Abstract
Telbivudine is a nucleoside analogue that has been approved for the treatment of chronic hepatitis B virus (HBV) infection in adults at 600 mg/day. We conducted a phase I, open-label, first-in-pediatrics study to investigate the safety and pharmacokinetics of a single dose of telbivudine in HBV-infected children and adolescents. Eligible patients were enrolled sequentially from older to younger groups, with evaluation of safety and available pharmacokinetic data after each stratum. Adolescent patients (>12 to 18 years) received a single dose of 600 mg telbivudine as an oral solution, while children aged 2 to 12 years received a single dose of 15 or 25 mg/kg of body weight up to a maximum of 600 mg. Telbivudine was well tolerated; all adverse events were mild, and none occurred in more than one patient. The plasma telbivudine concentration-versus-time profiles in adolescents given 600 mg were similar to the mean profile of healthy adults receiving the same oral dose. Children aged 2 to <6 and 6 to 12 years receiving a single 15-mg/kg dose showed similar plasma exposures. To predict the steady-state exposure, plasma concentration-versus-time profiles for patients aged 2 to 12 years (15 mg/kg) and >12 to 18 years (600 mg) were fitted to a two-compartment 1st-order, microconstant, lag time, 1st-order elimination pharmacokinetic (PK) model. This analysis predicted the following dosages to mimic exposures in healthy adults receiving 600 mg/day: 20 mg/kg/day for children 2 to 12 years and 600 mg/day for adolescents. Studies are ongoing to evaluate the efficacy of the recommended dose in pediatric patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00907894.)
INTRODUCTION
Chronic hepatitis B virus (HBV) infection remains an important global health problem, with an estimated 350 to 400 million individuals affected worldwide (1). While infection of adults results in the majority of subjects clearing the virus, infants who are exposed perinatally predominately develop partial immunologic tolerance, with life-long, chronic infection in over 90% of cases (1). Children often exhibit an initial phase of the disease characterized by high viral loads but little evidence of liver damage (2). The subsequent immune active phase of HBV infection, however, is characterized by hepatic enzyme elevations, fibrosis, and necroinflammatory liver injury. Over decades, persistent HBV replication can result in cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
Antiviral therapy for HBV aims to slow the progression of liver disease by cessation or prolonged suppression of viral replication. Current treatments for chronic HBV include alfa interferon, pegylated alfa interferon, and orally bioavailable nucleoside and nucleotide analogues lamivudine, adefovir, tenofovir, entecavir, and telbivudine. Only alfa interferon, lamivudine, and adefovir have been approved by the U.S. FDA for pediatric use (3). Alfa interferon was shown to result in HBV e antigen (HBeAg) seroconversion and viral DNA clearance in 26% of treated children, compared to 11% of the control group (4). This treatment, however, has significant side effects, including flu-like symptoms, neutropenia, nausea, and psychiatric effects. Use of nucleoside and nucleotide analogues, while effective in viral suppression, is associated with development of viral resistance and return of detectable HBV over time (3, 5–7).
Telbivudine (LDT600, Sebivo, Tyzeka) is the unmodified l-enantiomer of the naturally occurring nucleoside thymidine and has been approved for the treatment of chronic HBV infection in adults. In the phase III GLOBE study of 1,370 patients ≥16 years of age, treatment with telbivudine (600 mg/day) for 52 weeks resulted in undetectable serum HBV DNA levels in 60% of HBeAg-positive and 88.3% of HBeAg-negative patients; lamivudine (100 mg/day) treatment achieved the same response in 40.4% and 71.4% of each group, respectively (8). After 2 years of treatment, therapeutic response—as defined by undetectable HBV DNA and either HBeAg loss or normalization of alanine aminotransferase (ALT) levels—was superior for telbivudine compared to lamivudine for both HBeAg-positive (63% versus 48%) and HBeAg-negative (78% versus 66%) patients (9). Adverse events (AEs) were observed with similar frequencies between groups, although telbivudine treatment resulted in more significant increases in creatine kinase.
Given the antiviral activity and safety of telbivudine in adults, we initiated the first study of the pharmacokinetics (PK) and safety of the drug in HBV-infected children and adolescents aged 2 to 18 years (registration no. NCT00907894). The study design, which tested single ascending oral doses, was discussed and agreed to prior to study initiation by both U.S. and European health authorities.
MATERIALS AND METHODS
Patients.
The study was conducted at 11 sites in the United Kingdom, Belgium, Germany, Philippines, Bulgaria, and Egypt. Procedures were in accordance with the Declaration of Helsinki and good clinical practice, and the study protocol was approved by the institutional review boards (IRB) for the centers. All patients or their guardians provided written informed consent.
Eligible participants were children and adolescents (male and female) aged 2 to 18 years with documented chronic HBV infection and positive HBV surface antigen (HBsAg) at screening. Eligible patients had to weigh within the 15th to 85th percentile of normal relative to age and to have creatinine clearance (CLCR) of ≥80 ml/min/1.73 m2 as estimated by the Schwartz formula. All female patients of reproductive potential were required to have a negative serum pregnancy test at screening and negative urine pregnancy test on day −1. Exclusion criteria included decompensated liver disease or other clinically significant condition or laboratory abnormality unrelated to HBV infection. Patients were excluded if they had been treated with interferon within 6 months of screening, nucleoside or nucleotide reverse transcriptase inhibitors within 3 months of screening, any other antiviral therapy within 30 days of study drug dosing, or antibiotics within 7 days of screening. Patients were also excluded if they had participated in a clinical drug study within 30 days of screening, were pregnant or breast-feeding, or had abused alcohol or illicit drugs within the past 2 years.
Study design.
This was a phase I, open-label, first-in-pediatrics study to investigate the safety and pharmacokinetics of telbivudine in children. Estimated doses were selected by taking into consideration the renal clearance of telbivudine, its linear pharmacokinetics, the approved adult dose of 600 mg (10), and its resulting exposure as the target for the pediatric population. Similar to the nucleoside analogues lamivudine and adefovir, telbivudine is primarily eliminated by renal clearance. Renal function is known to be increased in young children and progressively decreases with age until it reaches adult levels by 10 to 12 years (11). For lamivudine and adefovir, approximately twice the adult doses (on a mg/kg basis) resulted in similar exposures in pediatric patients (12, 13); the selected doses in mg/kg of telbivudine are 2 to 3 times the adult dosing in young children and equal to the approved adult dose in adolescents. Eligible patients 2 to 18 years of age were stratified as follows: stratum 1, 2 to <6 years old (n = 12), with substrata of 2 to <4 years (n = 4) and 4 to <6 years (n = 8); stratum 2, 6 to 12 years old (n = 8), with substrata of 6 to <9 years (n = 4) and 9 to 12 years (n = 4); and stratum 3, >12 to 18 years old (n = 8). The dosing started with the oldest children and then, after evaluation of safety and available PK data, proceeded sequentially to the younger age groups. Adolescent patients in stratum 3 received a single dose of 600 mg telbivudine as an oral solution. Following review of stratum 3 safety and PK parameters, a subgroup for each age group was dosed with the 15-mg/kg dose and evaluated before proceeding to the 25-mg/kg dose. No subject received a total dose higher than 600 mg. A previous clinical trial determined that the oral solution and the approved tablet formulation of telbivudine were bioequivalent (Novartis data on file). Patients were monitored to day 6, after which the trial was concluded.
Safety assessment.
Safety assessments consisted of collecting all adverse events with their severity and relationship to study drug, physical examinations, pharmacokinetic monitoring, and laboratory evaluations.
PK parameters and assessment.
Telbivudine levels in plasma were evaluated prior to dosing (predose) and at 1, 2, 3, 4, 8, 12, 24, 48, 72, and 120 h after a single oral dose of the drug. Blood samples (1.0 ml whole blood to generate ∼0.5 ml plasma at each time point) were collected in heparinized Vacutainer tubes (BD, Franklin Lakes, NJ), processed by centrifugation at ∼2,000 × g for 15 min, and stored below −20°C until analysis. Plasma telbivudine was measured by a validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) method with a lower limit of quantification (LLOQ) of 10 ng/ml, linear range of 10 to 5,000 ng/ml, and intra- and interday variabilities of 4.9% and 8.3%, respectively. Concentrations below the LLOQ were treated as zero. Conventional PK parameters, including maximum concentration (Cmax), time to maximum concentration (Tmax), area under the time-concentration curve from time zero to infinity (AUC0–∞), oral total plasma clearance (CL/F), and apparent oral total volume of distribution (V) for each patient, were generated by noncompartmental methods using WinNonlin Professional, version 5.2 (Pharsight Corp., St. Louis, MO). After review of the individual data, the mean plasma telbivudine concentration-versus-time profiles for children aged 2 to 12 years administered a single 15-mg/kg dose of telbivudine and for children aged >12 to 18 years administered a single 600-mg dose of telbivudine were fitted to a two-compartment 1st-order absorption, microconstant, lag time, 1st-order elimination PK model (WinNonlin, version 5.2) in order to extrapolate single-dose profiles to steady state. Model selection was based on achieving a higher R2, less variability around shared parameters, and a lower AIC value as determined by the program outputs. To estimate the variability around the extrapolated exposure parameters, a coefficient of variation (CV) of 30% was used, as this is both the historical experience and the observed variability in the current study.
Statistical methods.
Safety parameters were summarized for each age and dose group. PK parameters were summarized by descriptive statistics.
RESULTS
Subject demographics.
The study planned to enroll 28 pediatric and adolescent patients with chronic HBV infection. Despite including 11 sites in multiple countries, recruitment into the study was slower than anticipated. After 22 patients had been recruited and completed the study, a preliminary analysis of the pharmacokinetics and safety was performed. A summary of this preliminary analysis with a pediatric dose recommendation was shared by Novartis with European and U.S. health authorities. Based on this interaction, there was agreement on early study closure. The study was terminated after enrollment of 23 out of the planned 28 patients, as it had met its primary objective. Therefore, only one subject in the 2- to <4-year-old group received the 25-mg/kg single dose of telbivudine. The demographics of the subjects enrolled and evaluated in the study are shown in Table 1 and reflect the countries of enrollment.
Table 1.
Patient demographics
| Demographic variable | Value for age group |
||
|---|---|---|---|
| 2–<6 yrs (n = 7) | 6–12 yrs (n = 8) | >12–18 yrs (n = 8) | |
| Age, yrs | |||
| Mean (SD) | 3.9 (1.46) | 8.5 (2.07) | 15.3 (1.16) |
| Median | 5.0 | 8.5 | 15.5 |
| Range | 2–5 | 6–11 | 14–17 |
| Height, cm | |||
| Mean (SD) | 107.1 (18.21) | 132.3 (13.45) | 162.4 (9.07) |
| Median | 114.0 | 129.5 | 165.0 |
| Range | 82–128 | 115–156 | 149–173 |
| Weight, kg | |||
| Mean (SD) | 20.13 (6.879) | 30.44 (7.983) | 57.10 (10.364) |
| Median | 20.00 | 29.50 | 60.40 |
| Range | 13.0–32.0 | 21.0–45.2 | 40.0–67.0 |
| Body mass index, kg/m2 | |||
| Mean (SD) | 17.260 (2.0928) | 17.083 (1.4948) | 21.653 (3.8539) |
| Median | 17.654 | 16.729 | 20.628 |
| Range | 14.78–19.53 | 14.83–19.19 | 17.78–29.59 |
| Gender, n (%) | |||
| Male | 2 (28.6) | 4 (50.0) | 6 (75.0) |
| Female | 5 (71.4) | 4 (50.0) | 2 (25.0) |
| Race, n (%) | |||
| Caucasian | 6 (85.7) | 3 (37.5) | 2 (25.0) |
| Asian | 1 (14.3) | 4 (50.0) | 6 (75.0) |
| Other | 1 (12.5) | ||
| Ethnicity, n (%) | |||
| Hispanic/Latino | 1 (12.5) | ||
| Indian (Indian subcontinent) | 1 (12.5) | 1 (12.5) | |
| Mixed ethnicity | 1 (12.5) | 1 (12.5) | |
| Other | 7 (100.0) | 6 (75.0) | 5 (62.5) |
Safety and tolerability.
A single oral dose of telbivudine was generally well tolerated in children and adolescents. Among the 23 patients who received telbivudine, 4 (17.4%) experienced an adverse event; all AEs were mild in severity and consisted of protein in urine (15 mg/kg) and one report each of chills, diarrhea, malaise, nasopharynitis, postprocedural discomfort, and pruritus (25 mg/kg). There were no deaths or serious adverse events (SAEs) reported in the study, and no patient discontinued due to an adverse event. Of the adverse events reported, skin lesions, pruritus, protein in urine, and malaise were suspected to be related to the study drug.
Pharmacokinetic parameters of telbivudine.
Following oral administration of telbivudine to children and adolescents in all three age groups, peak plasma drug concentrations occurred at approximately 2 to 4 h postdose (Fig. 1). Plasma telbivudine concentrations subsequently decreased in a biexponential manner, with a mean terminal half-life ranging from 28 to 39 h. The interpatient variability for measures of systemic telbivudine exposure (Cmax and AUC) was ≤30%.
Fig 1.
Comparison of plasma telbivudine concentration-versus-time profiles of children to historical adult data. Black symbols are plasma telbivudine concentrations from individual children aged >12 to 18 years (600 mg, n = 8) (A), 6 to 12 years (15 mg/kg, n = 4) (B), 6 to 12 years (25 mg/kg, n = 4) (C), and 2 to <6 years (15 mg/kg, n = 6) (D). White symbols and lines represent mean (±standard deviation) historical plasma telbivudine concentrations in adults (n = 23) receiving a single 600-mg oral dose.
The single-dose summary pharmacokinetic parameters for the children in each age group and comparison to historical data (Novartis data on file) obtained after a single 600-mg dose in adults are shown in Table 2. Dose-proportional increases in telbivudine Cmax and AUC were observed in children aged 6 to 12 years receiving 15 mg/kg versus 25 mg/kg telbivudine. Comparison of children aged 2 to <6 years and 6 to 12 years receiving a single 15-mg/kg dose of telbivudine indicated similar plasma exposures (Cmax and AUC). Dose-proportional increases in Cmax and AUC could not be assessed for children aged 2 to <6 years because only one patient in this group received the 25-mg/kg dose; this individual showed an exposure (AUC) similar to that of the same age group receiving 15 mg/kg telbivudine. Dose proportionality in exposure could also not be assessed in children aged >12 to 18 years since only one dose of telbivudine (600 mg) was tested in that age group.
Table 2.
Pharmacokinetic parameters of telbivudine after a single oral dose in HBV-infected pediatric patients and in comparison to a historical study of healthy adults
| Subject group and type of valuea | Tmax (h) | Cmax (ng/ml) | AUC0–24 (ng · h/ml) | AUC0–inf (ng · h/ml) | t1/2 (h)b | CL/F (ml/h) |
|---|---|---|---|---|---|---|
| >12–18 yrs, 600 mg; n = 8 | ||||||
| Mean | 3,510 | 22,300 | 27,700 | 38.7 | 23,200 | |
| SD | 1,190 | 5,720 | 6,830 | 7.42 | 7660 | |
| CV (%), mean | 33.9 | 25.7 | 24.6 | 19.1 | 33.0 | |
| Geometric mean | 3,340 | 21,600 | 26,900 | 38.2 | 22,300 | |
| CV (%), geometric mean | 34.1 | 28.4 | 28.8 | 18.2 | 28.8 | |
| Median | 2.59 | 3,500 | 21,500 | 28,100 | 36.2 | 21,400 |
| Min; max | 1.97; 4.00 | 2,250; 5,710 | 12,600; 30,800 | 14,700; 37,500 | 29.7; 53.7 | 16,000; 40,700 |
| 6–12 yrs, 15 mg/kg; n = 4 | ||||||
| Mean | 3,290 | 17,600 | 21,500 | 36.3 | 19,200 | |
| SD | 748 | 3,400 | 4,610 | 6.81 | 2,060 | |
| CV (%), mean | 22.7 | 19.3 | 21.5 | 18.7 | 10.7 | |
| Geometric mean | 3,230 | 17,400 | 21,100 | 35.8 | 19,100 | |
| CV (%), geometric mean | 21.1 | 20.0 | 22.0 | 20.4 | 10.8 | |
| Median | 2.53 | 2,980 | 17,900 | 21,400 | 38.0 | 19,100 |
| Min; max | 1.83; 3.00 | 2,800; 4,400 | 13,800; 20,800 | 16,600; 26,500 | 26.9; 42.4 | 17,000; 21,500 |
| 6–12 yrs, 25 mg/kg; n = 4 | ||||||
| Mean | 5,430 | 33,100 | 40,500 | 28.0 | 15,000 | |
| SD | 1,530 | 9,530 | 9,680 | 7.03 | 3,820 | |
| CV (%), mean | 28.2 | 28.8 | 23.9 | 25.1 | 25.4 | |
| Geo-mean | 5,260 | 32,200 | 39,700 | 27.3 | 14,600 | |
| CV (%), geometric mean | 30.1 | 27.8 | 22.7 | 27.9 | 29.3 | |
| Median | 2.48 | 5,570 | 30,700 | 37,500 | 29.5 | 16,100 |
| Min; max | 1.92; 3.00 | 3,740; 6,840 | 24,800; 46,400 | 32,700; 54,400 | 18.8; 34.2 | 9,660; 18,300 |
| 2-<6 yrs, 15 mg/kg; n = 6 | ||||||
| Mean | 2,910 | 17,900 | 22,100 | 29.9 | 15,200 | |
| SD | 453 | 3,550 | 4,760 | 10.5 | 5,920 | |
| CV (%), mean | 15.6 | 19.8 | 21.6 | 35.2 | 39.0 | |
| Geometric mean | 2,870 | 17,600 | 21,700 | 28.3 | 14,000 | |
| CV (%), geometric mean | 17.3 | 20.9 | 20.9 | 39.0 | 48.1 | |
| Median | 2.00 | 3,060 | 17,500 | 20,900 | 29.8 | 15,400 |
| Min; max | 1.28; 3.03 | 2,080; 3,320 | 12,600; 21,900 | 17,000; 30,100 | 16.5; 41.9 | 6,490; 22,300 |
| 2-<6 yrs, 25 mg/kg; n = 1 | ||||||
| 4.00 | 2,440 | 15,300 | 20,400 | 28.3 | 17,100 | |
| Adult, 600 mg, oral solution | ||||||
| Mean | 3,456 | 25,437 | 32,440 | 43.8 | ||
| SD | 1,170 | 7,457 | 8,444 | 11.1 | ||
| CV (%), mean | 33.9 | 29.3 | 26.0 | 25.3 | ||
| Median | 3.00 | |||||
| Min; max | 2.00; 6.00 |
Min, minimum; max, maximum.
t1/2, half-life.
Comparison of pediatric telbivudine data to historical pharmacokinetic data from healthy adults.
The recommended dosage of telbivudine for the treatment of chronic hepatitis B in adults is 600 mg once daily. Based on the available adult pharmacokinetic data, the doses of telbivudine used in the current study were predicted to produce plasma exposures (AUCs) similar to those in adults treated with the recommended clinical dose. To test this hypothesis, telbivudine plasma concentration-versus-time profiles of individual pediatric patients receiving a single oral dose of telbivudine (15 mg/kg, 25 mg/kg, or 600 mg [approximately 10.3 mg/kg]) were compared to the mean profile of healthy adults administered a single dose (600 mg; approximately 8.2 mg/kg based on a mean weight of 73 kg) in the same oral solution formulation (reference 10 and Novartis data on file) (Fig. 1).
The plasma concentration-versus-time profiles in children age >12 to 18 years given 600 mg telbivudine were similar to the mean profile of healthy adults receiving the same oral dose. The arithmetic mean values for Cmax, AUC from 0 to 24 h (AUC0–24), AUC0–t (data not shown), and AUC0–∞ were also comparable between the children aged >12 to 18 years and adults (Table 2). Plasma exposure in children aged 6 to 12 years was lower at the 15-mg/kg dose (approximately 33% decrease in AUC) and higher at the 25-mg/kg dose (approximately 28% increase in AUC) than in adults who received 600 mg of the drug. Plasma exposures in children age 2 to <6 years receiving a single 15-mg/kg dose were similar to those in patients aged 6 to 12 years receiving the same dose. Plasma exposure in children aged 2 to <6 years who received a 15-mg/kg dose of telbivudine was also lower (approximately 31% decrease in AUC) than in adults.
To predict the steady-state exposure of pediatric and adolescent patients to telbivudine, mean plasma concentration-versus-time profiles for patients aged 2 to 12 years (15 mg/kg) and aged >12 to 18 years (600 mg) were fitted to a two-compartment 1st-order, microconstant, lag time, 1st-order elimination PK model (WinNolin, version 5.2) as described in Materials and Methods. The data from the 25-mg/kg group were excluded because fewer than the planned number of patients received this dose. This analysis predicted that steady-state telbivudine exposures in children would closely match those in healthy adults receiving 600 mg once daily at the following doses: 20 mg/kg/day for children aged 2 to 12 years and 600 mg/day for adolescents aged >12 to 18 years (Table 3).
Table 3.
Comparison of predicted telbivudine pharmacokinetics at the steady state in children aged 2 to 18 years to a historical study of healthy adults
| Subjects | Dose | Tmax (h) | Cmax (ng/ml; mean ± SD) | AUC0–24 (ng · h/ml; mean ± SD) | Ctrough (ng/ml) |
|---|---|---|---|---|---|
| Adultsa | 600 mg/day | 2 (1–4)b | 3,690 ± 1,250 | 26,100 ± 7,200 | 200–300 |
| Children aged 2–12 yrs | 20 mg/kg/day | 2.10 | 3,750 ± 1,120c | 28,300 ± 8,490c | 268–280 |
| Children aged >12–18 yrs | 600 mg/day | 2.16 | 3,340 ± 1,000c | 25,070 ± 7,520c | 227–244 |
All values from U.S. label for Tyzeka.
Mean (range).
Estimation of SD based on typical interpatient variability (CV, 30%) for telbivudine.
DISCUSSION
This first-in-pediatrics study assessed the safety, tolerability, and pharmacokinetics of a single dose of telbivudine in HBV-infected children and adolescents aged 2 to 18 years. The study started enrollment with the oldest children and, after assessment of safety, proceeded to each subsequent younger cohort. Enrollment in this phase I pediatric study was slow, with the main reasons being secondary to (i) parents after discussion of the study details declining to give consent, citing study complexity, and (ii) social issues relating to acknowledgment of their child's chronic hepatitis B virus infection.
There were no significant safety issues, and the single oral dose of telbivudine was well tolerated, as expected given the previous large amount of clinical experience in adults. Among the 23 patients who received telbivudine, with doses ranging from 15 mg/kg up to a maximum of 600 mg, 4 patients (17.4%) experienced an AE. All AEs were mild, and none occurred in more than one patient; skin lesions, pruritus, protein in urine, and malaise were suspected to be related to the study drug. No deaths or SAEs were reported in the study, and no patient discontinued due to an AE.
Dose estimations for this first-in-pediatrics study were based on the desired exposure of telbivudine, its linear pharmacokinetics, and extrapolation from previous experience with renally excreted nucleosides and nucleotides, such as lamivudine and adefovir. The predicted telbivudine CL/F versus age curve is similar to what has been shown for lamivudine (13), with a linear regression relationship of CL/F = 0.1939 × CLCR + 5.1277 (R2 = 0.64 [Novartis data on file]). The chosen pediatric dose for lamivudine is 3 mg/kg (about twice the adult dose), giving an exposure comparable to that produced by a 100-mg daily dose in adults. Similarly, for adefovir, doses of 0.3 mg/kg and 0.25 mg/kg (roughly twice the adult dose) were selected for children 2 to 6 and 7 to 11 years of age, respectively (12). The data from this study predicted a daily dose of 20 mg/kg for children, which was in the middle of the range predicted by comparing the telbivudine CL/F in children and adults based on previous experience, with extrapolation of renally excreted nucleosides, such as lamivudine and adefovir, from adults to children. For telbivudine, a 600-mg dose in adults (∼8.2 mg/kg) produces an AUC0–∞ of approximately 23,000 ng/ml · h (AUC0-24, ∼20,000 ng/ml · h). To achieve similar exposures in children 2 to 6 years old, a weight-based dose of 21 to 27 mg/kg was predicted; for the 7- to 12-year age group, a dose of 13 to 20 mg/kg was proposed. Discussion of these projections with health agencies resulted in the planned evaluation of both the 15- and 25-mg/kg doses. The data from this study with those of the two other renally excreted nucleosides and nucleotides indicate that the prediction methods are fairly accurate and a more compact study design could be considered for future investigations.
The comparison of drug exposures in this study to the historical data for healthy adults receiving a single 600-mg dose of telbivudine is appropriate since no pharmacokinetic data were available for adult patients infected with HBV receiving telbivudine with the oral solution and telbivudine pharmacokinetics are not different between healthy subjects and patients with chronic hepatitis B (10). In addition, bioequivalence for telbivudine between the oral solution and the tablets has been established (reference 10 and Novartis data on file); the estimated efficacious telbivudine dose for children should be applied for both formulations. This analysis recommended dosages of 20 mg/kg/day for children aged 2 to 12 years and 600 mg/day for adolescents aged >12 to 18 years, closely reflecting the predicted values. Limitations of this study are that it evaluated a single dose and efficacy was not assessed. Long-term safety and efficacy will be the focus of currently planned pediatric trials in HBV infection.
In conclusion, this study's main findings are as follows. (i) Telbivudine was safe and well tolerated in HBV-infected children receiving a single oral dose up to 600 mg. All AEs were mild in severity, and no patient discontinued the study due to an AE. (ii) A dosage of 20 mg/kg per day (up to a maximum of 600 mg per day) of telbivudine is recommended for pediatric use, as this resulted in plasma exposure similar to that seen in historical comparison to a healthy adult population receiving the marketed dose of 600 mg per day. The results have enabled additional large multicenter, multidose studies to assess the safety and activity in HBV-infected children.
ACKNOWLEDGMENTS
We thank the subjects and their parents for agreeing to participate in this study, Macy Guiont (INC Research) for assistance in running the study, and Catherine Jones for editorial support.
The study site investigators and authors from the LDT600A2104 study were as follows: Etienne Sokal, Cliniques Universitaries, St. Luc, Brusels, Belgium; Juliet Sio-Aguilar, Philippine General Hospital, Office of the Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Ermita Manila, Philippines; Grace Uy, Philippine Children's Medical Center, Quezon City, Philippines; Stefan Wirth, Zentrum für Kinder- und Jugendmedizin der Klinikum Wuppertal GmbH, Wuppertal, Germany; Thomas Lang, Klinikum Starnberg Klinik für Kinder- und Jugendmedizin, Starnberg, Germany; Miguel Gascon, J. W. Goethe-Universität, Zentrum für Kinder- und Jugendmedizin, Frankfurt am Main, Germany; Deirdre Kelly, University of Birmingham, Birmingham Children's Hospital, The Liver Unit, Birmingham, United Kingdom; Giorgina Mieli-Vergani, King's College Hospital, London, United Kingdom; Mortada El-Shabrawi, Cairo University, Cairo, Egypt; Miroslava Bosheva, University Multi-profile Hospital for Active Treatment “St. Georgi,” Clinic of Children's Diseases and Genetic Disorders, Bulgaria; and Vania Nedkova, University Multi-profile Hospital for Active Treatment “Georgi Stranski,” Clinic of Children's Diseases, Pleven, Bulgaria.
Footnotes
Published ahead of print 17 June 2013
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