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PHARMACOKINETICS |
From Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey (Mr Bifano, Mr Olsen, Dr Smith, Dr Zhang, Dr Grasela, Dr LaCreta) and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Yan).
Address for reprints: Marc Bifano, MS, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543-4000; e-mail: marc.bifano{at}bms.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Entecavir • pharmacokinetics • healthy subject
Five drugs are currently available for the treatment of chronic hepatitis B: interferon 
-2a, lamivudine, pegylated interferon -2a, adefovir dipivoxil, and entecavir. Interferon -2a is effective in only 30% to 40% of patients and is associated with a high incidence of adverse events.3,4 Lamivudine and adefovir dipivoxil allow for more convenient once-daily oral dosing. However, the use of lamivudine is limited by the emergence of lamivudine-resistant HBV mutants, which occur in up to 70% of patients after 4 years of treatment.5-7 Discontinuation of lamivudine therapy has been occasionally associated with fatal hepatic flare.8 Although adefovir-resistant HBV mutants emerge less frequently than lamivudine-resistant HBV mutants, resistance to adefovir develops in up to 3.0% of HBeAg-positive patients after 3 years of treatment9 and 29% of HBeAg-negative patients after 5 years of treatment.10 Hepatic flares are also a concern with adefovir, occurring in up to 25% of patients following discontinuation of therapy.11
Entecavir is a novel, guanosine analogue with potent and selective activity against HBV DNA polymerase.12,13 It was recently approved by the US Food and Drug Administration (FDA) and regulatory agencies in other countries for the treatment of chronic hepatitis B in adults, based on the findings of 3 pivotal phase III clinical trials; 2 in nucleoside-naïve patients and 1 in lamivudine-refractory patients. In the 2 trials conducted in nucleoside-naïve patients, entecavir 0.5 mg once daily resulted in superior 48-week histologic improvement, virologic response, and alanine aminotransferase (ALT) normalization compared to lamivudine 100 mg once daily and demonstrated a similar safety profile, in both HBeAg-positive and HBeAg-negative patients.14,15 In lamivudine-refractory patients, switching from lamivudine to entecavir 1 mg once daily provided superior 48-week histologic improvement, virologic response, and ALT normalization with a comparable safety profile as lamivudine.16
The selection of entecavir doses for study in phase III clinical trials was based on a prospective evaluation of data from in vitro, animal model, clinical pharmacology, and clinical development studies.17
Two multiple ascending dose studies were conducted during the clinical development of entecavir. The first was conducted at higher doses (data not published) prior to the phase II studies. The second study (the current study) was conducted after the completion of the phase II program. The phase II data suggested that entecavir daily oral doses for the phase III trials should be 0.5 mg for nucleoside-naïve patients and 1 mg for lamivudine-refractory patients.17 Therefore, the present study was performed to evaluate the pharmacokinetics, safety, and tolerability of entecavir at clinical relevant doses of 0.1, 0.5, or 1 mg daily for a period of 14 days.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Specific exclusion criteria included a history or current evidence of any significant acute or chronic illness, current or recent (within 3 months) history of gastrointestinal disease, any major surgery within 4 weeks of enrollment, a history of any gastrointestinal surgery that could influence drug absorption, blood transfusion within 4 weeks of enrollment, and a history of recent (within 6 months) drug or alcohol abuse. Subjects who tested positive on blood screening for hepatitis B surface antigen or hepatitis C antibody or on urine screening for drugs of abuse were also excluded.
Subjects were deemed ineligible for enrollment if they had been exposed to any investigational drug or placebo within 4 weeks of enrollment, used any prescription drugs or over-the-counter acid controllers within 4 weeks prior to enrollment, or used any other drugs (including over-the-counter medications and herbal preparations) within 1 week prior to enrollment.
Study Design
This was a randomized, double-blind, placebo-controlled, dose-escalation study in healthy adult subjects. Subjects were screened during the 21 days prior to receiving their first dose of study drug and were admitted to the clinical unit the evening prior to dosing. Eight subjects were assigned to each of 3 sequential dose panels (0.1 mg, 0.5 mg, or 1 mg) and were randomized in a 3:1 ratio to receive entecavir or matching placebo. On days 1 to 14, after fasting for at least 8 hours, each subject received a single oral dose of either entecavir (n = 6) or placebo (n = 2). The subjects were confined to the clinical unit for at least 7 days after their last dose of study drug (day 21) and were discharged from the study 14 days after their last dose of study drug (day 28). Dose escalation was implemented only after the safety data, collected on day 7 (in at least 6 of these 8 subjects), showed that the prior dose was safe and well tolerated.
During the treatment phase of the study (days 1 to 14), the subjects fasted (ate or drank nothing except water) for at least 8 hours prior to dosing. On the days when serial pharmacokinetic sampling was performed (days 1, 7, and 14), the subjects continued to fast until 4 hours after study drug administration but drank 240 mL water within 1 hour of dosing to promote urine production and thereafter consumed water ad libitum. On the days when serial pharmacokinetic sampling was not performed (days 2-6 and 8-13), the subjects continued to fast until 2 hours after study drug administration but were allowed water ad libitum. Every day during the treatment phase, the subjects were served lunch, dinner, and a snack at 4, 8, and 12 hours postdose, respectively. The food content of the lunches was standardized, but that for the dinners and snacks varied.
Blood samples (5 mL) were collected for the assessment of plasma entecavir concentrations on days 1, 7, and 14 immediately prior to dosing and at 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, and 24 hours after dosing. The 24-hour samples were taken prior to taking the next day's dose and were considered the trough blood samples for the mornings of days 2, 8, and 15. Trough blood samples were also collected immediately before dosing on the mornings of days 3, 4, 5, 6, 9, 10, 11, 12, and 13. Following the last dose on day 14, blood samples were also collected at 36, 48, 72, 96, 120, 144, 168, and 336 hours after dosing. Each blood sample was collected into a labeled tube containing tripotassium EDTA as the anticoagulant.
Urine was collected for the assessment of urinary entecavir concentrations on days 1, 7, and 14, over the periods of 0 to 3, 3 to 6, 6 to 12, and 12 to 24 hours postdose. A predose urine sample was also collected on day 1.
The subjects were not permitted to consume alcohol-containing beverages or grapefruit-containing products within 3 days of dosing and until discharge from the study. In addition, they were not permitted to take any medications (including over-the-counter medications and herbal preparations), smoke, or engage in strenuous exercise, contact sports, or sun-bathing, for the duration of the study.
The study protocol was approved by the Institutional Review Board of Robert Wood Johnson University, One Hamilton Place, Hamilton, New Jersey, and conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.
Sample Analysis
Within 60 minutes of collection, blood samples were centrifuged, and the plasma was transferred to screw-capped polypropylene tubes and stored at -20°C until assayed. One 10- to 14-mL aliquot of each urine sample was transferred to labeled screw-capped polypropylene tubes and stored at -20°C until analysis. Stability of entecavir was tested in the plasma and urine samples under the storage condition used in the study. Entecavir was found to be stable in plasma and urine during storage at -20°C for the entire storage period and following 3 freeze-thaw cycles.
Plasma samples from the study were assayed for entecavir by a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Plasma samples (1 mL each) were processed using an Oasis HLB 96-well extraction plate with a robotic liquid handling system. Study samples, quality control samples, and calibration standards were loaded into the extraction plate wells followed by the internal standard (lobucavir) in water. Vacuum was subsequently applied to draw the liquid through, whereas entecavir and internal standard were retained. The wells were then washed with water, and the analytes were eluted with methanol to a clean collection plate. The wells of the collection plate were subsequently dried under nitrogen flow, and the resulting residues reconstituted in water. The plate was vortexed, and the samples were filtered and transferred to an autosampler for injection. Chromatographic separation was achieved with gradient elution on a Waters Xterra MS C18 analytical column (2.1 x 50 mm, 5 µ; Waters Corp, Milford, Mass). The mobile phases contained 5 mM ammonium bicarbonate and 0.15% NH4OH; mobile phase A was prepared in water, and mobile phase B was prepared in 90% methanol. The analytes were detected by positive ion electrospray tandem mass spectrometry on a Sciex API-3000 LC/MS instrument (Sciex, Foster City, Calif). The electrospray positive ion first quadrupole mass spectrum of each compound was dominated by the respective [M+H]+ ion: mass-to-charge ratio (m/z) 278 for entecavir and m/z 266 for the internal standard. For selected reaction monitoring, the transitions monitored were m/z 278 to m/z 152 for entecavir and m/z 266 to m/z 152 for the internal standard. The following gradient was used with the flow rate of 0.3 mL/min: 0 to 0.5 minutes at 100% A, followed by linear gradient to increase percentage of B from 0% to 60% in 2 minutes; the percentage of B was then decreased from 60% to 0% in 0.01 minute, followed by 100% A for 2.49 minutes, with a total run time of 5 minutes. The standard curves, which ranged from 0.005 to 25 ng/mL for entecavir, were fitted to a 1/x weighted quadratic regression model.
Urine samples from the study were assayed for entecavir by a validated LC/MS/MS method. Urine samples (0.4 mL each) were prepared using a 3M C18 96-well extraction plate with a robotic liquid handling system. After spiking internal standard to each study, quality control, and calibration standard samples, the samples were loaded on to the extraction plate, and vacuum was subsequently applied to draw the liquid through, whereas entecavir and internal standard were retained. The extraction wells were washed with water, and the analytes were eluted with methanol into a clean collection plate. The wells of the collection plate were subsequently dried under nitrogen flow, and the resulting residues reconstituted in water. The plate was vortexed and centrifuged before the samples were transferred to an autosampler for injection. Chromatographic separation was achieved with a binary gradient elution on a Waters Xterra MS C18 analytical column (2.1 x 50 mm, 5 µ; Waters Corp). The mobile phases contained 0.1% formic acid; mobile phase A was prepared in water, and mobile phase B was prepared in 100% acetonitrile. The analytes were detected by positive ion electrospray tandem mass spectrometry on a Sciex API-3000 LC/MS instrument. The electrospray positive ion first quadrupole mass spectrum and the selected reaction monitoring (the transitions) for urine samples were the same as the plasma samples for both entecavir and the internal standard. The following gradient was used with the flow rate of 0.3 mL/min: 0 to 0.5 minutes at 100% A, followed by linear gradient to increase percentage of B from 0% to 20% in 2 minutes, which was held for 0.5 minutes; the percentage of B was then increased from 20% to 80% in 0.01 minute; 80% B was held for 0.5 minutes, followed by decreasing the percentage of B from 80% to 0% in 0.01 minute; 100% A was then maintained for the rest of total run time of 5 minutes. The standard curves, which ranged from 0.25 to 500 ng/mL for entecavir, were fitted to a 1/x weighted quadratic regression model.
The acceptance criteria established for analytical runs of both plasma and urine samples were as follows: (1) the predicted concentrations of at least three fourths of the standards shall be within ±15% of their individual nominal concentration values; (2) at least 1 replicate of the lowest concentration in the standard curve shall be within ±20% of the nominal concentration for that level to be qualified as the lower limit of quantitation (LLQ), otherwise the next level is subject to the same test and the LLQ raised accordingly; and (3) the predicted concentrations of at least two thirds of the quality control samples shall be within ±15% of their individual nominal concentration values with at least 1 from each concentration level meeting the acceptance criteria.
Plasma samples from the study were analyzed for entecavir in a total of 20 analytical runs that met the previously established acceptance criteria. Values for between-run and within-run precision for analytical quality control samples were no greater than 9.7% coefficient of variation (CV), with deviations from the nominal concentrations of no more than ±4.8%. Values for between-run and within-run precision for analytical quality control samples in the assay for urine samples from the study (a total of 6 analytical runs) were no greater than 4.6% CV, with deviations from the nominal concentrations of no more than ±1.8%.
Pharmacokinetic Analysis
The plasma concentration-time data and urinary excretion data of entecavir were analyzed by noncompartmental methods,18,19 using the MENU/PKMENU application and the Statistical Analysis System (SAS, version 6.12, SAS Institute Inc, Cary, NC) software package. The peak plasma concentration, Cmax, the time to reach the peak concentration, tmax, and the trough plasma concentration, Cmin, were obtained directly from experimental observations. The area under the plasma concentration-time curve over one dosing interval (AUC
) was calculated using the linear trapezoidal method. The first-order rate constant of decline of entecavir concentrations in the terminal phase of the plasma concentration-time curve (
) was estimated by log-linear regression and, for day 14 only, the apparent terminal elimination half-life (t
) was estimated from . Apparent oral clearance (CLT/F) was calculated as the dose divided by AUC. The total urinary recovery (UR) of entecavir was calculated as the cumulative amount excreted over the 24-hour interval and expressed as a percentage of the administered dose (%UR). Renal clearance (CLR) was estimated by dividing UR by the AUC. The accumulation ratios for entecavir on days 7 and 14 were determined by dividing the AUC on day 7 or day 14 by the AUC on day 1.
Safety and Tolerability Assessments
Safety assessments were based on medical review of adverse event reports and the results of vital sign measurements (body temperature, respiratory rate, seated blood pressure, and heart rate), electrocardiograms, physical examinations, and clinical laboratory tests. Vital signs were recorded prior to dosing on days 1 through 14, at discharge from the clinical unit on day 21, and at study discharge on day 28. In addition, blood pressure and heart rate were measured on days 1 through 14 at 1 and 6 hours postdose. Twelve-lead electrocardiograms were recorded prior to dosing and at 1 hour postdose on days 1, 7, and 14, at discharge from the clinical unit on day 21, and at study discharge on day 28. Physical examinations were performed prior to dosing on day 1, at discharge from the clinical unit on day 21, and at study discharge on day 28. Blood and urine samples for clinical laboratory testing were collected prior to dosing on day 1, at discharge from the clinical unit on day 21, and at study discharge on day 28.
Subjects were closely monitored for adverse events from the time of enrollment until discharge from the study. Adverse events included any illness, sign, symptom, or clinically significant laboratory test abnormality that appeared or worsened during the course of the study, regardless of any causal relationship to the study drug.
Statistical Analysis
The SAS statistical software package, version 6.12 (SAS Institute Inc), was used for the statistical analyses. The distributions of the pharmacokinetic parameters were summarized, using descriptive statistics, by dose and study day. Summary statistics were conducted for the entecavir Cmax, tmax, AUC, t, CLT/F, %UR, and CLR. Geometric means and CV were determined for Cmax and AUC; medians and ranges were determined for tmax, and means and standard deviations were determined for the other pharmacokinetic parameters. Mean Cmin values were plotted, by study day and dose, to assess the attainment of steady state. All subjects who received study drug were included in the data set used for safety evaluation.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
The mean (SD) plasma concentration time profiles of entecavir on days 1, 7, and 14 are depicted in Figure 1. Entecavir was rapidly absorbed following oral administration of doses from 0.1 to 1 mg, with Cmax generally occurring within 1 hour of dosing. Disposition of the drug appeared to be rapid, with mean plasma concentrations in all 3 dosing panels falling to approximately 10% or less of the mean Cmax values 24 hours after dosing.
For all 3 doses, the plasma concentration-time profiles of entecavir on day 1 were lower than those on days 7 and 14, suggesting that drug accumulation occurred after multiple daily doses and that the steady-state exposure occurred between 7 and 14 days after the initiation of once-daily dosing. Based on visual inspection of mean trough values, it appeared that entecavir reached steady state by day 10 (Figure 2). The mean plasma concentration-time profiles for each dose of entecavir on day 14 are shown in Figure 3, which shows entecavir concentrations increased with an increase in dose and also illustrates the prolonged terminal phase of drug elimination. The steady-state (day 14) exposures of entecavir are approximately dose linear (Table I) for doses in the therapeutic range (0.5 mg and 1 mg).
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Summary statistics for entecavir pharmacokinetic parameters by study day and dose are listed in Table I. For the 0.1-mg dose, the mean steady-state (day 14) Cmax was 0.60 ng/mL, and the AUC was 2.51 ng·h/mL. For the 0.5-mg and 1-mg doses, the corresponding Cmax and AUC values were 4.23 ng/mL and 14.78 ng·h/mL, and 8.24 ng/mL and 26.38 ng·h/mL, respectively. At steady state, the mean AUC, increased in an approximate proportion to dose and exhibited low intersubject variability (CV 
21%). An approximately dose-proportional relationship was also observed for Cmax.
Entecavir had a mean plasma terminal elimination half-life ranging from 128 to 149 hours. Entecavir was predominantly eliminated through renal excretion as unchanged drug. At steady state, mean UR of the parent drug ranged from 62% to 73% across the studied dose range, and the mean CLR ranged from 360 to 471 mL/min.
Safety and Tolerability
There were no serious adverse events or deaths in this study. Of the 26 randomized subjects, 24 completed the study and 2 discontinued early (1 in the placebo panel and the other in the entecavir 0.1 mg panel). One subject who received 0.1 mg entecavir had an accident and subsequently developed paronychia of the fourth finger of the right hand. The second subject, who was in the placebo panel, developed cellulitis in the right forearm proximal to the indwelling intravenous catheter. Both adverse events were classified as unrelated to study drug.
A total of 15 treatment-emergent adverse events were reported: 4, 1, and 5 for subjects receiving 0.1, 0.5, and 1 mg/d entecavir, respectively, and 5 for subjects receiving placebo. The most common adverse events for all subjects (entecavir or placebo) were erythema reported in 3 of 26 subjects (11.5%), accidental injury reported in 2 of 26 subjects (7.7%), and dysuria reported in 2 of 26 subjects (7.7%). The most common adverse events for subjects receiving entecavir were erythema reported in 2 of 19 subjects (10.5%), accidental injury reported in 2 of 19 subjects (10.5%), and dysuria reported in 2 of 19 subjects (10.5%). Dysuria was the only adverse event reported in more than 1 subject on any treatment, being reported in 2 subjects who were both receiving 1 mg/d entecavir.
All adverse events resolved before discharge from the study. No laboratory abnormalities were identified as adverse events. There was no evidence that entecavir had any clinically relevant effects on vital sign measurements, and no clinically meaningful changes were apparent on the electrocardiograms or during the physical examinations.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Entecavir was rapidly absorbed following oral administration, with peak plasma levels generally occurring within 1 hour of dosing. Entecavir plasma concentrations declined biexponentially, suggesting that the disposition of entecavir fits a 2-compartment model. The drug reached steady-state by day 10 and showed an approximate 2-fold accumulation upon multiple dosing, which is associated with an effective accumulation half-life of 24 hours. Mean plasma concentrations in all 3 dosing panels declined by approximately 90% of the mean Cmax values 24 hours after dosing, indicating rapid disposition of the drug. At steady state, the mean exposure increased in an approximate proportion to dose across the dose range of 0.1 mg to 1 mg and exhibited low intersubject variability (CV 21%).
The results from the present study demonstrated that the day 14 AUC of 14.78 ng·h/mL for the 0.5-mg/d dose was in agreement with the results from the population pharmacokinetic-pharmacodynamic modeling and simulation performed using data from phase II clinical trials in nucleoside-naïve HBV-infected patients, suggesting that the pharmacokinetics of entecavir are similar between healthy subjects and nucleoside-naïve HBV-infected patients. The AUC0-24 from the population-based pharmacokinetic analysis was 14.0 ng·h/mL and was associated with a mean HBV DNA reduction of at least 4.7 log10 copies/mL, which was 95% of the maximum achievable viral reduction.20 The exposure associated with 0.5 mg/d entecavir in the current study was consistent with the exposure required to achieve 95% of the maximum viral reduction in nucleosidenaïve HBV-infected patients by the population pharmacokinetic-pharmacodynamic modeling and simulation, and thus this dose was selected for further study in nucleoside-naïve patients in the phase III studies.17
Similar to the findings for entecavir, exposures in patients with HBV infection and healthy subjects have also been reported to be similar in the case of the other 2 currently available antiviral drugs for HBV infection, lamivudine and adefovir dipivoxil.21,22 Entecavir is a purine nucleoside analogue, lamivudine is a pyrimidine nucleoside analogue, and adefovir dipivoxil is an acyclic adenine nucleoside phosphonate analogue, which is structurally similar to purine nucleoside analogues. They are all phosphorylated in cells to their active metabolites, entecavir triphosphate, lamivudine triphosphate, and adefovir diphosphate, respectively, which inhibit viral DNA polymerase and exert antiviral activity.11,23,24 These drugs are all nucleoside/nucleotide analogues, they share some common pharmacokinetic characteristics. The absorption of these drugs is usually rapid, with a median tmax of less than 2 hours postdose. The oral bioavailabilities of these drugs are all relatively high (
60%). The elimination is predominantly via renal excretion including glomerular filtration and net tubular secretion, which is believed to involve renal drug transporters. At steady state, the mean UR for entecavir ranged from 62% to 73% across the studied dose range, and the mean CLR ranged from 360 to 471 mL/min. The magnitude of the CLR for entecavir is indicative of both glomerular filtration and net tubular secretion.
The major differences in the pharmacokinetics between entecavir, lamivudine, and adefovir appear to be the apparent plasma elimination half-lives, which is approximately 140 hours for entecavir, whereas the half-lives of lamivudine and adefovir are about 6 and 7 hours, respectively.11,24 Two contributing factors may be responsible for the difference in half-life: the rate of dephosphorylation and/or bioanalytical sensitivity.
Entecavir is rapidly metabolized to the active intracellular triphosphate (ETV-TP) with a subsequent relatively slow dephosphorylation of ETV-TP back to entecavir.25 Thus, intracellular ETV-TP may form an additional kinetic "compartment" that contributes to the observation of a long terminal plasma half-life. Supporting this is the observation that compared to lamivudine, entecavir is more efficiently phosphorylated to the triphosphate in HepG2 and HBV-transfected 2.215 human hepatoma cell lines.25 ETV-TP is the predominant intracellular form, compared to entecavir and ETV-diphosphate, whereas lamivudine accumulates primarily as the diphosphate.25-27 Structurally, entecavir closely resembles naturally occurring D-deoxynucleosides; therefore, the efficient phosphorylation in mammalian cells is not surprising.25 Although the intracellular half-life of lamivudine triphosphate is comparable to that of ETV-TP (
15 hours),25,28 as aforementioned, the predominant intracellular phosphorylated form of lamivudine is its diphosphate. As dephosphorylation back to parent drug from triphosphate takes 1 more step than from the diphosphate, release of entecavir from intracellular ETV-TP back to the systemic circulation requires a longer period of time than lamivudine, contributing to the observed prolonged apparent elimination half-life in the circulation system.
The bioanalytical assays used in the analysis of entecavir or lamivudine may also contribute to the differences in half-lives between these nucleosides. The entecavir assay used in the current study employed an ultrasensitive LC/MS/MS method, with an LLQ of 0.005 ng/mL, to allow quantification of entecavir following the administration of low oral doses. The assay method enabled quantification of entecavir plasma concentrations at times up to 336 hours after a single oral dose, which also contributed to the observation of a long apparent terminal elimination half-life. These factors may also apply to the comparison between the terminal elimination half-lives of entecavir and adefovir. Although entecavir demonstrates a long terminal half-life, this long terminal half-life does not contribute to drug accumulation, because only a small fraction of the dose remains in the body at the beginning of the terminal elimination phase. Entecavir drug accumulation at steady state is approximately 2-fold, which is indicative of an effective accumulation half-life of 24 hours, supporting the use of a once-daily dosing regimen.
Entecavir was found to be safe and well tolerated in this study. Few adverse events were reported, and they were all mild to moderate in intensity. The proportion of entecavir recipients reporting at least one adverse event (31.6%) was similar to that for placebo recipients (28.6%). Among the subjects who received entecavir, the most frequently reported adverse events were erythema, accidental injury, and dysuria, which all occurred in 2 subjects (10.5%) and were of mild intensity and self-limiting. Among these, only dysuria appeared to be dose-related because both subjects were in the 1-mg entecavir dose group. This adverse event was not observed with increased frequency in large, phase II/III pivotal trials.29,30 Few marked laboratory abnormalities were reported, and there was no clear indication that any of these were dose related. No other clinically relevant adverse events were reported in this study.
In conclusion, entecavir is rapidly absorbed following oral administration, exhibits rapid disposition and approximately dose-proportional exposure, is predominantly eliminated unchanged by the kidney, and has an effective accumulation half-life that supports once-daily administration. Entecavir, ranging from 0.1 mg/d to 1 mg/d, was safe and well tolerated when administered for 14 days.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Authors are employees and stockholders of Bristol-Myers Squibb.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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