215© SEEd Tutti i diritti riservatiFarmeconomia e percorsi terapeutici 2008; 9(4) BRIEF DRUG PROFILE Address for correspondence sdp@advancedresearch.it IntroductIon Hepatitis B is the most common serious liver infection in the world, with about 350 million people who are infected with the hepatitis B virus (HBV) and about 1 million deaths annually. Hepatitis B is characterized by an acute and a chronic phase, if the subject fails to produce adequate immune response. About 5-10% of adults infected with HBV go on to develop chronic infection and become chronic carriers (CHB); moreover, the liver damage, if not stopped, continues until cirrhosis or hepatocellular carcinoma. In the natural history of HBV infection, the most important event is HBeAg seroconversion, characterized by loss of HBeAg (a specific antigen of the virus) and development of anti-HBe antibodies (HBeAg-positive patients). If the seroconversion has occurred early (when liver damage is not already significant) and is maintained, long-term prognosis is excellent. The disease can follow a more aggressive course if active viral replication persists despite anti-HBe positivity. This state, characterized by continuing viral replication, has been termed as HBeAg-negative CHB, and is the most prevalent form in Italy. At the moment, there are 4 approved antiviral drug classes, with different antiviral efficacy, for the treatment of chronic hepatitis B: interferons, nucleoside analogues, nucleotide analogues, and cyclopents. The primary target of the treatment is a prolonged suppression of viral replication, in order to avoid long term complications and increase survival. IndIcatIons and dosIng Telbivudine is a new synthetic thymidine nucleoside analogue with selective activity against HBV; it is the unmodified beta-L enantiomer of the naturally occurring nucleoside thymidine. The drug is indicated for the treatment of chronic hepatitis B in adults with compensated liver disease, evidence of active viral replication and signs of liver damage. Telbuvidine is orally administred at a once daily dose of 600 mg. Telbuvidine is currently included by AIFA (Agenzia Italiana del Farmaco) in a drug efficacy and safety monitoring program. PharmacokInetIcs Telbuvidine pharmacokinetics data are similar in healthy subjects and CHB patients; there are not significant gender- or race-related differences. Dose adjustment is recommended in patients with moderate to severe renal dysfunction and in those undergoing hemodialysis, seen the prevalently renal excretion of this substance. telbivudine (sebivo) in patients with hepatitis B virus (hBV) chronic infection Edited by AdRes Health Economics & Outcomes Research Last revision June 2008 absorption Bioavailability cmax tmax Binding to plasma proteins About 42% 3.2 ± 1.1 μg/l 3 h (1-6) 3.3 (2-5)% metabolism and distribution Volume of distribution metabolism metabolites Biological activity of metabolites 8.2 ± 4.1 l/kg - No metabolites - elimination clearance Plasma terminal half-life elimination Interactions 130 ml/min 40-49 h Primarily urinary Drugs that alter renal function table I Absorption, distribution, metabolism and elimination of telbivudine after oral administration 216 © SEEd Tutti i diritti riservati Farmeconomia e percorsi terapeutici 2008; 9(4) PharmacodynamIcs Telbuvidine is a synthetic thymidine analogue who must be activated by phosphorylation by cellular kinases; after activation, it selectively inhibits HBV polymerase (reverse transcriptase) by competing with one of its natural substrates, thymidine 5’-triphosphate. effIcacy and safety Telbivudine efficacy and safety have been tested in three phase III trials, two of them using lamivudine as comparator, and one using adefovir dipivoxil. For the main study GLOBE, the vast majority of the population enrolled was asian; only 98 caucasian patients included in the study received telbivudine. Results showed the non-inferiority of telbuvidine over lamuvidine for both HBeAg-positive and negative patients; superiority of the telbuvidine treatment is showed only in the HBeAg-positive group. Generally, telbuvidine treatment provides greater antiviral and clinical efficacy than lamuvidine, with less development of resistance. Preliminary 2-year results show that telbivudine-treated patients exhibit higher rates of maintained responses on all key efficacy measures examined in both HBeAg-positive and HBeAg-negative patients populations. Two safety events of special interest have been identified in the GLOBAL trial: ALT flares and CK elevations. The first ones are globally more frequently reported in lamivudine than in telbivudine- treated patients (13.1% vs 10.0%). CK elevations were reported with higher incidence in telbivudine treated patients: because the rise of this enzyme is related to muscular toxicity, telbivudine treatment needs a close monitoring program for muscle-related side effects. economIc eValuatIons Costs of currently approved products for the treatment of chronic hepatitis B can vary widely: factors affecting costs include the direct cost of the drug, length of treatment, and complication associated with continued therapy, like development of resistance or intolerable adverse events. study design comparator efficacy (telbivudine vs lamivudine) safety GLOBE study, 2007 1,367 chronic hepatitis B patients distinguished in HBeAg-positive and negative. Double blind, randomized 70-30%, multicenter, international phase III trial Telbivudine 600 mg daily Lamivudine 100 mg daily hBeag-positive patients (n = 921) Therapeutic response*: 75.3% vs 67.0% p = 0.0049 Histologic response**: 64.7% vs 56.3% p = 0.0105 Showed superiority to lamivudine (52 weeks) Incidence of adverse events was comparable between the two groups; AEs most commonly reported for telbivudine are infection and infestations, gastrointestinal disorders, general disorders and administration site conditions hBeag-negative patients (n = 446) Therapeutic response*: 75.2% vs 77.2% p = 0.6187 Histologic response**: 66.6% vs 66.0% p = 0.8994 Showed non-inferiority to lamivudine (52 weeks) Hou J et al., 2008 332 chronic hepatitis B patients distinguished in HBeAg-positive and negative. Double blind, randomized, multicenter, international phase III trial Telbivudine 600 mg daily Lamivudine 100 mg daily hBeag-positive patients (n = 290) Reduction of serum HBV DNA: 6.3 log 10 vs 5.5 log 10 , p < 0.001 HBV DNA polymerase chain-reaction negative: 67% vs 38%, p < 0.001 ALT normalization: 87% vs 75%, p = 0.007 Therapeutic response: 85% vs 62%, p < 0.001 HBeAg loss: 31% vs 20%, p = 0.047 HBeAg-negative patients (n = 42) Treatment effects showed similar pattern Clinical adverse events were similar in the two treatment groups Chan HL et al., 2007 135 treatment-naïve, chronic hepatitis B HBeAg-positive patients. Open- label, randomized, controlled, phase III trial (1) Telbivudine daily (52 weeks) (2) Adefovir daily (52 weeks) (3) Adefovir (24 weeks) + Telbivudine (28 weeks) hBeag-positive patients (n = 131) Reduction of serum HBV DNA: (1) 6.30 log 10 vs (2)+(3) 4.97 log 10 , p < 0.001 HBV DNA polymerase chain-reaction negative: (1) 39% vs (2)+(3) 12%, p = 0.001 Mean residual HBV DNA level: (1) 3.01 log 10 vs (2) 4.00 log 10 vs (3) 3.02 log 10 , p = 0.004 AEs were similar across groups; the most common were upper respiratory symtoms, headache, back pain, diarrhea table II Summary of main studies investigating efficacy and safety of telbivudine in hepatitis B chronic patients AEs = adverse events. * primary endpoint, defined as serum HBV DNA < 5 log 10 copies/ml associated with either HBeAg loss or ALT normalization at week 52 ** secondary endpoint, defined as at least 2-point reduction in the Knodell necroinflammatory score with no worsening in the fibrosis score 217© SEEd Tutti i diritti riservatiFarmeconomia e percorsi terapeutici 2008; 9(4) Currently there are six approved drugs for hepatitis B therapy: interferon alpha-2b, pegylated interferon alpha-2a, and four oral monotherapeutic agents (adefovir dipivoxil, entecavir, lamivudine and telbivudine). Injectable interferons and oral drugs represent two different pharmacological approaches, one based on host immunity stimulation, and the other on direct antiviral action. Furthermore, polymerase inhibitors need to be indefinitely administered since they are unable to induce a sustained response even after years of continuous administration. Costs of treatment with oral drugs represent a drastic reduction compared to subcutaneous therapy, and these treatments are also associated with a good response rate and excellent safety profile, making the overall treatment with oral drugs cost effective. The main limitation of these drugs is the emergence of resistance during the treatment: in particular patients treated with lamivudine, which is effective and not expensive, reported high resistance rates, ranging from 14-32% after 1 year of therapy to 58% with 2-3 years. In Table III we calculated the monthly pharmaceutical cost of available hepatitis B treatments in Italy: this is not to be intended as a cost-minimization analysis, but as a simple overlook of currently available treatments. Considered dosages are those derived from reference trials or from the SPCs of the products. For interferon alpha-2b, we considered a dosing of 9-10 MIU/3 times a week for HBeAg+ patients and of 5-6 MIU/3 times a week for HBeAg-, as seen in a national treatment protocol. Prices of the drugs are deduced from Informatore Farmaceutico 2008: we always considered ex-factory price. Globally, the monthly cost of telbivudine is nearly the same of entecavir (379 €), and similar to the one of adefovir; the cost of peginterferon is almost twice, and the less costly drug results lamivudine, with a monthly cost of about 54 €. Name of the Medicinal Product Sebivo Marketing Authorisation Holder Novartis Europharm LTD Active Substance Telbivudine Pharmaco-therapeutic Group Antiviral for systemic use ATC Code J05AF11 Date of issue of Marketing Authorisation valid throughout the European Union 24 April 2006 rs frequency Package Price ex-factory price monthly price** self-injectable drugs Interferon alpha-2b (HBeAg+ pts) PHT 10 MIU 3 times a week 1 vial 88.46 53.60 611.03 Interferon alpha-2b (HBeAg+ pts) PHT 18 MIU 3 times a week 1 vial 147.46 89.35 565.87 Interferon alpha-2b (HBeAg+ pts) PHT 25 MIU 3 times a week 1 vial 203.69 123.42 562.78 Interferon alpha-2b (HBeAg- pts) PHT 10 MIU 4 times a week 1 vial 88.46 88.46 353.75 Interferon alpha-2b (HBeAg- pts) PHT 18 MIU 5 times a week 1 vial 147.46 147.46 327.61 Interferon alpha-2b (HBeAg- pts) PHT 25 MIU 6 times a week 1 vial 203.69 203.69 325.82 Peginterferon alpha-2a* PHT 180 mcg 3 times a week 1 vial 321.41 194.75 778.98 oral drugs Adefovir dipivoxil* H 10 mg Daily 30 tablets 705.55 427.50 399.00 Entecavir* H 0.5 mg Daily 30 tablets 670.28 406.13 379.05 Entecavir* H 1 mg Daily 30 tablets 670.28 406.13 379.05 Lamivudine PHT 100 mg Daily 28 tablets 89.57 54.27 54.27 Lamivudine PHT 5 mg Daily Oral solution (240 ml) 38.43 23.29 54.33 Telbivudine* H 600 mg Daily 28 tablets 625.58 379.04 379.04 table III Monthly pharmaceutical costs of different available therapies for chronic hepatitis B treatments * Price neglects further negotiated discounts on supplies for NHS ** Four weeks H = hospital prontuary; PHT = hospital-territorial prontuary; pts = patients; RS = reimbursement status; MIU = million international unit 218 © SEEd Tutti i diritti riservati Farmeconomia e percorsi terapeutici 2008; 9(4) references AIFA – Agenzia Italiana del Farmaco – Elenco dei farmaci sottoposti a monitoraggio - intensivo. 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