Lamivudine (Page 4 of 6)

12.4 Microbiology

Mechanism of Action:Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate, 3TC-TP. The principal mode of action of 3TC-TP is the inhibition of the RNA- and DNA­ dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian α, β, and γ-DNA polymerases.

Antiviral Activity:Activity of lamivudine against HBV in cell culture was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. EC 50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 µM (2.3 ng per mL) to 5.6 µM (1.3 mcg per mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used. See the EPIVIR prescribing information for information regarding activity of lamivudine against HIV.

Resistance:Lamivudine-resistant isolates were identified in subjects with virologic breakthrough, defined when using solution hybridization assay as the detection of HBV DNA in serum on 2 or more occasions after failing to detect HBV DNA on 2 or more occasions and defined when using PCR assay as a greater than 1 log 10 (10-fold) increase in serum HBV DNA from nadir during treatment in a subject who had an initial virologic response.

Lamivudine-resistant HBV isolates develop rtM204V/I substitutions in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory substitutions improving replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include rtL80I and rtA181T.

In 4 controlled clinical trials in adults with HBeAg-positive chronic hepatitis B virus infection (CHB), YMDD-mutant HBV was detected in 81 of 335 subjects receiving lamivudine tablets (HBV) 100 mg once daily for 52 weeks. The prevalence of YMDD substitutions was less than 10% in each of these trials for subjects studied at 24 weeks and increased to an average of 24% (range in 4 trials: 16% to 32%) at 52 weeks. In limited data from a long-term follow-up trial in subjects who continued 100 mg per day lamivudine tablets (HBV) after one of these trials, YMDD substitutions further increased from 18% (10 of 57) at 1 year to 41% (20 of 49), 53% (27 of 51), and 69% (31 of 45) after 2, 3, and 4 years of treatment, respectively. Over the 5-year treatment period, the proportion of subjects who developed YMDD-mutant HBV at any time was 69% (40 of 58).

In a controlled trial, treatment-naive subjects with HBeAg-positive CHB were treated with lamivudine tablets (HBV) or lamivudine tablets (HBV) plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only lamivudine tablets (HBV). In another controlled trial, combination therapy was evaluated in adult subjects with HBeAg-positive CHB who had YMDD-mutant HBV and diminished clinical and virologic response to lamivudine tablets (HBV). Following 52 weeks of lamivudine tablets (HBV) plus adefovir dipivoxil combination therapy (n = 46) or therapy with only lamivudine tablets (HBV) (n = 49), YMDD-mutant HBV was detected less frequently in subjects receiving combination therapy, 62% versus 96%.

A published trial suggested that the rates of lamivudine resistance in subjects treated for HBeAg-negative CHB appear to be more variable (0% to 27% at 1 year and 10% to 56% at 2 years).

Pediatric Subjects: In a controlled trial in pediatric subjects, YMDD-mutant HBV was detected in 31 of 166 (19%) subjects receiving lamivudine tablets (HBV) for 52 weeks. For a subgroup that remained on therapy with lamivudine tablets (HBV) in a follow-up trial, YMDD substitutions increased from 24% (29 of 121) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of treatment with lamivudine tablets (HBV).
Cross-Resistance: HBV containing lamivudine resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (30 fold) and telbivudine (greater than 100 fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine. Similarly, HBV with entecavir resistance-associated substitutions (I169T/M250V and T184G/S202I) have greater than 1,000-fold reductions in susceptibility to lamivudine.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice) and 200 times (rats) those observed in humans at the recommended therapeutic dose for chronic hepatitis B.
Mutagenesis: 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 per kg producing plasma levels of 60 to 70 times those in humans at the recommended dose for chronic hepatitis B. Impairment of Fertility: In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 80 to 120 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

14 CLINICAL STUDIES

14.1 Clinical Studies of Lamivudine Tablets (HBV) in Adult Patients

The safety and efficacy of lamivudine tablets (HBV) 100 mg once daily versus placebo were evaluated in 3 controlled trials in subjects with compensated chronic hepatitis B virus infection. All subjects were aged 16 years or older and had chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of HBV replication (serum HBeAg-positive and positive for serum HBV DNA) and persistently elevated ALT levels and/or chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The results of these trials are summarized below.

  • Trial 1 was a randomized, double-blind trial of lamivudine tablets (HBV) 100 mg once daily versus placebo for 52 weeks followed by a 16-week no-treatment period in 141 treatment-naive US subjects.
  • Trial 2 was a randomized, double-blind, 3-arm trial that compared lamivudine tablets (HBV) 25 mg once daily versus lamivudine tablets (HBV) 100 mg once daily versus placebo for 52 weeks in 358 Asian subjects.
  • Trial 3 was a randomized, partially-blind trial conducted primarily in North America and Europe in 238 subjects who had ongoing evidence of active chronic hepatitis B despite previous treatment with interferon alfa. The trial compared lamivudine tablets (HBV) 100 mg once daily for 52 weeks, followed by either lamivudine tablets (HBV) 100 mg or matching placebo once daily for 16 weeks (Arm 1), versus placebo once daily for 68 weeks (Arm 2).

Principal endpoint comparisons for the histologic and serologic outcomes in subjects receiving lamivudine tablets (HBV) (100 mg daily) or placebo in these trials are shown in the following tables.

Table 7. Histologic Response at Week 52 Among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo

A ssessment Trial 1 Trial 2 Trial 3
Lamivudine Tablets (HBV) (n = 62) Placebo (n = 63) Lamivudine Tablets (HBV) (n = 131) Placebo (n = 68) Lamivudine Tablets (HBV) (n = 110) Placebo (n = 54)
Improvement a 55% 25% 56% 26% 56% 26%
No Improvement 27% 59% 36% 62% 25% 54%
Missing Data 18% 16% 8% 12% 19% 20%

a Improvement was defined as a greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded.

Table 8. HBeAg Seroconverters a at Week 52 Among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo

Seroconversion Trial 1 Trial 2 Trial 3
Lamivudine Tablets (HBV) (n = 63) Placebo (n = 69) Lamivudine Tablets (HBV) (n = 140) Placebo (n = 70) Lamivudine Tablets (HBV) (n = 108) Placebo (n = 53)
Seroconverters 17% 6% 16% 4% 15% 13%

a Three-component seroconversion was defined as Week 52 values showing loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the solution-hybridization assay limit. Subjects with negative baseline HBeAg or HBV DNA assay were excluded from the analysis.

Normalization of serum ALT levels was more frequent with lamivudine tablets (HBV) treatment compared with placebo in Trials 1 to 3.

The majority of subjects treated with lamivudine tablets (HBV) showed a decrease of HBV DNA to below the assay limit early in the course of therapy. However, reappearance of assay-detectable HBV DNA during treatment with lamivudine tablets (HBV) was observed in approximately one-third of subjects after this initial response.

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