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PHARMACOKINETICS |
From the Peking Union Medical College Hospital, Beijing, People's Republic of China (Dr Hu, Dr Jiang, Dr Wang), and Idenix Pharmaceuticals Inc, Cambridge, Massachusetts (Mr Pietropaolo, Dr Chao, Dr Brown, Dr Zhou).
Address for reprints: Xiao-Jian Zhou, PhD, Idenix Pharmaceuticals Inc, 60 Hampshire Street, Cambridge, MA 02139; e-mail: zhou.xiao-jian{at}idenix.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Telbivudine • hepatitis B • pharmacokinetics • Chinese subjects
Four agents, 
-interferon, lamivudine, adefovir dipivoxil, and entecavir, are currently approved for the treatment of chronic HBV infection; however, these agents are all associated with therapeutic limitations, including tolerability, resistance, possible nephrotoxicity, and carcinogenicity concerns, respectively.6-8 There is thus a continuous demand for new therapies with improved safety and efficacy profiles.
Telbivudine (ß-L-2'-deoxythymidine) is an oral L-nucleoside with potent and specific antiviral activity against HBV.9 Like other nucleoside analogues, telbivudine requires intracellular phosphorylation to its pharmacologically active metabolite, 5'–triphosphate, by cellular kinases. The telbivudine 5' –triphosphate inhibits HBV DNA polymerase (a reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of the 5'-triphosphorylated telbivudine into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication.9
Recent clinical trials in adults with chronic HBV infection have established that once-daily telbivudine is well tolerated by patients and exhibits dose-dependent potent antiviral activity.10-12 Pharmacokinetic studies in healthy volunteers and in patients with chronic HBV infection showed that oral telbivudine is absorbed rapidly, with maximum plasma concentrations reached within 1 to 3 hours.12-16 Telbivudine exhibits dose-proportional pharmacokinetics.12 Systemic telbivudine is primarily eliminated via the renal pathway as unchanged drug. Its renal clearance (CLR) approaches the normal glomerular filtration rate,13 suggesting that passive diffusion is the main mechanism mediating the CLR of telbivudine. Recovery within 7 days is 42.0% in urine and 49.6% in feces for a total of 91.6% of administered dose. Telbivudine is not a substrate or an inhibitor of human hepatic CYP450 isozymes. No telbivudine metabolites were detected in human plasma, urine, or feces (X. J. Zhou, B. A. Fielman-Constance, G. C. Chao, N. A. Brown, unpublished data, October 2005).
Telbivudine is currently being evaluated in phase III trials for the treatment of chronic HBV infection, including many sites in China. This open-label, randomized study was conducted to evaluate the pharmacokinetics of telbivudine after single doses ranging from 200 to 800 mg and after repeat dosing at 600 mg/d (the intended clinical dose), as well as the safety profile of telbivudine in healthy Chinese volunteers.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Design
This phase I, open-label, randomized, parallel group, dose-ranging study assessed the safety and pharmacokinetics of telbivudine in healthy Chinese subjects. The clinical phase was conducted from September 12 to 29, 2005, at the Clinical Pharmacology Research Center, Peking Union Medical College Hospital (Beijing, China). Forty-two subjects were randomized to 1 of 4 treatment groups in which they received a single oral dose of the study drug, in the form of 200-mg tablets, at 200 mg, 400 mg, 600 mg, or 800 mg on day 1. Subjects in the 600-mg dose group continued to receive the study drug daily from days 6 through 13. There were 10 subjects per dose in the 200-, 400-, and 800-mg dose groups, and 12 subjects in the 600-mg group. Subjects observed a fasting period of approximately 10 hours prior to dosing on day 1 (all dose groups) and day 13 (600-mg dose group only) and continued fasting for an additional 4 hours after dosing. Subjects in the 600-mg dose group received a light breakfast 2 hours prior to dosing on days 6 through 13.
Blood and Urine Sample Collection
Serial blood samples (5 mL at each time point) were collected into heparinized Vacutainer tubes on day 1 (all dose groups) and day 13 (600-mg dose group only) for the determination of plasma telbivudine levels at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 48, 72, 96, and 120 hours. In the 600-mg dose group, predose blood samples were obtained prior to daily dosing on days 7 through 12 for the determination of trough plasma level of telbivudine. Blood samples were centrifuged, and plasma was collected and frozen at –20°C or below until analysis.
Fractionated urine samples were collected for the measurement of telbivudine urinary excretion in the 600-mg dose group before and after dosing on day 1 over 32 hours at the following time intervals: –2 to 0 hours (predose), and 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 32 hours postdose.
Plasma and Urine Sample Analysis
All plasma and urine concentrations of telbivudine were quantitated using validated high-performance liquid chromatographic (HPLC) methodologies with tandem mass spectrometric (MS/MS) detection. Briefly, internal standard (25 ng of ß-L-2'-deoxyadenosine [LdA]) and thymidine phosphorylase (EC 2.4.2.4
[EC]
, Sigma Chemical Co, St Louis, Mo, >1 unit/µL) were added to 100 µL of calibration standards (Plasma: 10 to 5000 ng/mL; Urine: 30 to 5000 ng/mL), quality controls (QCs; Plasma QCs: 30 to 4000 ng/mL; Urine QCs: 90 to 4000 ng/mL), and unknown plasma or urine samples. The mixture was vortexed thoroughly and incubated at 37°C for 1 hour to digest any endogenous thymidine that may interfere with telbivudine assay. After incubation, acetonitrile (200 µL) was added to the plasma sample mixture to precipitate protein. Samples were then centrifuged, and the supernatant was transferred to injection vials. Following incubation, 500 µL water was added to the urine sample mixture. After vortex mixing, the urine sample mixture was loaded on a Bond–Elut C18 solid-phase extraction cartridge (100 mg/1 mL, Varian, Palo Alto, Calif) pretreated with methanol (2 x 1 mL) and water (1 mL). The loaded cartridge was washed with 1 mL water, and the eluent was discarded. The cartridge was then eluted with 2 x 1 mL of methanol and eluent was collected, evaporated to dryness at 40°C under a gentle stream of nitrogen. The residual was reconstituted in 200 µL methanol by vortex mixing for 1 minute. Extraction recovery from both matrices was near complete. Liquid chromatography was performed on a TSK-GEL Amide-80 column (4.6 x 150 mm, 5 µm; Tosoh Bioscience, Montgomeryville, Penn). For plasma extracts, elution was performed isocratically at 1 mL/min with a mobile phase of 90:10 (volume/volume [v/v]) methanol:25 mM ammonium formate (pH 3.5). Under these conditions, the retention time was approximately 1.69 and 1.74 minutes for telbivudine and LdA, respectively. For urine extracts, elution was performed isocratically at 1 mL/min with a mobile phase of 98:2 (v/v) methanol:formic acid (1%, v/v). Under these conditions, the retention time was approximately 3.80 and 4.00 minutes for telbivudine and LdA, respectively. Telbivudine and LdA were monitored using a PE Sciex API 3000 MS/MS mass analyzer at mass transition of 243.0 
127.1 mass-to-charge ratio (m/z) and 252.0 136.0 m/z, respectively. There was no interference at the specific mass transitions indicating absence of matrix effect. The mass analyzer was operated under positive mode using electrospray ionization. The plasma assay has a lower limit of quantitation of 10 ng/mL, with calibration curve ranging from 10 to 5000 ng/mL. The intra- and interday precision (percentage coefficient of variation) and accuracy (percentage deviation) were from 1.1% to 10.7% and –9.9% to 9.1%, respectively, based on plasma QC samples with spiked concentrations ranging from 30 to 4000 ng/mL. The urine assay has a lower limit of quantitation of 30 ng/mL with calibration curve ranging from 30 to 5000 ng/mL. The intra- and interday precision (percentage coefficient of variation) and accuracy (percentage deviation) were from 2.4% to 10.7% and –12.4% to 7.6%, respectively, based on urine QC samples with spiked concentrations ranging from 90 to 4000 ng/mL.
Pharmacokinetic and Statistical Analysis
Noncompartmental analysis was employed to calculate pharmacokinetic parameters. The maximum plasma drug concentration (Cmax) and time to Cmax (tmax) were directly obtained from the plasma concentration-time profiles. The terminal-phase elimination half-life (t
z) was calculated as 0.693/
z, where z is the slope of the apparent elimination phase of the natural logarithmic (ln) transformation of plasma drug concentration time curve estimated using liner regression. Area under the plasma concentration time curve from time zero to t (AUC0-t), where t is the time of last measurable sample, was calculated according to the linear trapezoidal rule. The AUC from time zero to infinity (AUC0-
) was estimated as AUC0-t + Ct/z, where Ct is the plasma concentration of the last measurable sample. The steady-state AUC (AUCss) over the dosing interval (
= 24 hours) was also calculated. Apparent total clearance (CL/F) was calculated as Dose/AUC0- or Dose/AUCss, and apparent total volume of distribution (Vz/F) as CL/z. Renal clearance was estimated as Au0-t/AUC0-t, where Au0-t was the cumulative amount of drug excreted in urine from time zero to t (32 hours) and AUC0-t was area under the plasma concentration–time curve over the same time interval.
Attainment of steady-state telbivudine by day 10 after 5 consecutive daily doses in the 600-mg group was evaluated by regressing the ln transformation of trough concentrations over time for days 7 through 10. Steady state was concluded if the slope was not statistically different from zero.
Safety Analysis
Safety and tolerability were evaluated through adverse event reporting by the investigators and subjects, on the basis of clinical laboratory measurements (blood chemistry, hematology, urinalysis, and liver functions), 12-lead ECG, physical examination, and vital signs. Adverse events were assessed by the investigators with regard to severity (mild, moderate, severe, and life-threatening) and by relationship to study treatment (reasonably or possibly related, not reasonably or possibly related).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetics
Mean (SD) plasma concentration–time curves after oral administration of a single dose of 200, 400, 600, or 800 mg, as well as multiple doses of 600 mg/d telbivudine are depicted in Figure 1, and pharmacokinetic parameters are shown in Table II. Telbivudine was absorbed quickly, with plasma Cmax reached at a median tmax of 2.0 to 2.5 hours across all dose cohorts. Mean Cmax increased from 1.8 µg/mL for the 200-mg dose to 3.7 µg/mL for the 600-mg dose. Mean Cmax for the 800-mg dose was 3.5 µg/mL, comparable to that of the 600-mg dose. By contrast, mean C24h increased in the full dose range from 56.6 ng/mL for the 200-mg dose to 137.0 ng/mL for the 800-mg dose. Similarly, total systemic exposure also increased in the full dose range: mean AUC0- was 12.8, 22.9, 26.4, and 28.8 for the 200-, 400-, 600-, and 800-mg dose cohorts, respectively. AUC0-24h represented, on average, 80% to 85% of AUC0-t and AUC0-. The telbivudine plasma concentrations at this time point represented only about 4% of Cmax. After reaching peak exposure, the disappearance of telbivudine from plasma was biphasic, with terminal elimination phase starting at a median time of 32 hours after dosing (range 20 to 48 hours). The mean terminal phase tz was 43.3, 49.1, 39.4, and 46.7 hours for the 200-, 400-, 600-, and 800-mg single dose, respectively, and was independent of administered doses. Mean oral apparent total plasma clearance (CL/F) and Vz/F were 16.3 L/h and 1305.9 L, 18.3 L/h and 1291.4 L, 24.8 L/h and 1344.0 L/h, and 29.7 L/h and 2144.3 L after a single telbivudine dose of 200, 400, 600, and 800 mg, respectively.
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Subjects in the 600-mg dose group received 8 additional once-daily consecutive telbivudine doses from days 6 through 13. Regression analysis of the ln transformation of Ctrough over time ascertained attainment of steady state on day 10 after 5 consecutive doses in 11 of the 12 subjects and on day 11 in 1 subject (slope ranged from –0.09 to 0.11, and P from .18 to .88). Mean ± SD Ctrough was 242.4 ± 73.5, 279.6 ± 98.2, 278.4 ± 119.2, and 252.7 ± 74.0 ng/mL on days 10, 11, 12, and 13, respectively. Telbivudine accumulated slightly following repeat dosing in the 600-mg dose group, with a steady state–to–single dose ratio of 1.23 based on AUCss/AUC0-24h and 1.41 based on AUC0-t. The steady state–to–single dose ratio of Ctrough/C24h was 2.23. The mean Cmax after repeat dosing of 600 mg/d was 3.7 µg/mL reached at a median tmax of 2.0 hours, identical to the single-dose values. The mean AUCss after repeat dosing of 600 mg/d was 26.1 µg·h/mL, comparable to the single-dose AUC0-. The mean tz was 48.8 hours, also similar to the single-dose results.
Following the single dose on day 1 in the 600-mg group, fractionated urine samples were collected over a period of 32 hours. Cumulative urinary excretion over the collection interval was 146.4 ± 49.8 mg, representing 24.4% of the administered dose. The mean estimated CLR of telbivudine was 6.6 ± 1.5 L/h (range, 4.6-9.5 L/h).
Safety Analysis
There were no serious adverse events reported in this study and no subjects discontinued because of adverse events. Fifteen treatment-emergent adverse events were reported by 8 (19%) of the 42 subjects during the trial. Clinical adverse events included dizziness, fatigue, and muscle strain. Eleven of the reported adverse events were changes in clinical laboratory values (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and blood cell counts). An increase in ALT was the adverse event noted in the greatest number of subjects (4 subjects, 9.5%), followed by increases in AST (3 subjects, 7.1%) and fatigue (2 subjects, 4.8%). Increases in liver enzymes were low in magnitude (within 1.5 x the upper limit of the normal range) and did not appear to be dose related. All adverse events were mild in intensity; 8 events (53%) were considered reasonably or possibly related to the study drug by the investigator. There were no clinically meaningful changes from baseline in clinical laboratory results, vital sign assessments, or physical examination results after dosing.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In a phase I/IIa dose-escalation trial in HBV-infected patients of primarily Chinese ethnicity, telbivudine has been shown to be well tolerated at doses from 25 to 800 mg/d for 4 weeks and to exhibit dose-related reductions in serum HBV DNA with near maximum suppression observed in the dose range of 400 to 800 mg/d.10,12 The long-term safety, tolerability, and anti-HBV efficacy of telbivudine 400 and 600 mg/d has further been demonstrated in a more recently completed international phase IIb trial that also enrolled a high proportion of Chinese patients.11 Dose-response and safety data from these studies led to the selection of 600 mg/d as the intended clinical dose of telbivudine. This dose is currently under evaluation in international multicenter pivotal phase III clinical trials including those underway in China.
Safety and efficacy data of telbivudine to date therefore fully supported the dose selection as well as the parallel dosing scheme without escalation used in the current study. The doses of 200 mg, 400 mg, 600 mg, and 800 mg in this trial allowed for a comprehensive characterization of the pharmacokinetics of telbivudine in healthy Chinese volunteers and comparison with historical pharmacokinetic and safety data from trials in healthy subjects and in patients with chronic HBV conducted outside mainland China.
The present study demonstrates that the single- and multiple-dose pharmacokinetic parameters of telbivudine in healthy Chinese subjects are similar to those found in previous phase I studies that primarily enrolled subjects of other ethnicities. For comparison purpose, historical data of telbivudine plasma exposure are summarized in Table III. In the current study, after a single oral dose, telbivudine was quickly absorbed reaching peak plasma level within 2.0 to 2.5 hours (medians) after dosing across all doses, similar to median values from 1 to 3 hours from other studies in HBV-infected patients and healthy subjects.12-16 In the 200- to 800-mg dose range, mean single-dose Cmax and AUC0-24h, were 1.8 to 3.5 µg/mL and 10.3 to 23.4 µg·h/mL, respectively, in healthy Chinese subjects versus mean values of 1.0 to 4.2 µg/mL for Cmax and 5.0 to 26.6 µg·h/mL for AUC0-24h in previous studies12-16 (X. J. Zhou, D. Frank, L. Deborah, B. Fielman-Constance, G. C. Chao, N. A. Brown, unpublished data, October 2005). Similarly, the mean steady-state Cmax and AUCss after repeat dosing of 600 mg/d was 3.7 µg/mL and 26.1 µg·h/mL, respectively, in this study, comparable to mean values from 2.2 to 3.7 µg/mL for Cmax and 16.5 to 29.0 µg·h/mL for AUCss in previous studies12,14,16 (X. J. Zhou, D. Frank, L. Deborah, B. Fielman-Constance, G. C. Chao, N. A. Brown, unpublished data, October 2005).
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In the current study, the single-dose plasma exposure of telbivudine increased with increasing dose but became less than dose-proportional in the 600- to 800-mg dose range, resulting in an apparent increase in plasma clearance as dose increased. Although the origin of this observation is not clear, it is unlikely a result of saturable absorption. In a phase I/IIa dose-escalation study conducted in HBV-infected patients, mostly of Chinese ethnicity, telbivudine exhibited dose-proportional single-dose and steady-state pharmacokinetics in terms of Cmax and AUC over the dose range of 25 to 800 mg.12 The telbivudine dose proportionality was further confirmed in a healthy subject study in which subjects received multiple doses of telbivudine at 600 mg/d (N = 57) and 1800 mg/d (N = 55). Plasma exposure of telbivudine was dose proportional with a 3-fold increase in Cmax and AUCss when dose tripled from 600 mg to 1800 mg, the highest dose so far studied (X. J. Zhou, S. I. Harris, G. C. Chao, C. Rossi, D. Frank, B. A. Fielman-Constance, N. A. Brown, unpublished data, December 2005). Collectively, these data strongly suggest that oral absorption of telbivudine is not a saturable process within the dose range studied (25 to 1800 mg).
After reaching peak exposure, the disposition of telbivudine was biphasic. Plasma levels fell to approximately 4% of Cmax 24 hours after dosing. Accordingly, plasma exposure beyond 24 hours contributed only about 15% to 20% to total AUC. These results suggest that a sampling period of 24 hours is adequate for assessing plasma exposure of telbivudine, although a longer sampling period would be needed for characterizing the true terminal phase. In the current study, plasma samples were collected over a period of 120 hours, thus allowing a thorough characterization of the terminal elimination phase. Mean tz ranged from 39.4 to 49.1 hours as estimated based on terminal phase starting at a median time of 32 hours. The estimate of terminal half-life (t) in healthy Chinese subjects was similar to mean values from 41.4 to 43.8 hours (N = 30) in studies with comparable sampling intervals from 120 to 168 hours (X. J. Zhou, G. Dubuc-Patrick, L. Deborah, G. C. Chao, N. A. Brown, unpublished data, November 2005). After repeat dosing with 600 mg/d, the telbivudine half-life and oral clearance remained unchanged, suggesting that the disposition of telbivudine is time independent.
The long plasma half-life results in a slight accumulation after once-daily dosing. The accumulation index was approximately 1.23 to 1.41 based on AUC and 2.23 based on Ctrough in healthy Chinese subjects receiving repeat 600 mg/d telbivudine dose for 8 consecutive days. Steady state was reached after 5 to 6 days of dosing in Chinese subjects, being in the range of 5 to 7 days found in other studies involving repeat daily doses of telbivudine at 200, 600, and 800 mg/d14,16 (X. J. Zhou, D. Frank, B. A. Fielman-Constance, G. C. Chao, N. A. Brown, unpublished data, November 2005). The slight accumulation resulted in sustained plasma exposure upon daily dosing. With the intended clinical dose regimen of 600 mg/d, mean steady-state trough level was 252.7 ng/mL in healthy Chinese subjects, comparable to a mean of approximately 300 ng/mL observed in other studies (X. J. Zhou, D. Frank, B. A. Fielman-Constance, G. C. Chao, N. A. Brown, unpublished data, Novemer 2005). Because telbivudine exhibits a low binding to plasma protein (
3.3%, E. Bridges,unpublished data, November 2005), the trough levels of unbound telbivudine are therefore consistently above the in vitro concentration inhibiting 50% of viral replication (IC50) of 48 ng/mL in inhibiting HBV replication observed in the 2.2.15 cell line9 and are expected to exert continuous suppression in HBV-infected patients.
After a single oral dose of 600 mg in healthy Chinese subjects, telbivudine exhibited a mean CLR of 6.6 L/h or 110 mL/min. The latter is consistent with data reported from previous studies in healthy volunteers of mostly white and black ethnicities with mean CLR ranging from 7.6 to 10.3 L/h13 (X. J. Zhou, G. Dubuc-Patrick, L. Deborah, G. C. Chao, N. A. Brown, unpublished data, November 2005).
Telbivudine was well tolerated in this population of healthy Chinese subjects. The nature and frequency of adverse events in healthy Chinese subjects were comparable to those previously reported in other phase I studies of telbivudine.
In summary, results from this study demonstrated that the single-dose and steady-state telbivudine pharmacokinetics and safety profile in healthy Chinese subjects were comparable to those obtained from phase I studies conducted outside of China that encompassed a wide cohort of ethnic groups, which is indicative of a lack of ethnic sensitivity in telbivudine pharmacokinetics and tolerability. The absence of ethnic sensitivity in the pharmacokinetics of telbivudine observed in this study has further been confirmed by population pharmacokinetic analyses using pooled data from various ethnic groups including mainly white, black, Hispanic/Latino, and Asian (X-J. Zhou, H. S. Pentikis, G. C. Chao, N. A. Brown, unpublished results, December 2005). Finally, although it is unknown whether genetic differences in cellular kinases among the populations might result in differences in intracellular phosphorylation, recent data from a large global phase III trial of telbivudine showed consistent pharmacodynamic responses among ethnic groups with respect to reduction in serum HBV DNA and undetectability by polymerase chain reaction, suggesting absence of ethnic sensitivity in antiviral activity of telbivudine.17
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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