Tyzeka

CLINICAL PHARMACOLOGY

Mechanism of Action

Tyzeka is an antiviral drug [see Microbiology].

Pharmacodynamics

In a randomized, partially single-blinded, placebo and active-controlled, four-period crossover trial, 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 microgram per mL (mean ± SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1 ± 7.2 microgram * hour per mL (mean ± SD), and trough plasma concentrations (Ctrough) were approximately 0.2-0.3 microgram per 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 per min [see DOSAGE AND ADMINISTRATION].

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

  Renal Function (Creatinine Clearance in mL/min
Normal (greater than 80)
(n=8) 600 mg
Mild (50-80) (n=8) 600 mg
(n=6) 200 mg
Moderate (30-49)
(n=8) 400 mg
Severe (less than 30) ESRD/Hemodialysis
(n=6) 200 mg
Cmax (μg/mL) 3.4 ± 0.9 3.2 ± 0.9 2.8 ± 1.3 1.6 ± 0.8 2.1 ± 0.9
AUC0-INF (μg•hr/mL) 28.5 ± 9.6 32.5 ± 10.1 36.0 ± 13.2 32.5 ± 13.2 67.4 ± 36.9
CLRENAL (L/hr) 7.6 ± 2.9 5.0 ± 1.2 2.6 ± 1.2 0.7 ± 0.4  

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 micromolar) and second strand synthesis (EC50 value = 0.2 ± 0.2 micromolar). Telbivudine 5'-triphosphate at concentrations up to 100 micromolar 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 micromolar.

Antiviral Activity

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 micromolar. 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 was not antagonistic to the anti-HIV activity of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine. Transient reductions in HIV-1 RNA have been seen in some patients after administration of telbivudine in the absence of antiretroviral therapy. The clinical significance of these reductions has not been determined.

Resistance

Trial NV-02B-007 (007 GLOBE)

In an as-treated analysis of the Phase III global registration trial, 59% (251/429) of treatment-na´ve HBeAg-positive and 89% (202/227) of treatment-na´ve HBeAg-negative subjects receiving Tyzeka 600 mg once daily achieved undetectable serum HBV DNA levels (less than 300 copies per mL) by Week 52. Of those who continued treatment beyond Week 52, 58% (243/418) and 85% (190/224) of HBeAg-positive and HBeAg-negative Tyzeka recipients, respectively, had undetectable HBV DNA at Week 104 (or at the end of dosing in treatment Year 2).

Genotypic analysis of paired baseline and treatment failure isolates from 181 evaluable subjects with amplifiable HBV DNA and greater than or equal to 16 weeks of Tyzeka treatment showed that the rtM204I/V substitution was associated with virologic failure (HBV DNA greater than or equal to 1,000 copies per mL) and virologic rebound (HBV DNA greater than or equal to 1 log10 increase above nadir). The rtM204I/V substitution was detectable in isolates from 78% (142/181) of evaluable subjects, and was frequently found with substitutions rtL80I/V and rtL180M. The rtM204I/V 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.

Trial CLDT600A2303

After 2 years of Tyzeka monotherapy in the 007 GLOBE trial, 77% (505/656) of subjects entered the open-label CLDT600A2303 extension trial to continue Tyzeka for up to 2 additional years, including 349 subjects who had undetectable levels of HBV DNA and 156 subjects who were viremic at entry. The rtM204I/V substitution was detectable in the virus from 83% (39/47) of the subjects losing viral suppression and having evaluable genotypic data. Of evaluable viremic subjects entering the extension, 25/33 (76%) developed rtM204I/V substitutions. Overall, 64 subjects developed genotypic resistance to Tyzeka with evidence of emerging rtM204I/V substitutions during the 2 years of Tyzeka treatment in this extension trial.

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 per mL at Week 24 had lower rates of genotypic resistance to Tyzeka. The cumulative frequency of genotypic resistance (emergence of the rtM204I/V substitution) to Tyzeka in nucleos(t)ide treatment-na´ve subjects was 7% and 22% at Weeks 52 and 104 of the controlled 007 GLOBE trial, and 30% and 35% at Weeks 156 and 208 of the open-label extension trial (CLDT600A2303), respectively (Table 5).

One-hundred-sixty-seven subjects (25% of those in the 007 GLOBE trial) were treated with Tyzeka according to current dosing recommendations [see INDICATIONS AND USAGE]. Eighty-four percent (140/167) of these subjects qualified at 24 weeks for continued Tyzeka treatment (HBV DNA less than 300 copies per mL). Retrospective calculation of the cumulative rate of genotypic resistance to Tyzeka for this subgroup of subjects was 0%, 3%, 12%, and 16% at Weeks 52, 104, 156, and 208, respectively (Table 5).

Table 5 : Cumulative Rates of Genotypic Resistance to Tyzeka through Week 208

Trial   Cumulative genotypic resistance rate1
Overall study population Subjects treated with Tyzeka according to current dosing recommendations2
NV-02B-007 (007 GLOBE trial) Week 52 7% 0%
Week 104 22% 3%
CLDT600A2303 (104-week extension trial) Week 156 30% 12%
Week 208 35% 16%
1The cumulative rates of genotypic resistance to Tyzeka were calculated using the formula previously described by Pawlotsky et al. (2008).
2Tyzeka dosing recommendations are provided in this Package Insert [see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION].

Cross-Resistance

Cross-resistance has been observed among HBV nucleos(t)ide 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 HBV expressing rtM204V alone. Most subjects (92%, 155/169) whose virus developed lamivudine resistance-associated substitutions (rtM204I/V) during 2 years of lamivudine treatment in the 007 GLOBE trial remained viremic (HBV DNA greater than 300 copies per mL) after up to 2 years of Tyzeka monotherapy in the CLDT600A2303 extension trial, including 91% (50/55) of the subjects with the rtM204V substitution.

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 subjects 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-Na´ve Adults

The safety and efficacy of long-term (104-week) Tyzeka treatment were evaluated in one active-controlled, clinical trial (NV-02B-007 GLOBE Trial) that included 1,367 subjects with chronic hepatitis B and a smaller supportive trial (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 Trial

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

The 007 GLOBE trial was a Phase III, randomized, double-blind, multinational trial 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-na´ve 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 per mL; and mean serum ALT was 153 IU per 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 per mL; and mean serum ALT was 140 IU per 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 per 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 subjects, 75% of Tyzeka subjects and 67% of lamivudine subjects had a Therapeutic Response; in HBeAg-negative subjects, 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 6.

Table 6 : Histological Improvement and Change in Ishak Fibrosis Score at Week 52 (007 GLOBE Trial)

  HBeAg-positive (n=797) HBeAg-negative (n=417)
Tyzeka 600 mg
(n=399)1
Lamivudine 100 mg
(n=398)1
Tyzeka 600 mg
(n=205)1
Lamivudine 100 mg
(n=212)1
Histologic Response2
Improvement 69% 60% 69% 68%
No Improvement 19% 26% 23% 25%
Missing Week 52 Biopsy 12% 15% 8% 7%
Ishak Fibrosis Score3
Improvement 41% 46% 48% 44%
No Change 39% 32% 34% 43%
Worsening 9% 7% 10% 5%
Missing Week 52 Biopsy 12% 15% 8% 7%
1Subjects with greater than or equal to one dose of trial drug with evaluable baseline liver biopsies and baseline Knodell Necroinflammatory Score greater than or equal to 2
2Histologic Response defined as greater than or equal to 2 point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score
3For Ishak Fibrosis Score, improvement defined as greater than or equal to a 1-point reduction in Ishak Fibrosis Score from baseline to Week 52

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 trial treatment to Week 104. At Week 104, in HBeAg-positive subjects, 63% of Tyzeka subjects and 48% of lamivudine subjects had a Therapeutic Response, while in HBeAg-negative subjects 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 7.

Table 7 : Virological, Biochemical and Serologic Endpoints at Weeks 52 and 104 (007 GLOBE Trial)

Response Parameter HBeAg-positive
(n=921)
HBeAg-negative
(n=446)
Tyzeka 600 mg
(n=458)
Lamivudine 100 mg
(n=463)
Tyzeka 600 mg
(n=222)
Lamivudine 100 mg
(n=224)
Week 52 Week 104 Week 52 Week 104 Week 52 Week 104 Week 52 Week 104
Mean HBV DNA Reduction from Baseline (log10 copies/mL) ± SEM1 -6.45 (0.11) -5.74 (0.15) -5.54 (0.11) -4.42 (0.15) -5.23 (0.13) -5.00 (0.15) -4.40 (0.13) -4.17 (0.16)
% Subjects HBV DNA undetectable by PCR 60% 56% 40% 39% 88% 82% 71% 57%
ALT Normalization2 77% 70% 75% 62% 74% 78% 79% 70%
HBeAg Seroconversion3 23% 30% 22% 25% NA NA NA NA
HBeAg Loss3 26% 35% 23% 29% NA NA NA NA
1Roche COBAS Amplicor® Assay (LLOQ less than or equal to 300 copies/mL).
2ALT normalization assessed only in subjects with ALT greater than ULN at baseline.
3HBeAg seroconversion and loss assessed only in subjects with detectable HBeAg at baseline.

Subjects 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.

NV-02B-015 Trial

The efficacy results of the 007 GLOBE trial were supported by results of trial NV-02B-015. This was a Phase III, randomized, double-blind, trial 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-na´ve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese subjects. The primary efficacy endpoint was serum HBV DNA reduction from baseline. In this trial, the composite endpoint Therapeutic Response was a key secondary endpoint. Histological response was not assessed as an outcome measure in this trial.

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 per 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 trial was small (n=42), definitive conclusions could not be drawn regarding efficacy outcomes in this subpopulation.

Last reviewed on RxList: 2/19/2013
This monograph has been modified to include the generic and brand name in many instances.

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