title: Can low-dose clozapine pharmacokinetics predict steady-state plasma concentration?
abstract: Plasma concentrations of clozapine at a given dose vary considerably between patients, but drug levels are not routinely monitored during the normal 4- to 8-week dose escalation period at the beginning of therapy. We hypothesized that the dose required to give a putative threshold therapeutic concentration of 350 micrograms/L could be individualized using pharmacokinetic predictions made at the beginning of normal dose escalation. Low-dose clozapine (25-75 mg every 12 h) was administered to 21 treatment-resistant patients with schizophrenia who had been split into three groups. In group A (six patients), individual target doses were predicted from area under the concentration-time curve data after a single 50-mg dose. In group B (five patients), predictions were made as in group A but at steady state. In group C (10 patients), predictions were based on trough clozapine levels obtained at steady state immediately before dose increase. Dosage was increased, if tolerated, by 25 mg twice daily three times a week for 4-8 weeks according to established clinical practice. Clozapine concentrations were measured weekly, and actual target doses were determined for each patient from dose-concentration plots. In groups A and B, the correlation between actual and predicted target dose was not significant (r = 0.18, p = 0.59). In group C, however, it was significant (r = 0.86, p = 0.0016). These results suggest that individualized doses of clozapine for treatment-resistant patients with schizophrenia can be conveniently predicted from trough drug levels at the start of therapy. Such information would facilitate a more rapid, individualized, and consistent attainment of therapeutic doses than is now the case in clinical practice.
authors.affiliation: Department of Psychiatry, University of Western Ontario, London, Canada.
authors.forename: L K
authors.initials: LK
authors.lastname: Oyewumi
authors.forename: D J
authors.initials: DJ
authors.lastname: Freeman
authors.forename: D
authors.initials: D
authors.lastname: Vollick
mesh_terms: D000328:Adult; D003024:Clozapine / Q000097:blood* / Q000493:pharmacokinetics*; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008433:Mathematics; D008875:Middle Aged; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D004304:Dosage Forms; D003024:Clozapine