A Dose Ranging Study of the Pharmacokinetics, Safety, and Preliminary Efficacy of Lamivudine in Children and Adolescents with Chronic Hepatitis B

Abstract

Fifty-three patients with chronic hepatitis B and active viral replication were studied for 4 weeks while on treatment and for 12 weeks after treatment with the oral nucleoside analogue lamivudine. Children aged 2 to 12 years were randomized to receive twice-daily doses of 0.35, 1.5, or 4 mg of lamivudine solution per kg of body weight or once-daily doses of 3 mg of lamivudine solution per kg. Adolescents aged 13 to 17 years received lamivudine at 100 mg (as tablets). Blood samples for pharmacokinetic assay were taken on days 1 and 28. Lamivudine was rapidly absorbed following oral administration, with the maximum concentration in serum being reached 0.5 to 1 h postdosing. Apparent oral clearance (CL/F) was higher in younger children and decreased with age, with CL/F values for adolescents reaching those seen for adults by the age of 12. All doses produced a dramatic fall in serum hepatitis B virus (HBV) DNA levels, with a median reduction of >/=99.5% after 4 weeks of treatment and with the levels returning to the baseline levels posttreatment. The correlation of dose, area under the concentration-time curve (AUC), and changes in HBV DNA levels, as measured by the Chiron Quantiplex assay, showed maximal antiviral effects (99.9% inhibition and a reduction of the amount of HBV DNA of approximately 3 log(10)) at 3 mg/kg/day, with no discernible increase in effect seen whether the drug was given at 4 mg/kg twice daily or whether it was given once daily or twice daily. The limit of detection of the assay (2.5 pg/ml) was reached for some but not all patients across the dose ranges, with the smallest number (n = 2) of those having values negative by the Chiron Quantiplex assay being in the lowest-dose group. The 13- to 17-year-olds showed a similar overall response in terms of the HBV DNA level reduction compared to that for patients younger than age 13. Analysis of the same samples by PCR, which has a lower limit of sensitivity than the Chiron Quantiplex assay, also showed average drops in HBV DNA levels of about 3 log(10) at 4 weeks for patients for which the AUC was >/=4,000 ng. h/ml, confirming the conclusions given above. Lamivudine treatment was well tolerated at all doses, with no significant adverse events or laboratory data changes. On the basis of pharmacokinetic and pharmacodynamic data, a 3-mg/kg/day dose in children (ages 2 to 12 years) with chronic hepatitis B provides levels of exposure and trough concentrations similar to those seen in adults following the receipt of doses of 100 mg. The 100-mg dose is being evaluated in a large phase III study with HBV-infected pediatric patients.

Phase I, Open-Label, Single-Dose Study To Evaluate the Pharmacokinetics and Safety of Telbivudine in Children and Adolescents with Chronic Hepatitis B

“…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 ϭ 0.1939 ϫ CL CR ϩ 5.1277 (R 2 ϭ 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.…”

“…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 Ͻ6 years old (n ϭ 12), with substrata of 2 to Ͻ4 years (n ϭ 4) and 4 to Ͻ6 years (n ϭ 8); stratum 2, 6 to 12 years old (n ϭ 8), with substrata of 6 to Ͻ9 years (n ϭ 4) and 9 to 12 years (n ϭ 4); and stratum 3, Ͼ12 to 18 years old (n ϭ 8).…”

501 Lamivudine therapy in children with chronic hepatitis B

“…Due to the limited number of data on representative groups of patients, establishing the optimal dose especially for children under the age of 12 years appears still problematic. It appears that increase in daily dose or in frequency of lamivudine administration does not improve the results [12,13,15,26] . The recommended dose of lamivudine results in the same serum concentration of the drug in children as in adults receiving 100 mg per 24 h [26] .…”

“…It appears that increase in daily dose or in frequency of lamivudine administration does not improve the results [12,13,15,26] . The recommended dose of lamivudine results in the same serum concentration of the drug in children as in adults receiving 100 mg per 24 h [26] . The experiences with treatment of chronic hepatitis B in adult patients suggest that this dose of lamivudine seems to be satisfactory.…”

Clinical Trial of Lamivudine in Children with Chronic Hepatitis B

“…Patients were randomly assigned (in a 2:1 ratio) to receive either lamivudine solution at a dose of 3 mg per kilogram of body weight (maximal dose, 100 mg) or a matching placebo solution orally once daily for 52 weeks. 5 …”