TY - JOUR
T1 - A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B
AU - Sokal, E M
AU - Roberts, E A
AU - Mieli-Vergani, G
AU - McPhillips, P
AU - Johnson, M
AU - Barber, J
AU - Dallow, N
AU - Boxall, E
AU - Kelly, D
PY - 2000/3
Y1 - 2000/3
N2 - 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 greater than or equal to 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 greater than or equal to 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),vith 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.
AB - 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 greater than or equal to 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 greater than or equal to 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),vith 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.
UR - http://www.scopus.com/inward/record.url?scp=0033998661&partnerID=8YFLogxK
U2 - 10.1128/AAC.44.3.590-597.2000
DO - 10.1128/AAC.44.3.590-597.2000
M3 - Article
VL - 44
SP - 590
EP - 597
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 3
ER -