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This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.
Telbivudine is an orally bioavailable l-nucleoside with potent and specific antiviral activity against hepatitis B virus (HBV) (2). In HepG2 cells, telbivudine is efficiently converted into high concentrations of the active triphosphate, which acts through preferential inhibition of HBV second-strand (DNA-dependent) DNA synthesis, a mode of action that differs from that of nucleoside analogs developed earlier (5, 13). Cellular pharmacology studies have shown that telbivudine exhibits a high in vitro therapeutic index and is unlikely to be associated with hematologic, mitochondrial, or neurologic toxicity (2).
Animal toxicology studies with telbivudine doses up to 2,000 mg/kg of body weight did not identify any preclinical safety issues for telbivudine (2). In woodchucks chronically infected with woodchuck HBV, up to 28 days of telbivudine treatment produces consistent, multilog reductions in circulating serum woodchuck HBV DNA levels (2). The favorable preclinical safety and antiviral activity profile of this agent led to clinical investigation into its use as a treatment for chronic hepatitis B (2, 9, 10).
In a phase I/II dose-escalation trial of telbivudine in 43 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, telbivudine at 400 to 800 mg/day resulted in a reduction in serum HBV DNA levels of approximately 4 log10 after only 4 weeks of treatment (10). Telbivudine was well tolerated at doses ranging from 25 to 800 mg/day, with a safety profile comparable to that of placebo and with no apparent dose- or treatment-related adverse events. A subsequent randomized multicenter trial compared the 1-year efficacy and safety of telbivudine at 400 or 600 mg/day, alone or in combination with lamivudine at 100 mg/day, versus those of lamivudine at 100 mg/day in 104 HBeAg-positive patients with chronic hepatitis B (9). At 1 year, all telbivudine-containing treatments resulted in a reduction in serum HBV DNA levels of greater than 6 log10, which was significantly greater than that achieved with lamivudine monotherapy, which resulted in an approximate 4.6 log10 reduction. Telbivudine monotherapy also produced an overall better response in terms of clinical end points, including the undetectability of HBV by PCR, alanine aminotransferase (ALT) level normalization, and HBeAg seroconversion.
Pharmacokinetic studies with healthy subjects and HBV-infected patients demonstrated that following oral dosing, telbivudine is rapidly absorbed, with maximum plasma concentrations (Cmax) reached within 1 to 3 h (16, 17, 18, 19). Following intravenous and oral administration of telbivudine at 10 mg/kg to cynomolgus monkeys, 77.0% and 36.6% of the administered drug, respectively, was eliminated in the urine within 14 days (unpublished data). In humans receiving a single oral dose of telbivudine at 600 mg, recoveries within 7 days are 42.0% in urine and 49.6% in feces, for a total elimination of 91.6% of the administered dose. Following oral administration of telbivudine at 10 mg/kg to duct-cannulated Sprague-Dawley rats, biliary excretion of the drug accounted for less than 1% of the administered dose over 72 h. Telbivudine is not a substrate or an inhibitor of human hepatic CYP450 isozymes. No telbivudine metabolites were detected in human plasma, urine, or feces (unpublished data). Together these data indicate that systemic telbivudine is primarily eliminated as unchanged drug by renal clearance; therefore, hepatic impairment is not expected to alter the pharmacokinetics of telbivudine.
Because telbivudine is ultimately expected to be used for the treatment of patients with chronic hepatitis B and impaired liver function, including those with decompensated disease currently being recruited into a phase III telbivudine trial, it is important to assess its pharmacokinetics and safety in subjects with hepatic impairment. The objective of this study was to evaluate the effect of hepatic impairment on the pharmacokinetics of telbivudine and to monitor the safety of telbivudine administered orally as a single 600-mg dose.
This was a phase I, open-label, single-dose, parallel-group study to evaluate the pharmacokinetics and safety of telbivudine (β-l-2′-deoxythymidine) in subjects with normal or impaired hepatic function. A total of 24 subjects, with 6 subjects in each of the four hepatic function groups (normal function and mild, moderate, and severe impairment), were enrolled in the study and administered a single oral dose of 600 mg telbivudine as three 200-mg tablets (manufactured and packaged for Idenix Pharmaceuticals Inc. by Quintiles Limited, Scotland).
Subjects with mild, moderate, and severe hepatic impairment were required to have Child-Pugh scores of 5 to 6 (category A), 7 to 9 (category B), or 10 to 15 (category C), respectively. Subjects with normal or impaired hepatic function were selected to have matching ages, body weights, and sexes. A total of 24 subjects, with 6 subjects in each of the four hepatic function groups, were enrolled in the study.
Eligible subjects were men and women from 18 to 75 years of age with body weights equal to or greater than 50 kg for the men and 45 kg for the women but within 35% of the normal body weight relative to their heights and frame sizes. Subjects with normal hepatic function were free of significant medical histories or abnormal laboratory findings and were not permitted to take any medication from within 7 days of dosing until the completion of pharmacokinetic blood sampling. Subjects with hepatic impairment were assigned corresponding Child-Pugh scores based on screening laboratory test results for bilirubin, serum albumin, and prothrombin time and the stage of hepatic encephalopathy, with or without ascites. They were allowed to continue taking their regularly prescribed medications until 8 h before and 4 h after dosing. Women who were not postmenopausal were required to have a negative pregnancy test upon study entry. All subjects were required to have a negative prestudy alcohol breath test result on study entry. Subjects were excluded from the study for any of the following reasons: the presence of any medical or surgical conditions that might significantly interfere with the gastrointestinal absorption, distribution, or excretion of telbivudine; a history of tuberculosis, asthma, or glaucoma; a history of clinically significant cardiovascular disease, renal disease (creatinine clearance [CLCR], <50 ml/min by the Cockcroft-Gault method), pulmonary disease, neurologic disease, metabolic disease, or psychiatric disease; a history of malignancy, human immunodeficiency virus infection, or other serious disease; participation in a clinical drug study during the preceding 4 weeks; or a requirement for the use of a comedication known to affect renal tubular function, except for the use of diuretics required for the management of the subject's hepatic disease.
Within 3 weeks prior to dosing, subjects underwent a screening visit that included assessment of the Child-Pugh score, medical history, physical examination, determination of vital signs, clinical laboratory testing, and an electrocardiogram (ECG).
All subjects gave written, informed consent prior to participation in the study. The trial was conducted at the Orlando Clinical Research Center (Orlando, Fla.), New Orleans Center for Clinical Research (New Orleans, La.), and DaVita Clinical Research (Minneapolis, Minn.). The ethics committee of each center approved the trial. The first subject was recruited on 29 July 2002, and the last subject was recruited on 1 April 2003; the last subject completed the trial on 4 April 2003.
Blood samples (7 ml at each time point) were collected into heparinized evacuated blood collection tubes (Vacutainer) immediately before dosing (0 h) and at 0.5, 0.75, 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 48 h postdosing. Blood samples were centrifuged at 2,000 × g for 15 min, and plasma was collected and frozen at −20°C or below until analysis.
Plasma concentrations of telbivudine were measured by a validated high-performance liquid chromatographic method with tandem mass spectrometric (MS/MS) detection. Briefly, to 100 μl of calibration standards (10 to 5,000 ng/ml), quality controls (30, 1,500, and 4,000 ng/ml), and unknown plasma samples were added 50 μl of internal standard (β-l-2′-deoxyadenosine [LdA] at 40 μg/ml) and 6 μl of thymidine phosphorylase (EC 18.104.22.168; >1 U/μl; Sigma Chemical Co., St. Louis, Mo.). The mixture was vortexed thoroughly and incubated at 37°C for 1 h to digest any endogenous thymidine. After incubation, acetonitrile (1.5 ml) was added to precipitate protein. The samples were centrifuged, and the supernatant was recovered and evaporated to dryness. Prior to chromatographic analysis, dry residues were reconstituted with 150 μl of mobile phase (20 mM phosphate buffer containing 2% [vol/vol] acetonitrile) and centrifuged. Chromatography was performed on a TSK-GEL Amide-80 column (4.6 by 150 mm; 5 μm; Tosoh Bioscience, Montgomeryville, Pa.). Elution was carried out isocratically at 1 ml/min with a mobile phase of 90:10 (vol/vol) methanol and 25 mM ammonium formate (pH 3.5). Under these conditions, the retention times were approximately 1.68 and 1.73 min for telbivudine and LdA, respectively. Telbivudine and LdA were monitored with a PE Sciex API 3000 MS/MS mass analyzer at mass transitions of 243.0 to 127.1 m/z and 252.0 to 136.0 m/z, respectively. The mass analyzer was operated under the positive mode by using atmospheric pressure chemical ionization. This assay has a limit of quantification of 10 ng/ml, with a calibration curve range from 10 to 5,000 ng/ml. The intra- and interday precisions (percent coefficient of variation) and accuracy (percent deviation) were from 2.3% to 5.6% and −4.2% to 1.4%, respectively, based on the results for quality-control samples with concentrations ranging from 30 to 4,000 ng/ml.
Noncompartmental pharmacokinetic analysis was used to calculate pharmacokinetic parameters by using the computer program Kinetica (version 4.3; Thermo Electron Corporation, Waltham, Mass.). Cmax and the time to reach Cmax (Tmax) were obtained directly from the concentration-time data. The observed elimination half-life (t1/2) was calculated as 0.693/kel, where kel, the elimination rate constant, is the slope of the observed natural logarithm-linearized elimination phase estimated by linear regression analysis. The area under the plasma concentration-time curve (AUC) from time zero to time t (AUC0-t), where t is the time of the last measurable concentration, was calculated according to the linear trapezoidal rule. The AUC from time zero to infinity (AUC0-∞) was estimated as AUC0-t + Ct/kel, where Ct is the concentration in the last plasma sample with a measurable concentration. The apparent total oral plasma clearance (CL/F) was calculated as dose/AUC0-∞ and was adjusted for body weight.
Differences in pharmacokinetic parameters with respect to the degree of impairment of liver function were assessed by analysis of variance and regression analysis, as implemented in the general linear model procedure in SAS (version 8.0; SAS Institute Inc., Cary, N.C.). Geometric mean (GM) ratios and the associated 90% confidence intervals (CIs) between subjects with hepatic impairment and subjects with normal hepatic function were calculated for AUC, Cmax, t1/2, and CL/F.
Safety assessments included adverse event reports, vital sign evaluations, physical examinations, clinical laboratory tests, and ECGs. All adverse events were recorded, including adverse events that the subjects reported spontaneously, those observed by the investigator, and those elicited by the investigator in response to open-ended questions during scheduled visits to a study center; follow-up safety and pharmacokinetic evaluations occurred on days 1 through 3. Samples for clinical laboratory tests (hematology, blood chemistry, and urinalysis) were collected on the day prior to dosing and at the time of discharge. Vital signs were measured on the day prior to dosing, on day 1, and at the time of discharge. Physical examination and a 12-lead ECG were performed at the screening visit and at the time of discharge. Descriptive statistics were used to summarize safety parameters by degree of impairment in hepatic function.
Twenty-four subjects (15 men and 9 women) participated in the study. Seventy-five percent of the subjects were Caucasian. As shown in Table Table1,1, baseline characteristics were similar among the subjects in the four hepatic function groups, although the group with severe impairment had a slightly lower mean body weight of 73.7 kg, whereas the means for the other groups were 76.7 to 81.8 kg. The four groups were also comparable with respect to the mean values of creatinine clearance, with the groups with moderate and severe impairments having higher variability: two subjects (one from each of the last two groups) exhibited CLCR values (51.8 to 52.2 ml/min) close to the range of moderate renal impairment (Table (Table1).1). All subjects enrolled in the study completed the study, and there were no dose modifications or premature study discontinuations.
Subjects with normal hepatic function discontinued all medications and supplements. Subjects with impaired hepatic function were allowed to continue the use of comedications until 8 h prior to and 4 h after study drug dosing to manage their liver diseases, including ascites and edema (diuretics [spironolactone and furosemide]), encephalopathy (lactulose), and cirrhosis (ursodeoxycholic acid). Other comedications were primarily for diabetes, pain, and nutritional supplementation.
The values of the telbivudine single-dose pharmacokinetic parameters in subjects with mild, moderate, and severe hepatic impairment were comparable to those in subjects with normal hepatic function (Table (Table2).2). Plasma concentration-time profiles were similar in subjects with normal and impaired hepatic function, as shown in Fig. Fig.1.1. Telbivudine concentrations rapidly increased to a mean Cmax of 2.8 μg/ml (median, 2.5 μg/ml) at a median Tmax of 2.5 h postdosing in subjects with normal hepatic function. In subjects with hepatic impairment, the mean Cmax of telbivudine ranged from 3.4 to 3.7 μg/ml (median range, 2.8 to 3.2 μg/ml), and the median Tmax varied from 2.5 to 4.0 h postdosing. The GM ratios of Cmax for subjects with hepatic impairment to the Cmax for subjects with normal hepatic function ranged from 1.10 to 1.22. The mean and median AUCs were similar across the four hepatic function groups: AUC0-t and AUC0-∞ were 20.1 and 22.5 μg · h/ml (mean) and 20.1 and 22.2 μg · h/ml (median), respectively, in subjects with normal hepatic function; and AUCs were 22.5 to 32.5 μg · h/ml (mean AUC0-t), 21.3 to 25.8 μg · h/ml (median AUC0-t), 24.7 to 35.9 μg · h/ml (mean AUC0-∞), and 23.6 to 28.7 μg · h/ml (median AUC0-∞) in those with hepatic impairment. GM ratios of AUC0-t and AUC0-∞ for subjects with hepatic impairment to the AUC0-t and AUC0-∞ for subjects with normal hepatic function ranged from 1.05 to 1.50. The 90% CI about the GM ratios contained unity for both the Cmax and the AUC comparisons. In addition, t1/2 and CL/F were also comparable between the normal and the impaired hepatic function groups (Table (Table2).2). Compared to the GM ratios for unadjusted CL/F, the GM ratios of the weight-adjusted CL/F for the impaired hepatic function groups to that for the normal hepatic function group were, in general, closer to unity, with a narrower 90% CI (Table (Table22).
Telbivudine was well tolerated by all subjects. There were no deaths, other serious adverse events, or discontinuations in the study. The frequency or types of adverse events reported were similar in subjects with normal and impaired hepatic function (Table (Table3).3). The degree of hepatic impairment had no effect on the incidence of adverse events. All adverse events resolved without residual effects. Three adverse events, including two instances of polyuria and one instance of headache, were considered possibly related to telbivudine. There were no changes in vital signs, physical examination findings, clinical laboratory results, or ECG findings attributable to telbivudine.
In view of the pharmacologic properties of telbivudine, i.e., predominant renal clearance as unchanged drug with negligible biliary excretion (20; unpublished data), hepatic impairment is therefore unlikely to have a major impact on its pharmacokinetics. In addition, data from a phase I/II trial with HBV-infected patients showed that telbivudine exhibited dose-proportional pharmacokinetics and an exposure-related viral response, with nearly maximum antiviral effects achieved with telbivudine doses in the range of 400 to 800 mg/day (10, 18). No dose-limiting toxicities were observed in that trial over the dose range studied, 25 to 800 mg/day (10). In fact, multiple doses of telbivudine of up to 1,800 mg/day were well tolerated by healthy subjects (unpublished data). These observations together suggest that telbivudine likely has a high therapeutic index with a wide therapeutic window, which favored the enrollment of a relatively few subjects per hepatic impairment category in the current study. On the practical side, due to the instability of their physiopathologic states, the timely recruitment of subjects with even transiently stable hepatic impairment but with adequate renal function has proven to be difficult. A sample size of six to eight subjects per study arm has previously been used for the assessment of the hepatic effect on the pharmacokinetics of nucleoside and nucleotide antiviral agents, including the anti-human immunodeficiency virus and/or anti-HBV agents lamivudine (6), stavudine (12), tenofovir disoproxil fumarate (7), adefovir dipivoxil (8), and entecavir (1).
The results of this single-dose study indicate that the pharmacokinetic properties of telbivudine in subjects with various degrees of hepatic impairment are comparable to those in subjects with normal hepatic function, although there was a slight increase in AUC and a decrease in CL/F in subjects with moderately to severely impaired hepatic function compared with those in subjects with normal hepatic function. These differences might not be clinically relevant and could partly be attributed to intrinsic factors for the subjects. Subjects with severe hepatic impairment had a slightly lower mean body weight compared to those for the remaining groups, and both the group with moderate hepatic impairment and the group with severe hepatic impairment also had more variable body weights (Table (Table1).1). The weight-adjusted CL/F had GM ratios that were, in general, closer to unity, with a narrower 90% CI compared to that for the unadjusted CL/F (Table (Table2),2), suggesting that weight might be a covariate of clearance.
The slight increase in telbivudine exposure also reflects the presence of impaired renal function, which is observed in some subjects with moderate to severe hepatic impairment and which is a complication frequently associated with advanced liver diseases (4, 14, 15). While there was no evidence of a significantly reduced mean CLCR in the moderate and the severe hepatic impairment groups, two subjects from those groups exhibited mild to moderate renal impairment (CLCR values, close to 50 ml/min). Since systemic telbivudine is primarily eliminated by the renal pathway and its clearance is directly proportional to CLCR (20), reduced renal function is expected to lead to higher plasma exposure. The telbivudine Cmax and AUC values in these two subjects were approximately two- to threefold of the respective group means, and their CL/F values were accordingly reduced by similar magnitudes. Because of the relatively small sample size, these “outliers,” although few in number, had a certain impact on the group mean values of key pharmacokinetic parameters, resulting in the observed trend toward increased mean exposure and decreased group clearance as hepatic function deteriorated; but the group medians were little affected (Table (Table2).2). One subject with mild hepatic dysfunction also had high plasma telbivudine exposure (about twofold of the group mean). This subject was obese, with a body mass index of 31.5. The traditional Cockcroft-Gault equation tends to overestimate CLCR for the obese population (3); however, the subject's adjusted CLCR, obtained by using the method of Salazar and Corcoran (11), was still in the normal range, therefore precluding renal impairment as a potential cause for the observed high plasma drug exposure. Other possible mechanisms, such as drug-drug interactions or the inhibition of clearance from endogenous waste product buildup, may also account for the observed differences in the pharmacokinetics of telbivudine. During the conduct of this study, subjects with impaired hepatic function continued the use of medications to manage their liver diseases, including the diuretics spironolactone and furosemide for ascites and edema, lactulose for encephalopathy, and ursodeoxycholic acid for cirrhosis, as well as comedications for diabetes, pain, and nutritional supplementation. Since diuretics can cause urine flow-dependent changes in renal function (i.e., the glomerular filtration rate), comedications were discontinued 8 h prior to telbivudine dosing to minimize any potential effect that they might have on the pharmacokinetics of telbivudine, but were resumed 4 h postdosing, as they were essential for the subjects' health. A population pharmacokinetic analysis with data from multiple studies is under way, and that analysis may provide additional insights into the effects of intrinsic and extrinsic factors on the pharmacokinetics of telbivudine.
The findings that telbivudine pharmacokinetics are similar between subjects with normal hepatic function and subjects with hepatic impairment were expected, given that telbivudine is a nucleoside analog that is known to be predominately cleared by the kidney (20; unpublished data). Previous studies have shown that the pharmacokinetics of other antiviral nucleoside and nucleotide analogs, such as lamivudine (6), stavudine (12), tenofovir disoproxil fumarate (7), adefovir dipivoxil (8), and entecavir (1), are unaffected in subjects with various degrees of hepatic impairment.
A single dose of telbivudine at 600 mg was well tolerated in subjects with normal and impaired hepatic function, with no serious adverse events. Only three adverse events, including two instances of polyuria and one instance of headache, were considered possibly related to telbivudine by the principal investigator. It should, however, be pointed out that one of the two instances of polyuria was reported in a subject receiving the diuretic drug spironolactone for ascites. The favorable tolerability and safety profile of telbivudine in human subjects has been demonstrated in other trials of telbivudine with both healthy subjects and HBV-infected patients (9, 10, 16, 17, 19).
In summary, the pharmacokinetics of telbivudine at 600 mg were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. A single dose of telbivudine was also well tolerated by all participants. The results of this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in HBV-infected patients with impaired liver function. A phase III trial evaluating the long-term safety and efficacy of telbivudine 600 mg/day in HBV-infected patients with decompensated liver diseases is in progress.
We thank the healthy volunteers, patients, and staff of Orlando Clinical Research Center, DaVita Clinical Research, and the New Orleans Center for Clinical Research. We are also grateful to R. Boehme for critical review of the manuscript and helpful suggestions.
X.-J. Zhou, G. Dubuc Patrick, G. C. Chao, and N. A. Brown are full-time employees of Idenix Pharmaceuticals Inc.; T. C. Marbury, H. W. Alcorn, and W. B. Smith are principal investigators involved in the clinical conduct of this study through a contractual agreement with Idenix Pharmaceuticals Inc.