Telbivudine Other names: Epavudine L-deoxythymidine Beta-l-thymidine

Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is efficiently phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine-5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine-5'-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication.

Pharmacodynamic effects

Telbivudine is an inhibitor of both HBV first strand (EC₅₀=0.4-1.3 μM) and second strand (EC₅₀=0.12-0.24 μM) synthesis, and shows a distinct preference for inhibiting second strand production. By contrast, telbivudine-5'-triphosphate at concentrations up to 100 μM did not inhibit cellular DNA polymerases α, β, or γ. In assays relating to mitochondrial structure, function and DNA content, telbivudine lacked appreciable toxic effect at concentrations up to at 10 μM and did not increase lactic acid production in vitro.

The in vitro antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15. The concentration of telbivudine that effectively inhibited 50% of viral synthesis (EC₅₀) was approximately 0.2 μM. The antiviral activity of telbivudine is specific to the hepatitis B virus and related hepadnaviruses. Telbivudine was not active against HIV in vitro. The absence of activity of telbivudine against HIV has not been evaluated in clinical trials. Transient reductions in HIV-1 RNA have been reported in a small number of patients after administration of telbivudine in the absence of antiretroviral therapy. The clinical significance of these reductions has not been determined.

The single- and multiple-dose pharmacokinetics of telbivudine were evaluated in healthy subjects and in patients with chronic hepatitis B. The pharmacokinetics of telbivudine were not evaluated with the recommended dose of 600 mg in patients with chronic hepatitis B. However telbivudine pharmacokinetics are similar between both populations.

Absorption

Following oral administration of a 600 mg single dose of telbivudine to healthy subjects (n=42), the peak plasma concentration (C_max) of telbivudine was 3.2 ± 1.1 μg/ml (mean ± SD) and occurred at median 3.0 hours post dose. The telbivudine area under the plasma concentration-time curve (AUC_0-∞) was 28.0 ± 8.5 μg·h/ml (mean ± SD). Inter-subject variability (CV%) for measures of systemic exposures (C_max, AUC) was typically approximately 30%.

Effect of food on oral absorption

Telbivudine absorption and exposure were unaffected when a single 600 mg dose was administered with food.

Distribution

In vitro binding of telbivudine to human plasma proteins is low (3.3%).

Biotransformation

No metabolites of telbivudine were detected following administration of ¹⁴C-telbivudine in humans. Telbivudine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.

Elimination

After reaching peak concentration, plasma disposition of telbivudine declined in a bi-exponential manner with a terminal elimination half-life (t_1/2) of 41.8 ± 11.8 hours. Telbivudine is eliminated primarily by urinary excretion of unchanged substance. The renal clearance of telbivudine approaches normal glomerular filtration rate, suggesting that filtration is the main mechanism of excretion.

Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of telbivudine. As renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing haemodialysis require a dose interval adjustment.

Linearity/non-linearity

Telbivudine pharmacokinetics are dose proportional over the range of 25 to 1,800 mg. Steady state was achieved after 5 to 7 days of once-daily administration with an approximate 1.5-fold accumulation in systemic exposure, suggesting an effective accumulation half-life of approximately 15 hours. Following once-daily administration of telbivudine 600 mg, steady-state trough plasma concentrations were approximately 0.2-0.3 μg/ml.

Special populations

Gender

There are no significant gender-related differences in telbivudine pharmacokinetics.

Race

There are no significant race-related differences in telbivudine pharmacokinetics.

Paediatrics and elderly (65 years age and above)

Pharmacokinetic studies have not been conducted in paediatric or elderly subjects.

Renal impairment

The single-dose pharmacokinetics of telbivudine (200, 400 and 600 mg) have been evaluated in patients (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 9, adjustment of the dose interval for telbivudine is recommended in patients with creatinine clearance of <50 ml/min.

Table 9. Pharmacokinetic parameters (mean ± SD) of telbivudine in subjects with various degrees of renal function:

Renally impaired patients on haemodialysis

Haemodialysis (up to 4 hours) reduces systemic telbivudine exposure by approximately 23%. Following dose interval adjustment for creatinine clearance, no additional dose modification is necessary during routine haemodialysis. Telbivudine should be administered after haemodialysis.

Hepatic impairment

The pharmacokinetics of telbivudine have been studied in patients (without chronic hepatitis B) with various degrees of hepatic impairment and in some patients with decompensated liver disease. There were no significant changes in telbivudine pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Telbivudine did not show any carcinogenic potential. No evidence of a direct toxic effect of telbivudine was seen in standard tests of reproduction toxicology. In rabbits doses of telbivudine providing exposure levels of 37 times those observed in humans at the therapeutic dose (600 mg) were associated with an increased incidence of abortion and early delivery. This effect was considered to be secondary to maternal toxicity.

Fertility was assessed in conventional studies performed in adult rats, and as part of a juvenile toxicology study.

In adult rats, fertility was reduced when both male and female rats were treated with telbivudine at doses of 500 or 1000 mg/kg/day (lower fertility index compared to concurrent controls). There were no abnormalities in sperm morphology or function, and the testes and ovaries were histologically unremarkable.

No evidence of impaired fertility was seen in other studies when either male or female rats were treated at doses up to 2000 mg/kg/day and mated with untreated rats (systemic exposure levels approximately 6-14 times higher than those achieved in humans).

In the juvenile toxicology study, rats were treated from day 14 to day 70 post-partum and were mated with rats receiving the same treatment (no sibling mating). Fertility was reduced in pairs given ≥1000 mg/kg/day as shown by decreases in fertility and mating indices, and reduced conception rate. However the ovarian and uterine parameters of those females mating successfully were unaffected.

The no observed adverse effect level (NOAEL) for effects on fertility or mating parameters amounted to 250 mg/kg/day, which provided exposure levels 2.5 to 2.8 times higher than those achieved in humans with normal renal function at the therapeutic dose.