies, lamivudine-resistant isolates of HIV have been selected in vitro. A known mechanism of lamivudine resistance is the change in the 184 amino acid of RT from methionine to either isoleucine or valine. In vitro studies indicate that zidovudine-resistant viral isolates can become sensitive to zidovudine when they acquire the 184 mutation. The clinical relevance of such findings remains, however, not well defined.
For isolates collected in clinical studies, phenotypic resistance data showed that resistance to lamivudine monotherapy developed within 12 weeks. Evidence in isolates from antiretroviral-naive patients suggests that the combination of lamivudine and zidovudine delays the emergence of mutations conferring resistance to zidovudine. Combination therapy with lamivudine plus zidovudine did not prevent phenotypic resistance to lamivudine. However, phenotypic resistance to lamivudine did not limit the antiretroviral activity of combination therapy with lamivudine plus zidovudine. In antiretroviral therapy-naive patients, phenotypic resistance to lamivudine emerged more slowly on combination therapy than on lamivudine monotherapy. In the zidovudine-experienced patients on lamivudine plus zidovudine, no consistent pattern of changes in phenotypic resistance to lamivudine or zidovudine was observed.
Pediatric subjects receiving lamivudine oral solution concomitantly with other antiretroviral oral solutions (abacavir, nevirapine/efavirenz or zidovudine) in the ARROW study developed viral resistance more frequently than those receiving tablets.
The potential for cross-resistance between HIV reverse transcriptase inhibitors and protease inhibitors is low because of the different enzyme targets involved. 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 and zalcitabine; the clinical significance of these findings is unknown. In vitro susceptibility testing has not been standardized and results may vary according to methodological factors. HIV isolates with multidrug resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of patients treated for ≥1 year with the combination of zidovudine and didanosine or zalcitabine. The pattern of resistant mutations in the combination therapy was different (Ala62→Val, Val75→Ile, Phe77→Leu, Phe116→Tyr and Gln151→Met) from monotherapy, with mutation 151 being most significant for multidrug resistance. Site-directed mutagenesis studies showed that these mutations could also result in resistance to zalcitabine, lamivudine, and stavudine.
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.
Genotypic and phenotypic analysis of on-therapy HIV-1 isolates from patients with virologic failure (see 14 CLINICAL TRIALS). The data indicates that through 48 weeks, 3TC once daily has been shown to be as effective as 3TC twice daily, and the use of 3TC once daily through 48 weeks does not increase the incidence or the time to emergence of resistance to 3TC or other study drugs in the regimen. The clinical relevance of genotypic and phenotypic changes associated with lamivudine therapy has not been fully established.
Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level ≥400 copies/mL) by Week 48. Twenty-eight patients were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of patients in the lamivudine once-daily group and lamivudine twice-daily groups were 4.9 log10 copies/mL and 4.6 log10 copies/mL, respectively.
Genotypic analysis of on-therapy isolates from 22 patients identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 patients contained treatment-emergent mutations associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 patients contained treatment-emergent mutations associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8/22 patients contained a treatment-emergent lamivudine resistance-associated mutation (M184I or M184V).
Genotypic analysis of on-therapy isolates from patients (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 patients contained treatment-emergent zidovudine resistance mutations, isolates from 7/22 contained treatment-emergent efavirenz resistance mutations, and isolates from 5/22 contained treatment-emergent lamivudine resistance mutations.
Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine once daily showed that isolates from 12/13 patients were susceptible to zidovudine; isolates from 8/13 patients exhibited a decrease in susceptibility to efavirenz, and isolates from 7/13 patients showed a decrease in susceptibility to lamivudine.
Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine twice daily showed that isolates from all 13 patients were susceptible to zidovudine; isolates from 4/13 patients exhibited a decrease in susceptibility to efavirenz, and isolates from 4/13 patients exhibited a decrease in susceptibility to lamivudine.
The results of cytotoxicity studies in various assays have shown little cytotoxic action with lamivudine. Cytotoxicity of lamivudine was compared with that of zidovudine, zalcitabine, and didanosine in four Tlymphoblastoid cell lines; one monocyte/ macrophage-like cell line; one B-lymphoblastoid cell line; and peripheral blood lymphocytes (PBLs) using both cell proliferation (CP) and [3H]-thymidine uptake (Td) assays. In the CP assay, lamivudine was the least toxic of the four compounds. [3H]-thymidine uptake results demonstrated a similar trend to those from the CP assays. Lamivudine had no cytotoxic effect when incubated for 10 days with phytohemagglutinin (PHA)-activated human lymphocytes or human macrophages.
The cytotoxicity of combinations of lamivudine with zidovudine, zalcitabine, or didanosine was evaluatedin PHA-activated PBLs and CEM cells by measuring cellular uptake of [3H]-thymidine. Lamivudine greatly reduced the cytotoxicity of zalcitabine, slightly reduced the cytotoxicity of zidovudine in some cases, and did not alter the cytotoxicity of didanosine.
In myelotoxicity studies in vitro, lamivudine demonstrated no toxic effects against erythroid, granulocyte-macrophage, pluripotent, or stromal progenitor cells from healthy human donors. Lamivudine was not toxic to human hematopoietic supportive stroma, nonadherent hematopoietic cells, or stromal fibroblasts and produced minimal changes in cytokine (GM-CSF) production from mitogen-stimulated bone marrow stromal cells. Lamivudine was less toxic than zidovudine, zalcitabine, ara-C, 3FT, and stavudine in these studies. In another study, lamivudine was not toxic to activated human T-cells.
Acute Toxicity:
Acute toxicity studies have been performed in the mouse and rat. The acute oral administration of very high doses of lamivudine (two doses of 2000 mg/kg) in mice was associated with transient increases in sexual activity in males and general activity in males and females. There were no deaths and no evidence of target organ toxicity. Therefore the maximum non-lethal oral dose of lamivudine in mice is greater than two doses of 2000 mg/kg.
The acute intravenous administration of lamivudine at 2000 mg/kg was well tolerated by both mice and rats and was not associated with any target organ toxicity. A number of non-specific clinical signs were observed which were more severe in rats but were all of relatively short duration.
Long-Term Toxicity:
In repeat-dose toxicity studies, lamivudine was very well tolerated in the rat at oral doses up to 2000 mg/kg b.i.d. for 6 months. Treatment-related effects were restricted to minor hematological (mainly red cell parameters), clinical chemistry and urinalysis changes, and the mucosal hyperplasia of the cecum (in the 6-month study). The no (toxicologically important) effect level was 450 mg/kg b.i.d.
In the dog, oral doses of 1500 mg/kg b.i.d. in males and 1000 mg/kg b.i.d. in females for a period of 12 months were well tolerated. Treatment-related changes included reductions in red cell counts at all dose levels associated with increased MCV and MCH, and reductions in total leucocyte, neutrophil and lymphocyte counts in high dose animals, but with no effect on bone marrow cytology. Deaths were seen in females dosed with 1500 mg/kg b.i.d. in a 3-month study but not in a 12-month study, using a dose of 1000 mg/kg b.i.d.
When administered orally for one month, at a dose of 1000 mg/kg b.i.d., lamivudine demonstrated low hematotoxic potential in the mouse, and did not significantly enhance the hematotoxicity of zidovudine or interferon α.
Carcinogenicity:
Traditional 24-month carcinogenicity studies using lamivudine have been conducted in mice and rats at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at recommended therapeutic doses. The following results should be noted. In mice, there appeared to be an increased incidence of histiocytic sarcoma in female mice treated with 180 mg/kg/day (6 of 60 mice) and 2000 mg/kg/day (5 of 60 mice) when compared to control mice (two control groups with 1 of 60 and 2 of 60 mice). There did not appear an increased incidence in histiocytic sarcoma in female mice treated with 600 mg/kg/day (3 of 60 mice). It should be noted that the control incidence of this type of tumour in this strain of mice can be as high as 10% similar to that found in the 180 and 2000 mg/kg/day groups. In rats, there appeared to be an increased incidence of endometrial epithelial tumours in female rats treated with 3000 mg/kg/day (5 of 55 rats) when compared to control rats (two control groups each with 2 of 55 rats). There did not appear to be an increased incidence for endometrial tumours in rats treated with 1000 mg/kg/day (2 of 55 rats) or 300 mg/kg/day (1 of 55 rats). It should be noted that there did not appear to be an increased incidences of any proliferative non-neoplastic epithelial lesions in treated female rats when compared to control rats, and the incidence of adenocarcinoma (5/55 or 9%) was only slightly higher than recorded controls at the laboratory where the study was conducted (4/50 or 8%). The statistical significance of the findings in mice and rats varied with the statistical analysis conducted, and therefore, the statistical and hence, the clinical significance of these findings are uncertain. However, based on the similarity to historical control data, it was concluded that the results of long-term carcinogenicity studies in mice and rats for lamivudine did not seem to show a carcinogenic potential relevant for humans.
Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg (approximately 65 times the recommended human dose based on body surface area comparisons).
Reproductive and Developmental Toxicology:
A range of studies has been performed to assess the effects of repeated oral administration of lamivudine upon mammalian reproduction and development.
In a rat fertility study, except for a few minor changes in high dose (2000 mg/kg b.i.d) animals, the overall reproductive performance of the F0 and F1 generation animals, and the development of the F1 and F2 generation, was unaffected by treatment with lamivudine.
Lamivudine was not teratogenic in the rat or rabbit, at doses up to 2000 mg/kg b.i.d. and 500 mg/kg b.i.d., respectively. In the rabbit a slight increase in the incidence of pre-implantation loss at doses 20 mg/kg b.i.d. and above indicates a possible early embryolethal effect. There was no such effect in the rat. These marginal effects occurred at relatively low doses, which produced plasma levels comparable to those achieved in patients.
In a peri-/post-natal/juvenile toxicity study in rats, some histological inflammatory changes at the anorectal junction and slight diffuse epithelial hyperplasia of the caecum were observed in dams and pups at the high dose level. An increased incidence of urination upon handling was also seen in some offspring receiving 450 or 2000 mg/kg. In addition, a reduction in testes weight was observed in juvenile males at 2000 mg/kg which was associated with slight to moderate dilatation of the seminiferous tubules.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
