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Mechanism of Action

Tyzeka is an antiviral drug [see Microbiology].

Pharmacodynamics

In a randomized, partially single-blinded, placebo and active-controlled, four-period crossover study, 53 healthy subjects were administered Tyzeka 600 mg, a supratherapeutic Tyzeka 1800 mg dose, placebo, and moxifloxacin 400 mg. After 7 days of dosing, Tyzeka did not prolong the QT interval. The maximum placebo-adjusted mean (upper 1-side 95% CI) change from baseline in QTcF on day 7 were 3.4 msec (5.9 msec) for the 600 mg and 4.4 msec (6.9 msec) for the 1800 mg dosing regimens.

Pharmacokinetics in Adults

The single- and multiple-dose pharmacokinetics of Tyzeka were evaluated in healthy subjects and in patients with chronic hepatitis B. Tyzeka pharmacokinetics are similar between both populations.

Absorption and Bioavailability

Following oral administration of Tyzeka 600 mg once-daily in healthy subjects (n=12), steady state peak plasma concentration (Cmax) was 3.69 ± 1.25 μg/mL (mean ± SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1 ± 7.2 μg h/mL (mean ± SD), and trough plasma concentrations (Ctrough) were approximately 0.2-0.3 μg/mL. Steady state was achieved after approximately 5 to 7 days of once-daily administration with ~1.5-fold accumulation, suggesting an effective half-life of ~15 hours.

Effects of Food on Oral Absorption

Tyzeka absorption and exposure were unaffected when a single 600 mg dose was administered with a high-fat (~55 g), high-calorie (~950 kcal) meal. Tyzeka may be taken with or without food.

Distribution

In-vitro binding of telbivudine to human plasma proteins is low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues. Telbivudine was equally partitioned between plasma and blood cells.

Metabolism and Elimination

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

After reaching the peak concentration, plasma concentrations of Tyzeka declined in a biexponential manner with a terminal elimination half-life (T½) of 40-49 hours. Tyzeka is eliminated primarily by urinary excretion of unchanged drug. The renal clearance of Tyzeka approaches normal glomerular filtration rate suggesting that passive diffusion 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 Tyzeka. Because renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing hemodialysis require a dose regimen adjustment [see DOSAGE AND ADMINISTRATION].

Special Populations

Gender: There are no significant gender-related differences in Tyzeka pharmacokinetics.

Race: There are no significant race-related differences in Tyzeka pharmacokinetics.

Pediatrics and Geriatrics: Pharmacokinetic studies have not been conducted in children or elderly subjects.

Renal Impairment: Single-dose pharmacokinetics of Tyzeka have been evaluated in subjects (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 4, adjustment of the dose regimen for Tyzeka is recommended in patients with creatinine clearance of less than 50 mL/min [see DOSAGE AND ADMINISTRATION].

Table 4 : Pharmacokinetic Parameters (mean ± SD) of Tyzeka in Subjects with Various Degrees of Renal Function

Renally Impaired Subjects on Hemodialysis: Hemodialysis (up to 4 hours) reduces systemic Tyzeka exposure by approximately 23%. Following dose regimen adjustment for creatinine clearance [see DOSAGE AND ADMINISTRATION], no additional dose modification is necessary during routine hemodialysis. When administered on hemodialysis days, Tyzeka should be administered after hemodialysis.

Hepatic Impairment: The pharmacokinetics of Tyzeka following a single 600 mg dose have been studied in subjects (without chronic hepatitis B) with various degrees of hepatic impairment. There were no changes in Tyzeka 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.

Drug Interactions

Drug-drug interaction studies show that lamivudine, adefovir dipivoxil, cyclosporine, pegylated interferon alfa2a and tenofovir disoproxil fumarate do not alter Tyzeka pharmacokinetics. In addition, Tyzeka does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, cyclosporine, or tenofovir disoproxil fumarate. No definitive conclusion could be drawn regarding the effects of Tyzeka on the pharmacokinetics of pegylated interferon alfa-2a due to the high inter-individual variability of pegylated interferon alfa-2a concentrations. At concentrations up to 12 times that in humans, telbivudine did not inhibit in-vitro metabolism mediated by any of the following human hepatic microsomal cytochrome P450 (CYP) isoenzymes known to be involved in human medicinal product metabolism: 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4. Based on the above results and the known elimination pathway of telbivudine, the potential for CYP450-mediated interactions involving telbivudine with other medicinal products is low.

Microbiology

Mechanism of Action

Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is 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. Telbivudine is an inhibitor of both HBV first strand (EC50 value = 1.3 ± 1.6 μM) and second strand synthesis (EC50 value = 0.2 ± 0.2 μM). Telbivudine 5'-triphosphate at concentrations up to 100 μM did not inhibit human cellular DNA polymerases α, β, or γ. No appreciable mitochondrial toxicity was observed in HepG2 cells treated with telbivudine at concentrations up to 10 μM.

Antiviral Activity in Cell Culture

The antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15, as well as in primary duck hepatocytes infected with duck hepatitis B virus. The concentration of telbivudine that effectively inhibited 50% of viral DNA synthesis (EC50) in both systems was approximately 0.2 μM. The anti-HBV activity of telbivudine was additive with adefovir in cell culture, and was not antagonized by the HIV NRTIs didanosine and stavudine. Telbivudine is not active against HIV-1 (EC50 value greater than 100 μM) and was not antagonistic to the anti-HIV activity of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine. The absence of activity of telbivudine against HIV has not been evaluated in clinical trials.

Resistance

In an as-treated analysis of the Phase III global registration trial (NV-02B-007 GLOBE study), 59% (252/430) of treatment-naïve HBeAg-positive and 89% (202/227) of treatment-naïve HBeAg-negative subjects receiving Tyzeka 600 mg once daily achieved non-detectable serum HBV DNA levels (less than 300 copies/mL) by Week 52. Of those who continued treatment beyond Week 52, 58% (243/418) and 85% (190/224) of HBeAgpositive and HBeAg-negative Tyzeka recipients, respectively, had undetectable HBV DNA at Week 104 (or at the end of dosing in treatment Year 2).

The cumulative frequency of genotypic resistance (emergence of the rtM204I/V substitution) to Tyzeka based on an as-treated analysis of HBeAg-positive and HBeAg-negative subjects at Weeks 52 and 104 was 7% and 22%, respectively. Genotypic analysis of paired baseline and Tyzeka-treatment failure isolates from 182 evaluable subjects with amplifiable HBV DNA and greater than or equal to 16 weeks of treatment showed that the rtM204I/V substitution was associated with virologic failure (HBV DNA greater than or equal to 1,000 copies/mL) and virologic rebound (greater than or equal to 1 log₁₀ increase above nadir). The rtM204I substitution was the most frequent substitution, detectable in isolates from 143/182 (79%) of evaluable subjects, and was frequently found with substitutions rtL80I/V and rtL180M. The rtM204I substitution was found infrequently with rtV27A, rtL82M, rtV173L, rtT184I/S, rtA200V, rtL229F/V/W, and rtR289K substitutions. The HBV of 16 subjects developed rtA181S/T amino acid substitutions while receiving Tyzeka. Eight of these 16 subjects had outgrowth of HBV expressing an rtM204I/V substitution without the rtA181 substitution and 1 subject's HBV had both the rtM204I and rtA181T substitutions.

Subjects with higher baseline viral load had higher rates of genotypic resistance to Tyzeka, while subjects who achieved HBV DNA levels less than 300 copies/mL at Week 24 had lower rates of genotypic resistance to Tyzeka. By Week 104, 32% (95/293) of HBeAg-positive subjects with baseline viral DNA levels greater than or equal to 9 log₁₀ copies/mL developed genotypic resistance to Tyzeka, compared to 15% (20/136) of the subjects with viral DNA levels less than 9 log₁₀ copies/mL. In HBeAg-negative subjects, 17% (22/132) of the subjects with baseline viral DNA levels greater than or equal to 7 log₁₀ copies/mL developed genotypic resistance to Tyzeka, compared to 5% (5/95) of the subjects with viral DNA levels less than 7 log₁₀ copies/mL. By Week 104, 41% (97/239) of HBeAg-positive subjects who failed to achieve viral DNA levels less than 300 copies/mL at Week 24 developed genotypic resistance to Tyzeka, compared to 9% (18/190) of the subjects with non-detectable serum HBV DNA levels (less than 300 copies/mL) at Week 24. In HBeAg-negative subjects, 35% (15/43) of the subjects who failed to achieve viral DNA levels less than 300 copies/mL at Week 24 developed genotypic resistance to Tyzeka, compared to 7% (12/184) of the subjects with non-detectable serum HBV DNA levels (less than 300 copies/mL) at Week 24.

Cross-Resistance

Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, lamivudineresistant HBV strains expressing either the rtM204I substitution or the rtL180M/rtM204V double substitution had greater than or equal to 1,000-fold reduced susceptibility to telbivudine. Telbivudine retained wild-type phenotypic activity (1.2-fold reduction) against the lamivudine resistance-associated substitution rtM204V alone. The efficacy of telbivudine against HBV harboring the rtM204V substitution has not been established in clinical trials.

HBV encoding the adefovir resistance-associated substitution rtA181V showed 3- to 5-fold reduced susceptibility to telbivudine in cell culture. The rtA181S and rtA181T substitutions conferred 2.7- and 3.5-fold reductions in susceptibility to telbivudine, respectively. The rtA181T substitution is associated with decreased clinical response in patients with HBV treated with adefovir and entecavir. HBV encoding the adefovir resistance-associated substitution rtN236T remained susceptible to telbivudine.

Clinical Studies

Clinical Experience in Nucleoside-Naïve Adults

The safety and efficacy of long-term (104-week) Tyzeka treatment were evaluated in one active-controlled, clinical study (NV-02B-007 GLOBE Study) that included 1,367 subjects with chronic hepatitis B and a smaller supportive study (NV-02B-015) that included 332 subjects. Subjects were 16 years of age or older, with chronic hepatitis B, evidence of HBV infection with viral replication (HBsAg-positive, HBeAg-positive or HBeAg-negative, HBV DNA detectable by a PCR assay), and elevated ALT levels greater than or equal to 1.3 x ULN, no evidence of hepatic decompensation, and chronic inflammation on liver biopsy compatible with chronic viral hepatitis.

NV-02B-007 GLOBE Study

The Week 52 and Week 104 results of the 007 GLOBE study are summarized below.

The 007 GLOBE study was a Phase III, randomized, double-blind, multinational study of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 1,367 (n= 680 Tyzeka; n=687 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative subjects. The primary data analysis was conducted after all subjects had reached Week 52.

HBeAg-positive Subjects: (n= 458 Tyzeka; n= 463 lamivudine) The mean age of subjects was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.52 log₁₀ copies/mL; and mean serum ALT was 153 IU/L. Pre- and post-liver biopsy samples were adequate for 86% of subjects.

HBeAg-negative Subjects: (n=222 Tyzeka; n= 224 lamivudine)The mean age of subjects was 43 years, 77% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 7.54 log₁₀ copies/mL; and mean serum ALT was 140 IU/L. Pre- and post-liver biopsy samples were adequate for 92% of subjects.

Clinical Results

Clinical and virologic efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative subject populations.

The primary endpoint of Therapeutic Response at Week 52 was a composite endpoint requiring suppression of HBV DNA to less than 5 log₁₀ copies/mL in conjunction with either loss of serum HBeAg or ALT normalization. Key secondary endpoints included histologic response, ALT normalization, and measures of virologic response.

At Week 52, in HBeAg-positive patients, 75% of Tyzeka subjects and 67% of lamivudine subjects had a Therapeutic Response; in HBeAg-negative patients 75% of Tyzeka subjects and 77% of lamivudine subjects had a Therapeutic Response.

Analysis of the histological response at Week 52 is shown in Table 5.

Table 5 : Histological Improvement and Change in Ishak Fibrosis Score at Week 52 (007 GLOBE Study)

Subjects were eligible to continue blinded treatment to Week 104. In the ITT population, 624/680 (92%) Tyzeka recipients and 599/687 (87%) lamivudine recipients completed study treatment to Week 104. At Week 104, in HBeAg-positive patients, 63% of Tyzeka subjects and 48% of lamivudine subjects had a Therapeutic Response, while in HBeAg-negative patients 78% of Tyzeka subjects and 66% of lamivudine subjects had a Therapeutic Response.

Selected virologic, biochemical, and serologic outcome measures at Weeks 52 and 104 are shown in Table 6.

Table 6 : Virological, Biochemical and Serologic Endpoints at Weeks 52 and 104 (007 GLOBE Study)

Patients who achieved non-detectable HBV DNA levels at 24 weeks were more likely to undergo e-antigen seroconversion, achieve undetectable levels of HBV DNA, normalize ALT, and were less likely to develop resistance at one and two years.

Study NV-02B-015

The efficacy results of the 007 GLOBE study were supported by results of study NV-02B-015. This was a Phase III, randomized, double-blind, study of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 (n=167 Tyzeka; n=165 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese subjects. The primary efficacy endpoint was serum HBV DNA reduction from baseline. In this study the composite endpoint Therapeutic Response was a key secondary endpoint. Histological response was not assessed as an outcome measure in this study.

Clinical Results

Among HBeAg-positive subjects (n=147 Tyzeka; n=143 lamivudine) results for key endpoints at Week 104 included Therapeutic Response (66% vs. 41%), mean HBV DNA reduction (-5.47 vs. -3.97 log₁₀ copies/mL), HBV DNA PCR negativity (58% vs. 34%), ALT normalization (73% vs. 59%), HBeAg loss (40% vs. 28%) and HBeAg seroconversion (29% vs. 20%), for Tyzeka and lamivudine, respectively. Because the number of HBeAg-negative subjects in this study was small (n=42), definitive conclusions could not be drawn regarding efficacy outcomes in this subpopulation.

Last reviewed on RxList: 1/23/2012
This monograph has been modified to include the generic and brand name in many instances.