J Clin Pharmacol
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PEDIATRICS

The Pharmacokinetics and Safety of Adefovir Dipivoxil in Children and Adolescents With Chronic Hepatitis B Virus Infection

Etienne M. Sokal, MD, Deirdre Kelly, MD, Stefan Wirth, MD, Jacob Mizerski, MD, Anil Dhawan, MD and David Frederick, PhD

From the Pediatric Research Institute, Université Catholique de Louvain & Cliniques, St. Luc, Bruxelles, Belgium (Dr Sokal); University of Birmingham, Birmingham Children's Hospital, Birmingham, UK (Dr Kelly); Zentrum für Kinder- und Jugendmedizin, HELIOS Klinikum Wuppertal, Witten-Herdecke University, Germany (Dr Wirth); Oddzia-Chorób Infekcyinych Dzieci, Krakowski Szpital Specjalistyczny im. Jana Pawla II, Kraków, Poland (Dr Mizerski); King's College Hospital, London (Dr Dhawan); and Gilead Sciences, Foster City, California (Mr Frederick).

Address for correspondence: Etienne M. Sokal, Département de Pédiatrie, Université Catholique de Louvain and Cliniques St. Luc, 10 av Hippocrate, 1200 Brussels, Belgium; e-mail: etienne.sokal{at}uclouvain.be.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
There is a continued need for safe and effective treatments for children and adolescents with chronic hepatitis B. Adefovir dipivoxil (ADV) is a licensed treatment for chronic hepatitis B in adults. This study was designed to characterize the pharmacokinetic profile of adefovir following the administration of 0.14 mg/kg and 0.3 mg/kg of ADV (oral solution) in children aged 2 to 11 years and of ADV 10 mg in adolescents aged 12 to 17 years. Forty-five subjects were included in the pharmacokinetic and safety evaluations. Adefovir was rapidly absorbed. Adefovir levels rose rapidly in the first hour and then declined in a biphasic manner. Dose-proportional pharmacokinetics was observed in the 0.14-mg/kg and 0.3-mg/kg groups. The 0.3-mg/kg dose in children aged 2 to 6 and the 10-mg dose in adolescents resulted in exposures that were comparable to those seen previously in adults given ADV 10 mg. Adefovir dipivoxil was well tolerated at the doses evaluated in this study. Adverse events were generally mild and reported as being unrelated to study medication. There was 1 serious adverse event reported that was not related to study medication. No patient discontinued the study prematurely due to an adverse event related to the study drug.

Key Words: Adefovir dipivoxil • chronic hepatitis B • pediatric • pharmacokinetics • adolescent

Chronic hepatitis B infection in children is a significant global health care concern. Vertical transmission from mothers to infants or through close contact with infected individuals in childhood is still common in areas where hepatitis B virus (HBV) is endemic, despite the availability of effective vaccines. Approximately 90% of those infected perinatally, or within the first year of life, will become chronically infected.1 The Centers for Disease Control and Prevention estimates that 20% to 30% of adults with chronic hepatitis B in the United States were infected in childhood. The relative risk of developing hepatocellular carcinoma in adults was identified as being 9.6 times higher in patients who were hepatitis B surface antigen (HBsAg) positive and 60.2 times higher in HBsAg-positive patients who were also hepatitis e antigen (HBeAg) positive compared with those who were negative for both parameters.2 As in adults, treatment of childhood HBeAg-positive disease aims to accelerate the immunological response, leading to HBeAg loss and anti-HBe seroconversion, with the ultimate goal of HBsAg loss.1

In children, treatment with interferon alfa results in serum HBV DNA negativity and HBeAg loss in 26% of treated patients at 24 weeks.3 Higher long-term rates of HBeAg seroconversion have been demonstrated in children with serum alanine aminotransferase (ALT) levels ≥2 times the upper limit of normal (ULN) at baseline (73% after 7 years compared with 33% in children with lower serum ALT levels).3 However, treatment with interferon alfa has substantial limitations due to numerous side effects, including growth impairment.4,5


Figure 1
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  		Figure 1. Study design. ADV, adefovir dipivoxil; PK, pharmacokinetics; FU, follow-up

 
Lamivudine treatment in pediatric patients has been shown to induce HBeAg loss and DNA negativity in 23% of treated patients at 1 year.6 A subsequent 24-month treatment period in patients who had not initially achieved a virological response may increase the response rate.7 However, the development of YMDD (tyrosine, methionine, aspartate, aspartate) mutations in the HBV polymerase, detected in 19% of children and adolescents treated with lamivudine for 52 weeks, increased to 64% after an additional 24 months of treatment.6,7

These patients are candidates to alternative treatment with adefovir dipivoxil, which remains active against the YMDD mutant strain.8 The present study was therefore designed to explore the pharmacokinetics of adefovir in children and adolescents to assist in the identification of an appropriate pediatric dose to be further evaluated in phase III clinical trials.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Design
The objective of this study was to characterize the pharmacokinetic profile of adefovir dipivoxil (Hepsera, Gilead Sciences, Inc, Foster City, California) administered as an oral solution at 0.14 mg/kg and 0.3 mg/kg in children 2 to 11 years of age, as well as adefovir dipivoxil 10 mg administered as an oral suspension to adolescents aged 12 to 17 years.

From February to August 2003, 47 patients were recruited from 8 centers: 1 in Belgium, 3 in Germany, 2 in Poland, and 2 in the United Kingdom. The patients' parents or guardians provided written informed consent prior to enrolling into the study. The study was conducted in compliance with the Declaration of Helsinki and approved by the local Independent Ethics Committee prior to the commencement of subject screening.

At baseline, eligible patients aged 2 to 11 years were randomized to 1 of 2 treatment groups (A or B) and were administered multiple doses of adefovir dipivoxil oral suspension (0.14 mg/kg or 0.3 mg/kg; Figure 1) in a sequential order with a 7-day washout period in between doses. Patients were stratified into 2 age groups (2-6 years and 7-11 years) to ensure adequate numbers of subjects from each age group. The aim was to enroll 16 patients into each treatment group. Treatment group A received 0.14 mg/kg adefovir dipivoxil oral suspension on day 1 and, following a 7-day washout period, received 0.3 mg/kg adefovir dipivoxil oral suspension on day 8. Treatment group B received 0.3 mg/kg adefovir dipivoxil oral suspension on day 1 and, following a 7-day washout period, received 0.14 mg/kg adefovir dipivoxil oral suspension on day 8.

Patients aged 12 to 17 years were assigned to treatment group C and received 1 dose of adefovir dipivoxil 10 mg as an oral suspension on day 1 (Figure 1).

Subjects fasted for a minimum of 2 hours prior to dosing and 2 hours immediately following dosing. Water intake was limited to 240 mL for 2 hours before and 2 hours after drug dosing in addition to the 240 mL administered with study drug.

A follow-up assessment was conducted 7 days after completion of the dosing period, when a modified physical examination was performed and adverse events, concomitant medications, and laboratory parameters were assessed.

Clinical data were collected, monitored, and entered into a database by Parexel. Laboratory tests were conducted by Covance Laboratories (Geneva, Switzerland). Samples for determination of adefovir concentrations were analyzed using a sensitive and specific liquid chromatography mass spectrometry method with a lower limit of quantification of 1 ng/mL at Covance Bioanalytical Services (Indianapolis, Indiana).

Patients
Eligible patients included male or female children and adolescents, aged 2 to 17 years, with documented evidence of chronic hepatitis B with compensated liver function (defined as having a prothrombin time of ≤1 second above the normal range, serum albumin ≥30 g/L, total bilirubin <1.3 mg/dL or normal direct bilirubin, and no history of variceal bleeding, ascites, or encephalopathy). Patients had to have been serum HBsAg positive for at least 6 months prior to randomization, positive for HBV DNA (Roche Ampicor Monitor PCR assay, lower limit of quantification [LLQ] of 1000 copies/mL) within 4 weeks of the first dose, and HBsAg and HBeAg positive at study screening (ie, within 4 weeks of the first dose) before subjects could be enrolled into the study. In addition, children aged 7 to 17 years had to have a serum ALT level ≥1.2 x ULN.

Patients were excluded if they had a history of any serious or active medical condition, including decompensated liver disease, inadequate renal or hepatic function, and seropositivity for HIV, hepatitis C virus (HCV), or hepatitis D virus (HDV). Patients were also excluded if they had prior use of antiviral therapy with potential anti-HBV activity, other than lamivudine, within the previous 3 months; had participated in an investigational trial involving administration of any investigational compound within 2 months prior to screening; or had previously been treated with adefovir dipivoxil.

Females of childbearing potential must have had a negative pregnancy test (serum or urine) at screening.

Dose Selection
In a 70-kg adult, the approved 10-mg dose represents a dose of approximately 0.14 mg/kg of actual body weight. Children may require higher doses than adults, on a milligram per kilogram basis, to achieve comparable exposures. Therefore, an additional higher dose of 0.3 mg/kg was also explored in this study.

Pharmacokinetic Evaluations
Blood samples were collected at the following times postdose to assess adefovir drug levels: 0, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. Urine samples were also collected prior to dosing and 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours following each dose of adefovir dipivoxil.

Clinical Evaluations
Prior to the administration of each dose of adefovir dipivoxil, each subject had a physical examination and was asked about any concomitant medications. Blood samples were taken for hematology and clinical chemistry, and at least two 1-mL aliquots of serum were banked. A urine pregnancy test was conducted for women of childbearing potential. A urine sample for urinalysis was taken, and a 5-mL urine sample was frozen and banked for possible supplemental safety analysis.

Statistical Analysis
The pharmacokinetic parameters for adefovir were assessed by the application of a nonlinear curve-fitting software package (WinNonlin, Pharsight Corporation, Mountain View, California) using noncompartmental methods. The linear/log trapezoidal method was used in conjunction with extravascular input model 200, with input values for time of dose, plasma adefovir concentration, and corresponding real-time values based on drug dosing times whenever possible. Predose sample times of less than time 0 were converted to 0. Samples below the LLQ of the bioanalytical assay that occurred prior to the achievement of maximum plasma concentrations (Cmax) were treated as a concentration of 0 to allow for calculation of the initial area under the time-plasma concentration curve (AUC). Samples below the LLQ at all other time points were treated as missing data.

Analysis of variance (ANOVA) for the 2-period crossover design was used to assess for period or sequence effects within each age group (2- to 6-year-old and 7- to 11-year-old age groups).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Population
A total of 79 subjects were screened for study eligibility at 8 study centers, of which 47 were subsequently randomized: 13 subjects in the 2- to 6-year-old age group, 19 in the 7- to 11-year-old age group, and 15 in the 12- to 17-year-old age group (Table I). Two subjects, 1 in the 2- to 6-year-old age group and 1 in the 7- to 11-year-old age group, were never dosed. These subjects were excluded from the pharmacokinetic and safety analyses.


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  		Table I Baseline Characteristics

 

The 3 treatment groups were well matched with regards to baseline characteristics (Table I). Minor differences in the distribution of ethnicity were probably related to the small sample size in each group. Subjects in the 2- to 6-year-old age group had a lower median serum ALT level (33.0 IU/L) at baseline compared with the 7- to 11-year-old and 12- to 17-year-old age groups (71.5 IU/L and 74.5 IU/L, respectively). None in the 2- to 6-year-old age group had previously been treated with lamivudine, famciclovir, or interferon alfa, whereas a significant proportion of the older age groups had previously received treatment.

Pharmacokinetics
A total of 45 subjects were included in the pharmacokinetic analysis. Adefovir was rapidly absorbed, with the time for maximum drug concentration (tmax) values increasing slightly in the older age groups. As can be seen in Figure 2, adefovir levels increased rapidly over the first hour and then declined in a biphasic manner. The time of the last measurable concentrations (tlast) was similar between all groups except for in the 2- to 6-year-old 0.14-mg/kg group, where the tlast value was lower. Dose-proportional Cmax values were observed within each dosing group in the 2- to 6-year-old and 7- to 11-year-old groups, with Cmax values being 1.86 to 2.34 times higher in the 0.3-mg/kg group compared with the 0.14-mg/kg group (Table II). The AUC seen in the 0.3-mg/kg group was 2.14 to 2.35 times the values seen in the 0.14-mg/kg group. In the 7- to 11-year-old group, 2 subjects received doses greater than 10 mg due to their higher body weight. One subject received a dose of 11 mg and the other 11.6 mg. When these data were normalized to a dose of 10 mg, the mean AUC0-{infty} was 257.7 ng·h/mL.


Figure 2
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  		Figure 2. Median adefovir plasma concentration levels by age group.

 

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  		Table II Single-Dose Pharmacokinetic Parameters by Dose Group

 

The Cmax and AUC values seen in the 12- to 17-year-old 10-mg group were similar to the 0.3-mg/kg group (Figure 2, Table II). Mean adefovir elimination half-life (t1/2) values were similar across all doses and all age groups ranging from 5.45 to 6.84 hours.

Mean apparent clearance of adefovir (CL/F) levels appeared to increase with age and was independent of dose. Values ranged from 452 mL/min in the 2- to 6-year-old group to 745 mL/min in the 12- to 17-year-old group. A similar trend was seen with adefovir VzF, which appeared to increase with age but remained consistent within dosing groups.

The amount of adefovir excreted in urine (Ae) (Table III) appears to be age and dose related, with greater amounts of drug being excreted in the children older than 7 years and in the 0.30-mg/kg group as compared with the 0.14-mg/kg and 10-mg groups. Renal clearance appears to be unrelated to dose. However, it appears to increase with age, ranging from 4806 to 5085 mL/h in the 2- to 6-year-old group to 8879 mL/h in the 12- to 17-year-old group (Table III).


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  		Table III Urine Pharmacokinetic Parameters

 

Safety
In general, the adverse events reported were mild in intensity and judged to be unrelated to study medication. No subjects discontinued study medication prematurely due to an adverse event.

Seventeen (38%) subjects experienced at least 1 treatment-emergent adverse event. Four subjects in the 7- to 11-year-old group reported 6 adverse events that were considered as being possibly related to study medication: headache, vertigo, disturbance of attention and fatigue, and eye disorder and headache. One subject in the 12- to 17-year-old group reported 3 adverse events—rhinorrhea, sneezing, and a blister—that were considered as being possibly related to study medication.

There were no significant changes in hematology or clinical chemistry parameters reported during the study. Two subjects in the 7- to 11-year-old group had elevated serum ALT levels; both subjects had elevated serum ALT levels at screening.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
This study shows that adefovir dipivoxil administered in an oral suspension formulation is rapidly absorbed. The pharmacokinetic parameters (Cmax and AUC) of the 0.14-mg/kg and 0.3 mg/kg-doses appear to be dose proportional in the 2- to 11-year-old age groups, similar to observations in adults9 and similar to previous observations made in children for lamivudine.10 The rate and extent of adefovir absorption as indicated by tmax and AUC values following the 10-mg dose in the 12- to 17-year-old group was similar to that observed in the 0.3-mg/kg group in the younger children.

The results seen in the 0.3-mg/kg and 10-mg dosing groups are similar to the total exposure data previously seen in adults,9 although slightly higher Cmax values were seen in this study. The pharmacokinetic parameters of adefovir dipivoxil 10 mg in adults with chronic hepatitis B demonstrated a Cmax of 18.4 ng/mL and an AUC of 220 ng·h/mL. The significance of the higher Cmax values is currently unknown.

The 0.3-mg/kg dose resulted in higher adefovir levels in approximately half of the subject in the 7- to 11-year-old group. It is predicted, on the basis of the linear nature of the pharmacokinetics of adefovir, that a lower dose of 0.25 mg/kg, with a maximum dose of 10 mg, would result in a mean AUC of approximately 228 ng·h/mL, an exposure value that is similar to that seen in adults.

The urinary recovery of adefovir is lower in the younger children (2-6 years) compared with subjects aged 7 to 17 years. This observation may be due to possibly less reliable urine collection in the younger children.

Adefovir dipivoxil was well tolerated at all of the doses evaluated in this study. Adverse events were generally mild and reported as being unrelated to study medication. There was 1 serious adverse event reported that was not related to study medication. No patient discontinued the study prematurely due to an adverse event judged as being related to study medication. There were no unexpected changes in laboratory evaluations, vital signs, or physical examinations.

The pharmacokinetic and safety data from this study support the use of a 0.3-mg/kg adefovir dipivoxil dose in children aged 2 to 6 years. In children aged 7 to 11 years, a dose of 0.25 mg/kg of adefovir dipivoxil up to a maximum of 10 mg is recommended in light of the 0.3-mg/kg dose resulting in higher exposure values in this group. The recommended adefovir dipivoxil dose for patients aged 12 to 17 years is 10 mg given as a tablet. These dosing recommendation are being evaluated in a phase III controlled study in children and adolescents with chronic hepatitis B.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors would like to acknowledge the following investigators who also participated in this study: Dr Marek Woynarowski, Klinika Gastroenterologii, Hepatologii i Zywienia, Anstytut "Pomnik-Centrum Zdrowia Dziecka," Warszawa, Poland; Dr Hans-Georg Posselt, J. W. Goethe-Universität, Zentr. F. Kinder-u. Jugendmedizin, Frankfurt am Main, Germany; and Dr Ulrike Kullmer, Kinderklinik der Gutenberg Universität Mainz, Mainz, Germany. In addition, the authors thank John Fry for his assistance in the preparation of the manuscript and Annick Bourgois, Brussel's Pediatric Clinical Investigation Center, for coordination and data management.

Financial disclosure: This study was supported by Gilead Sciences, Inc, Foster City, California.

DOI: 10.1177/0091270007313325


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Sokal EM, Bortolotti F. Update on prevention and treatment of viral hepatitis in children. Curr Opin Pediatr. 1999;11: 384-389.[CrossRef][Medline] [Order article via Infotrieve]

2. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347: 168-174.[Abstract/Free Full Text]

3. Vo Thi DH, Bourgois A, Bontems P, et al. Chronic hepatitis B infection: long term comparison of children receiving interferon alpha and untreated controls. J Pediatr Gastroenterol Nutr. 2005;40: 141-145.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

4. Comanor L, Minor J, Conjeevaram HS, et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat. 2001;8: 139-147.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Sokal EM, Wirth S, Goyens P, Depreterre A, Cornu C. Interferon alfa-2b therapy in children with chronic hepatitis B. Gut. 1993;34: S87-S90.[Abstract/Free Full Text]

6. Jonas MM, Kelly DA, Mizerski J, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med. 2002;346: 1706-1713.[Abstract/Free Full Text]

7. Sokal EM, Kelly DA, Mizerski J, et al. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology. 2006;43: 225-232.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

8. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348: 808-816.[Abstract/Free Full Text]

9. Dando MT, Plosker GL. Adefovir dipivoxil: a review of its use in chronic hepatitis B. Drugs. 2003;63: 2215-2234.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Sokal EM, Roberts EA, Mieli-Vergani G, et al. A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B. Antimicrob Agents Chemother. 2000;44: 590-597.[Abstract/Free Full Text]
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This Article
Right arrow Abstract Freely available
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Right arrow All Versions of this Article:
0091270007313325v1
48/4/512    most recent
Right arrow Alert me when this article is cited
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Citing Articles
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