Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia
Department of Psychiatry
Medical Subject Headings
Adolescent; Aging; Antipsychotic Agents; Area Under Curve; Biotransformation; Child; Chromatography, High Pressure Liquid; Clozapine; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia, Childhood; Schizophrenic Psychology; Sex Characteristics; Spectrophotometry, Ultraviolet
Clozapine (CLZ) dose-related adverse effects may be more common in children than adults, perhaps reflecting developmental pharmacokinetic (PK) differences. However, no pediatric CLZ PK data are available. Accordingly, we studied CLZ and its metabolites, norclozapine (NOR), and clozapine-N-oxide (NOX) in six youth, ages 9-16 years, with childhood onset schizophrenia (COS). At the time of the PK study, mean CLZ dose was 200 mg (3.4 mg/kg). Serum was collected during week 6 on CLZ before and 0.5-8 h after a morning dose. Serum concentrations were assayed by liquid chromatography/UV-detection. Mean concentration, area-under-the-curve (AUC), and clearance were calculated. CLZ clearance averaged 1.7 L/kg-h. NOR concentrations (410) exceeded CLZ (289) and NOX (63 ng/ml) and AUC(0-8h) of NOR (3,356) > CLZ (2,359) > NOX (559 ng/ml-h) [53, 38, and 9% of total analytes, respectively]. In adults, NOR serum concentrations on average are 10-25% < CLZ, differing significantly from our sample. Dose normalized concentrations of CLZ (mg/kg-d) did not vary with age and were similar to reported adult values. Clinical improvement seen in 5/6 patients correlated with serum CLZ concentrations. In addition, clinical response and total number of side effects correlated with NOR concentrations. NOR (a neuropharmacologically active metabolite) and free CLZ may contribute to the effectiveness and adverse effects in youth.
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Citation: J Clin Psychopharmacol. 2003 Feb;23(1):87-91.
Frazier, Jean A.; Cohen, Louise Glassner; Jacobsen, Leslie K.; Grothe, Dale R.; Flood, James; Baldessarini, Ross J.; Piscitelli, Stephen C.; Kim, Grace S.; and Rapoport, Judith L., "Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia" (2003). Psychiatry Publications and Presentations. 390.