title: Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia.
abstract: 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.
authors.affiliation: Consolidated Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA. jfrazier@mclean.harvard.edu
authors.forename: Jean A
authors.initials: JA
authors.lastname: Frazier
authors.forename: Louise Glassner
authors.initials: LG
authors.lastname: Cohen
authors.forename: Leslie
authors.initials: L
authors.lastname: Jacobsen
authors.forename: Dale
authors.initials: D
authors.lastname: Grothe
authors.forename: James
authors.initials: J
authors.lastname: Flood
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Baldessarini
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
authors.forename: Grace S
authors.initials: GS
authors.lastname: Kim
authors.forename: Judith L
authors.initials: JL
authors.lastname: Rapoport
mesh_terms: D000293:Adolescent; D000375:Aging / Q000378:metabolism; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001711:Biotransformation; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D011569:Psychiatric Status Rating Scales; D012561:Schizophrenia, Childhood / Q000188:drug therapy / Q000378:metabolism*; D012565:Schizophrenic Psychology; D012727:Sex Characteristics; D013056:Spectrophotometry, Ultraviolet
chemical_list: D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine