Pharmaceutical Approval Update: Telbivudine (Tyzeka)

Posted by James

Manufacturer: Idenix, Cambridge, MA/Novartis, East Hanover, NJ

Indication: Telbivudine tablets are indicated for the treatment of chronic hepatitis B in adults with viral replication and either persistently elevated levels of serum alanine or aspartate aminotransferases (ALT or AST) or histologically active disease. This indication is based on virological, serological, bio­chemical, and histological responses after one year of therapy in nucleoside-naive adults with hepatitis B early antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B with compensated liver disease.

Drug Class: Telbivudine is a synthetic thymidine nucleoside analogue with activity against the hepatitis B virus (HBV). The chemical name is 1-((2S,4R,5S)-4-hydroxy-5-hydroxy-methyltetrahydrofuran-2-yl)-5-methyl-1H-pyrimidine-2,4-dione, or 1-(2-deoxy-p-L-ribofuranosyl)-5-methyluracil. Telbivudine is the unmodified p-L-enantiomer of the naturally occurring nucleoside, thymidine. Its molecular formula is C₁₀H₁₄N₂O₅ with a molecular weight of 242.23.

Uniqueness of Drug: Telbivudine inhibits HBV DNA poly-merase. Telbivudine is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine 59-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 59-triphosphate. Incorporation of telbivudine 59-triphosphate into viral DNA causes termination of the DNA chain, thereby inhibiting HBV replication.

Telbivudine blocks 50% of viral DNA of both HBV first-strand synthesis (EC₅₀ = 1.3 ± 1.6 mM) and second-strand synthesis (EC₅₀ = 0.2 ± 0.2 mM). At concentrations up to 100 mM, telbivudine 59-triphosphate did not inhibit human cellular DNA polymerases a, b, or g. No appreciable mitochondrial toxicity was observed in HepG₂ cells treated with telbivudine at concentrations up to 10 mM.

Antiviral Activity: The antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15 and in primary duck hepatocytes infected with duck HBV. The concentration of telbivudine that effectively inhibited 50% of viral DNA synthesis (EC₅₀) in both systems was approximately 0.2 mM.

The anti-HBV activity of telbivudine was additive with ade-fovir dipivoxil (Hepsera, Gilead) cell culture, and it was not antagonized by the HIV nucleoside reverse transcriptase inhibitors (NRTIs) generic didanosine (Videx medication, Bristol-Myers Squibb) and stavudine canadian (Drug Zerit, Bristol-Myers Squibb). Telbivudine is not active against HIV-1 (EC₅₀ above 100 mM) and is not antagonistic to the anti-HIV activity of abacavir tablet (Ziagen drug, Glaxo-SmithKline), didanosine, emtricitabine (Emtriva, Gilead), canadian lamivudine (Epivir-HBV generic, GlaxoSmithKline), stavudine, teno-fovir (Viread, Gilead), or medication zidovudine (formerly AZT; Retrovir canadian, GlaxoSmithKline).

Boxed Warning: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretroviral agents. Severe acute exacerbations of hepatitis B have been reported in patients who discontinued anti-hepatitis B therapy, including telbivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, anti-hepatitis B therapy may be resumed.

Warnings:

Exacerbations of hepatitis after discontinuation of treatment: Severe acute exacerbations of hepatitis B have been reported in patients who have anti-hepatitis B therapy. Hepatic function should be monitored closely for several months after discontinuation of therapy. If warranted, anti-hepatitis B therapy may be resumed.

Skeletal muscle: Cases of myopathy (persistent unexplained muscle aches and/or muscle weakness with elevated creatine kinase [CK] values) have been reported with telbivudine use several weeks to months after the start of therapy. Myopathy has also been reported with some other drugs in this class. Uncomplicated myalgia has been reported in telbivudine-treated patients. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness, or muscle weakness.

Among patients with telbivudine-associated myopathy, there has not been a uniform pattern in terms of the degree or timing of CK elevations. In addition, the predisposing factors for the development of myopathy among telbivudine recipients are unknown. Patients should be advised to promptly report unexplained muscle aches or pain, muscle tenderness, or muscle weakness. Telbivudine therapy should be interrupted if myopathy is suspected, and therapy should be discontinued if myopathy is diagnosed.

It is not known whether the risk of myopathy during treatment with drugs in this class is increased with the concurrent administration of other drugs associated with myopathy, such as corticosteroids, chloroquine, hydroxychloroquine, certain HMG-CoA reductase inhibitors (statins), fibric acid derivatives, penicillamine, zidovudine cyclosporine, erythromycin, niacin, or azole antifungal agents. Physicians considering potential benefits and risks should monitor patients for any signs or symptoms of unexplained muscle problems, particularly during periods of upward dosage titration.

Precautions:

Renal function:Telbivudine is eliminated primarily by renal excretion; thus, dose interval adjustment is recommended in patients with a creatinine clearance (CrCl) below 50 ml/minute, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis. The coadministration of tel-bivudine with drugs that affect renal function may alter plasma concentrations of telbivudine or the coadministered drug.

Resistance to antiviral drugs for hepatitis B: There are no adequate or well-controlled studies of telbivudine in patients with lamivudine-resistant HBV infection. In cell culture, telbivudine is not active against HBV encoding amino-acid substitutions of M204I or M204V/L180M. Telbivudine retains wild-type phenotypic activity against the lamivudine resistance-associated substitution of rtM204V alone; however, the efficacy of telbivudine against HBV harboring the rtM204V mutation has not been established in clinical trials.

Studies of telbivudine in patients with adefovir-resistant HBV infection are inadequate. HBV encoding the adefovir resistance-associated substitution of rtN236T remains susceptible to telbivudine, whereas HBV encoding an A181V amino-acid substitution showed a three-fold to five-fold reduced susceptibility to telbivudine in cell culture.

Liver transplant recipients: The safety and efficacy of telbivudine in liver transplant recipients are unknown. The steady-state pharmacokinetic properties of telbivudine were not altered after multiple-dose administration in combination with cyclosporine. If telbivudine treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant agent that may affect renal function (e.g., Generic cyclosporine, drug tacrolimus), renal function should be monitored both before and during telbivudine therapy.

Dosage and Administration:

Adults and adolescents (16 years of age or older): The recommended dose of telbivudine for chronic hepatitis B is 600 mg once daily, taken orally, with or without food. The optimal duration of treatment has not been established.

Renally impaired subjects: Telbivudine may be used to treat chronic hepatitis B in patients with impaired renal function. No adjustment to the recommended dose of telbivudine is necessary in patients whose CrCl is 50 ml/minute or above. Adjustment of the dose interval is required in patients with CrCl below 50 ml/minute, including those with end-stage renal disease (ESRD) who are receiving hemodialysis. For patients with ESRD, telbivudine should be administered after hemo-dialysis. Recommendations are as follows:

• CrCl of 50 ml/minute or more: 600 mg once daily
• CrCl of 30-49 ml/minute: 600 mg once every 48 hours
• CrCl below 30 ml/minute (if not requiring dialysis): 600 mg once every 72 hours
• ESRD: 600 mg once every 96 hours

Hepatically impaired patients: No dose adjustment is needed.

Commentary: Hepatitis B is a serious disease caused by a virus that attacks the liver. HBV can cause lifelong infection, cirrhosis and scarring of the liver, liver cancer, liver failure, and death. Approximately 70,000 Americans are infected with HBV each year. In patients with chronic HBV, telbivudine can suppress the virus and alleviate liver inflammation in a fashion comparable to that of lamivudine, one of five other drugs approved to treat chronic HBV.

Telbivudine is not a cure for hepatitis B, and the long-term treatment benefits of this drug are not known. The drug did not reduce the risk of transmission of HBV to others through sexual contact or blood contamination. It was generally well tolerated, and most adverse events have been mild to moderate.

Some patients who discontinued taking telbivudine experienced a sudden and severe worsening of hepatitis B. All patients who discontinue treatment should be closely monitored for several months. Patients should stop taking telbivudine only after a careful discussion with the prescribing physician. Drugs in the same class as telbivudine can cause lactic acidosis in some patients as well as severe enlargement and accumulation of fat in the liver.