Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

Zhou, Xiao‐Jian; Fielman, B.; Lloyd, Deborah; Chao, George; Brown, Nathaniel

doi:10.1128/aac.01313-05

Cited by 37 publications

(28 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pharmacokinetic parameters of telbivudine for subjects with normal renal function in the current study are consistent with those obtained in previous single-dose studies with comparable sampling durations (5,9,11,12). This study confirms that systemic telbivudine is eliminated predominantly by renal clearance, with pharmacokinetics dependent on renal function, consistent with findings for other anti-HBV nucleoside and nucleotide analogs, including lamivudine, entecavir, and adefovir (Epivir-HBV, Baraclude, and Hepsera product information).…”

Section: Discussionsupporting

confidence: 79%

“…Telbivudine is absorbed rapidly following oral administration, reaching maximum concentrations in plasma at ϳ3 h (5,(9)(10)(11)(12). Telbivudine exhibits dose-proportional pharmacokinetics with respect to the maximum concentration of the drug in plasma (C max ) and the area under the plasma concentrationtime curve (AUC), and a biphasic plasma disposition (5,10).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

Zhou

Swan

Smith

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL CR ), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL R ), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL R and CL CR . In ESRD subjects, a routine 3.5-to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of ϳ45%, representing a ϳ23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.

show abstract

Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

Zhou

Swan

Smith

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…The steady-state exposure to telbivudine at the NOAEL and animal-to-human exposure multiples in mice, rats, rabbits, and monkeys are presented in Table 6. Human steady-state maximum concentration of drug in serum (C max ) (3.4 g/ml) and the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) (27.5 g ⅐ h/ml) were obtained from healthy subjects following 7 days of once daily oral administration of 600 mg/day of telbivudine, the approved dose for patients with chronic HBV infection (31). In repeat-dose toxicity studies, the steady-state animal-to-human exposure multiples at the NOAEL were 41, 11, and 6 times the mean human C max value and 22, 6, and 5 times the mean human AUC 0-24 value in mice, rats, and monkeys, respectively.…”

Section: Resultsmentioning

confidence: 99%

Nonclinical Safety Profile of Telbivudine, a Novel Potent Antiviral Agent for Treatment of Hepatitis B

Bridges

Selden

Luo

2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Telbivudine is a novel nucleoside drug recently approved for the treatment of patients with chronic hepatitis B. Its nonclinical safety was evaluated in a comprehensive program of studies, including safety pharmacology, acute and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. There were no test article-related effects observed in an in vitro hERG assay or in a core battery of safety pharmacology studies (central nervous system, respiratory, and cardiovascular safety pharmacology studies). Telbivudine was well tolerated in rats and in monkeys following single oral doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in monkeys and occasional incidences of emesis, soft feces, and minor changes in body weight and food consumption, there was no target organ toxicity observed in mice, rats, or monkeys following oral administration for up to 3, 6, or 9 months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a 9-month study was considered equivocal, as the role of telbivudine in the injury could not be determined. Slightly higher incidences of abortion and premature delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity. These results suggest that telbivudine has a favorable safety profile and support its use in patients with chronic compensated hepatitis B viral infection.Telbivudine (␤-L-2Ј-deoxythymidine) is the unmodified ␤-L enantiomer of the naturally occurring nucleoside thymidine (Fig. 1).Its molecular formula is C 10 H 14 N 2 O 5 with a formula weight of 242 g/mol.Nucleoside/nucleotide analogs have been proven to be effective for the treatment of hepatitis B virus (HBV) and human immunodeficiency virus. To date, four nucleoside/nucleotide analogs, lamivudine, adefovir dipivoxil, entecavir, and telbivudine, have been approved by the United States Food and Drug Administration for the treatment of HBV (16,27). These agents vary with respect to antiviral and clinical efficacy, resistance profiles, and tolerability and safety (17). A major safety concern for this class of drugs is mitochondrial toxicity, which is manifested as hepatic failure, nephrotoxicity, pancreatitis, neuropathy, myopathy, and lactic acidosis (1,2,3,5,6,8,15,18,19,22,24,29). Furthermore, emergence of drug-resistant viruses in patients undergoing long-term maintenance therapy with these drugs can result in diminished drug efficacies (9, 30).Telbivudine shows potent, selective, and specific antiviral activity against HBV and other hepadnaviruses (4, 14). Telbivudine is phosphorylated by intracellular thymidine kinases to the active triphosphate form, which has an intracellular halflife of 14 h (12, 25). Telbivudine 5Ј-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, dTTP. Incorporation of telbivudine 5Ј-triphosphate into v...

show abstract

“…The phase III clinical GLOBE trial showed that telbivudine compared with lamivudine in HBeAg-positive and -negative patients gave a higher antiviral and clinical efficacy after 2 years of treatment [89]. From a pharmacokinetic point of view, telbivudine could be combined with lamivudine or adefovir, because no drug interaction was observed [90].…”

Section: Telbivudinementioning

confidence: 99%

Antiviral treatment of chronic hepatitis B virus infections: the past, the present and the future

Férir

Kaptein

Neyts

et al. 2007

Reviews in Medical Virology

View full text Add to dashboard Cite

A decade ago, standard therapy against chronic hepatitis B virus infections only consisted of lamivudine or IFN-alpha. Treatment with lamivudine and IFN has been compounded by, respectively, the emergence of drug-resistant virus strains and the appearance of serious side effects. In the last 10 years, hepatitis B treatment has made much progress. Several treatments are now licensed for the treatment of patients with chronic hepatitis B and others are under development. Here, we provide an overview of the potential and mode of action of anti-HBV agents that are currently available, and/or may become available in the near future. Foremost among these newer compounds are adefovir dipivoxil, entecavir and telbivudine.

show abstract

Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

Cited by 37 publications

References 24 publications

Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

Nonclinical Safety Profile of Telbivudine, a Novel Potent Antiviral Agent for Treatment of Hepatitis B

Antiviral treatment of chronic hepatitis B virus infections: the past, the present and the future

Contact Info

Product

Resources

About