A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B

Fifty-three patients with chronic hepatitis B and active viral replication were studied for 4 weeks while on treatment and for 12 weeks after treatmen t 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 lami vudine solution per kg of body weight or once-daily doses of 3 mg of lamivu dine solution per kg, Adolescents aged 13 to 17 years received lamivudine a t 100 mg (as tablets). Blood samples for pharmacokinetic assay were taken o n days 1 and 28, Lamivudine was rapidly absorbed following oral administrat ion, with the maximum concentration in serum being reached 0.5 to 1 h postd osing. Apparent oral clearance (CL/F) was higher in younger children and de creased 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 hepati tis B virus (HBV) DNA levels, with a median reduction of greater than or eq ual to 99.5% after 4 weeks of treatment and with the levels returning to th e baseline levels posttreatment, The correlation of dose, area under the co ncentration time curve (AUC), and changes in HBV DNA levels, as measured by the Chiron Quantiplex assay, showed maximal antiviral effects (99.9% inhib ition 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 dru g was given at 4 mg/kg twice daily or whether it was given once daily or tw ice 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 bein g 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 pati ents 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 av erage drops in HBV DNA levels of about 3 log(10) at 4 weeks for patients fo r which the AUC was greater than or equal to 4,000 ng . h/ml, confirming th e conclusions given above. Lamivudine treatment was well tolerated at all d oses, with no significant adverse events or laboratory data changes. On the basis of pharmacokinetic and pharmacodynamic data, a 3-mg/kg/day dose in c hildren (ages 2 to 12 years),vith chronic hepatitis B provides levels of ex posure 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 lar ge phase III study with HBV-infected pediatric patients.