Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors
ATC Code: J05AF05
Lamivudine is an antiviral agent which is active against hepatitis B virus in all cell lines tested and in experimentally infected animals.
Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half-life of the triphosphate in hepatocytes is 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase.
The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and subsequent chain termination.
Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little effect on mammalian cell DNA content.
In assays relating to potential substance effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA, and does not act as an inhibitor of mitochondrial DNA polymerase gamma.
In controlled studies, 1 year of lamivudine therapy significantly suppressed HBV DNA replication [34-57 % of patients were below the assay detection limits (Abbott Genostics solution hybridization assay, LLOD < 1.6pg/ml)}, normalised ALT level (40-72 % of patients), induced HBeAg seroconversion (HBeAg loss and HBeAb detection with HBV DNA loss [by conventional assay], 16-18 % of patients), improved histology (38-52 % of patients had a ≥ 2 point decrease in the Knodell Histologic Activity Index [HAI]) and reduced progression of fibrosis (in 3-17 % of patients) and progression to cirrhosis.
Continued lamivudine treatment for an additional 2 years in patients who had failed to achieve HBeAg seroconversion in the initial 1 year controlled studies resulted in further improvement in bridging fibrosis. In patients with YMDD mutant HBV, 41/82 (50 %) patients had improvement in liver inflammation and 40/56 (71 %) patients without YMDD mutant HBV had improvement. Improvement in bridging fibrosis occurred in 19/30 (63 %) patients without YMDD mutant and 22/44 (50 %) patients with the mutant. Five percent (3/56) of patients without the YMDD mutant and 13 % (11/82) of patients with YMDD mutant showed worsening in liver inflammation compared to pre-treatment. Progression to cirrhosis occurred in 4/68 (6 %) patients with the YMDD mutant, whereas no patients without the mutant progressed to cirrhosis.
In an extended treatment study in Asian patients (NUCB3018) the HBeAg seroconversion rate and ALT normalisation rate at the end of the 5 year treatment period was 48 % (28/58) and 47 % (15/32), respectively. HBeAg seroconversion was increased in patients with elevated ALT levels; 77 % (20/26) of patients with pre-treatment ALT > 2 x ULN seroconverted. At the end of 5 years, all patients had HBV DNA levels that were undetectable or lower than pre-treatment levels.
Further results from the trial by YMDD mutant status are summarised in Table 2.
Table 2. Efficacy results 5 years by YMDD status (Asian Study) NUCB3018:
| Subjects, % (αρ.) | ||
|---|---|---|
| YMDD mutant HBV status | YMDD1 | Non- YMDD1 |
| HBeAg seroconversion | ||
| All patients | 38 (15/40) | 72 (13/18) |
| Baseline ALT ≤ 1 x ULN2 | 9 (1/11) | 33 (2/6) |
| Baseline ALT > 2 x ULN | 60 (9/15) | 100 (11/11) |
| Undetectable HBV DNA | ||
| Baseline3 | 5 (2/40) | 6 (1/18) |
| Week 2604 | ||
| negative | 8 (2/25) | 0 |
| positive < baseline | 92 (23/25) | 100 (4/4) |
| positive > baseline | 0 | 0 |
| ALT normalisation | ||
| Baseline | ||
| normal | 28 (11/40) | 33 (6/18) |
| above normal | 73 (29/40) | 67 (12/18) |
| Week 260 | ||
| φυσιολογικό | 46 (13/28) | 50 (2/4) |
| above normal < baseline | 21 (6/28) | 0 |
| above normal > baseline | 32 (9/28) | 50 (2/4) |
1 Patients designated as YMDD mutant were those with ≥5% YMDD mutant HBV at any annual time-point during the 5-year period. Patients categorised as non-YMDD mutant were those with > 95% wild-type HBV at all annual time-points during the 5-year study period
2 Upper limit of normal
3 Abbott Genostics solution hybridisation assay (LLOD < 1.6 pg/ml
4 Chiron Quantiplex assay (LLOD 0.7 Meq/ml)
Comparative data according to YMDD status were also available for histological assessment but only up to three years. In patients with YMDD mutant HBV, 18/39 (46 %) had improvements in necroinflammatory activity and 9/39 (23 %) had worsening. In patients without the mutant, 20/27 (74 %) had improvements in necroinflammatory activity and 2/27 (7 %) had worsening.
Following HBeAg seroconversion, serologic response and clinical remission are generally durable after stopping lamivudine. However, relapse following seroconversion can occur. In a long-term follow-up study of patients who had previously seroconverted and discontinued lamivudine, late virological relapse occurred in 39 % of the subjects. Therefore, following HBeAg seroconversion, patients should be periodically monitored to determine that serologic and clinical responses are being maintained. In patients who do not maintain a sustained serological response, consideration should be given to retreatment with either lamivudine or an alternative antiviral agent for resumption of clinical control of HBV.
In patients followed for up to 16 weeks after discontinuation of treatment at one year, post-treatment ALT elevations were observed more frequently in patients who had received lamivudine than in patients who had received placebo. A comparison of post-treatment ALT elevations between weeks 52 and 68 in patients who discontinued lamivudine at week 52 and patients in the same studies who received placebo throughout the treatment course is shown in Table 3. The proportion of patients who had post-treatment ALT elevations in association with an increase in bilirubin levels was low and similar in patients receiving either lamivudine or placebo.
Table 3. Post-treatment ALT Elevations in 2 Placebo-Controlled Studies in Adults:
| Abnormal Value | Patients with ALT Elevation/Patients with Observations* | |
|---|---|---|
| Lamivudine | Placebo | |
| ALT ≥ 2 x baseline value | 37/137 (27 %) | 22/116 (19 %) |
| ALT ≥ 3 x baseline value† | 29/137 (21 %) | 9/116 (8 %) |
| ALT ≥ 2 x baseline value and absolute ALT >500 IU/l | 21/137 (15 %) | 8/116 (7 %) |
| ALT ≥ 2 x baseline value; and bilirubin >2 x ULN | ||
| 1/137 (0.7 %) | 1/116 (0.9 %) | |
* Each patient may be represented in one or more category.
† Comparable to a Grade 3 toxicity in accordance with modified WHO criteria. ULN = Upper limit of normal.
Initial data indicate the efficacy of lamivudine in patients with HBeAg negative CHB is similar to patients with HBeAg positive CHB, with 71 % of patients having HBV DNA suppressed below the detection limit of the assay, 67 % ALT normalisation and 38 % with improvement in HAI after one year of treatment. When lamivudine was discontinued, the majority of patients (70 %) had a return of viral replication. Data is available from an extended treatment study in HBeAg negative patients (NUCAB3017) treated with lamivudine. After two years of treatment in this study, ALT normalisation and undetectable HBV DNA occurred in 30/69 (43 %) and 32/68 (47 %) patients respectively and improvement in necroinflammatory score in 18/49 (37 %) patients. In patients without YMDD mutant HBV, 14/22 (64 %) showed improvement in necroinflammatory score and 1/22 (5 %) patients worsened compared to pre-treatment. In patients with the mutant, 4/26 (15 %) patients showed improvement in necroinflammatory score and 8/26 (31 %) patients worsened compared to pre-treatment. No patients in either group progressed to cirrhosis.
Lamivudine monotherapy results in the selection of YMDD mutant HBV in approximately 24 % of patients following one year of therapy, increasing to 69 % following 5 years of therapy. Development of YMDD mutant HBV is associated with reduced treatment response in some patients, as evidenced by increased HBV DNA levels and ALT elevations from previous on-therapy levels, progression of signs and symptoms of hepatitis disease and/or worsening of hepatic necroinflammatory findings. Given the risk of YMDD mutant HBV, maintenance of lamivudine monotherapy is not appropriate in patients with detectable serum HBV DNA at or beyond 24 weeks of treatment (see section 4.4).
In a double-blind study in CHB patients with YMDD mutant HBV and compensated liver disease (NUC20904), with a reduced virological and biochemical response to lamivudine (n=95), the addition of adefovir dipivoxil 10 mg once daily to ongoing lamivudine 100 mg for 52 weeks resulted in a median decrease in HBV DNA of 4.6 log10 copies/ml compared to a median increase of 0.3 log10 copies/ml in those patients receiving lamivudine monotherapy. Normalisation of ALT levels occurred in 31 % (14/45) of patients receiving combined therapy versus 6 % (3/47) receiving lamivudine alone. Viral suppression was maintained (follow-on study NUC20917) with combined therapy during the second year of treatment to week 104 with patients having continued improvement in virologic and biochemical responses.
In a retrospective study to determine the factors associated with HBV DNA breakthrough, 159 Asian HBeAg-positive patients were treated with lamivudine and followed up for a median period of almost 30 months. Those with HBV DNA levels greater than 200 copies/mL at 6 months (24 weeks) of lamivudine therapy had a 60 % chance of developing the YMDD mutant compared with 8 % of those with HBV DNA levels less than 200 copies/mL at 24 weeks of lamivudine therapy. The risk for developing YMDD mutant was 63% versus 13% with a cut off of 1000 copies/ml (NUCB3009 and NUCB3018).
Placebo controlled studies have been regarded as inappropriate in patients with decompensated liver disease, and have not been undertaken. In non-controlled studies, where lamivudine was administered prior to and during transplantation, effective HBV DNA suppression and ALT normalisation was demonstrated. When lamivudine therapy was continued post transplantation there was reduced graft re-infection by HBV, increased HBsAg loss and on one-year survival rate of 76-100 %.
As anticipated due to the concomitant immunosuppression, the rate of emergence of YMDD mutant HBV after 52 weeks treatment was higher (36 % - 64 %) in the liver transplant population than in the immunocompetent CHB patients (14 % - 32 %).
Forty patients (HBeAg negative or HBeAg positive) with either decompensated liver disease or recurrent HBV following liver transplantation and YMDD mutant were enrolled into an open label arm of study NUC20904. Addition of 10 mg adefovir dipivoxil once daily to ongoing lamivudine 100 mg for 52 weeks resulted in a median decrease in HBV DNA of 4.6 log10 copies/ml. Improvement in liver function was also seen after one year of therapy. This degree of viral suppression was maintained (follow-on study NUC20917) with combined therapy during the second year of treatment to week 104 and most patients had improved markers of liver function and continued to derive clinical benefit.
In a placebo-controlled study in 651 patients with clinically compensated chronic hepatitis B and histologically confirmed fibrosis or cirrhosis, lamivudine treatment (median duration 32 months) significantly reduced the rate of overall disease progression (34/436, 7.8 % for lamivudine versus 38/215, 17.7 % for placebo, p=0.001), demonstrated by a significant reduction in the proportion of patients having increased Child-Pugh scores (15/436, 3.4 % versus 19/215, 8.8 %, p=0.023) or developing hepatocellular carcinoma (17/436, 3.9 % versus 16/215, 7.4 %, p=0.047). The rate of overall disease progression in the lamivudine group was higher for subjects with detectable YMDD mutant HBV DNA (23/209, 11 %) compared to those without detectable YMDD mutant HBV (11/221, 5 %). However, disease progression in YMDD subjects in the lamivudine group was lower than the disease progression in the placebo group (23/209, 11 % versus 38/214, 18 % respectively). Confirmed HBeAg seroconversion occurred in 47 % (118/252) of subjects treated with lamivudine and 93 % (320/345) of subjects receiving lamivudine became HBV DNA negative (VERSANT [version 1], bDNA assay, LLOD < 0.7 MEq/ml) during the study.
Lamivudine has been administered to children and adolescents with compensated CHB in a placebo controlled study of 286 patients aged 2 to 17 years. This population primarily consisted of children with minimal hepatitis B. A dose of 3 mg/kg once daily (up to a maximum of 100 mg daily) was used in children aged 2 to 11 years and a dose of 100 mg once daily in adolescents aged 12 years and above. This dose needs to be further substantiated. The difference in the HBeAg seroconversion rates (HBeAg and HBV DNA loss with HBeAb detection) between placebo and lamivudine was not statistically significant in this population (rates after one year were 13 % (12/95) for placebo versus 22 % (42/191) for lamivudine; p=0.057). The incidence of YMDD mutant HBV was similar to that observed in adults, ranging from 19 % at week 52 up to 45 % in patients treated continuously for 24 months.
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. At therapeutic dose levels i.e. 100 mg once daily, Cmax is in the order of 1.1-1.5 µg/ml and trough levels were 0.015-0.020 µg/ml.
Co-administration of lamivudine with food resulted in a delay of Tmax and a lower Cmax (decreased by up to 47 %). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, therefore lamivudine can be administered with or without food.
From intravenous studies the mean volume of distribution is 1.3 l/kg. 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 cerebro-spinal fluid (CSF). The mean lamivudine CSF/serum concentration ratio 2-4 hours after oral administration was approximately 0.12.
Lamivudine is predominately cleared by renal excretion of unchanged substance. The likelihood of metabolic substance interactions with lamivudine is low due to the small (5-10 %) extent of hepatic metabolism and the low plasma protein binding.
The mean systemic clearance of lamivudine is approximately 0.3 l/h/kg. The observed half-life of elimination is 18 to 19 hours. The majority of lamivudine is excreted unchanged in the urine via glomerular filtration and active secretion (organic cationic transport system). Renal clearance accounts for about 70 % of lamivudine elimination.
Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction in patients with a creatinine clearance of < 50 ml/min is necessary (see section 4.2).
The pharmacokinetics of lamivudine are unaffected by hepatic impairment. Limited data in patients undergoing liver transplantation show that impairment of hepatic function does not impact significantly on the pharmacokinetics of lamivudine unless accompanied by renal dysfunction.
In elderly patients the pharmacokinetic profile of lamivudine suggests that normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min (see section 4.2).
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 reduction in liver weights. Reduction of erythrocytes and neutrophil counts were identified as the effects most likely to be of clinical relevance. These events were seen infrequently in clinical studies.
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 60-70 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed by in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.
Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect on male or female fertility. Lamivudine induces early embryolethality when administered to pregnant rabbits at exposure levels comparable to those achieved in man, but not in the rat even at very high systemic exposures.
The results of long term carcinogenicity studies with lamivudine in rats and mice did not shown any carcinogenic potential.
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