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 AUC0–8h 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.
*Consolidated Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; †McLean Division of Massachusetts General Hospital, Belmont, Massachusetts; ‡Joint Pediatric Psychopharmacology Unit, Massachusetts General and McLean Hospitals, Boston, Massachusetts; §Department of Pharmacy, Massachusetts General Hospital; ¶Department of Psychiatry Yale University, New Haven, Connecticut; |Clinical Pharmacokinetics Research Laboratory and Pharmacy Department, NIH, Bethesda, Maryland; ∥Clinical Chemistry Laboratory, Massachusetts General Hospital; **Department of Pathology, Harvard Medical School; ††Neuroscience Program, Harvard Medical School; ‡‡Child Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, Maryland.
Received June 13, 2001; accepted May 9, 2002
Supported by NIH (NIMH) Award MH-01573 and by McLean Private Donors to the Pediatric Psychotic Disorders Program (JAF); NIH grants MH-34006, MH-47370, and awards from the Bruce J. Anderson Foundation and the McLean Private Donors Neuropsychopharmacology Research Fund (RJB).
Address requests for reprints to: Jean A. Frazier, McLean Hospital, Pediatric Psychotic Disorders Program, Child Outpatient Service, 115 Mill St., Belmont, MA 02478. Address e-mail to: email@example.com