Influence of dose interval on the pharmacokinetics of both unbound and
total fractions of clozapine and norclozapine in psychiatric patients in the
Netherlands

The antipsychotic clozapine has widely been recognised as the golden standard
in treatment-resistant schizophrenia and partially responsive schizophrenia.
The Dutch Guideline for the use of clozapine recommends that, preferably,
clozapine should be given once daily (OID), before sleep, to relief the
discomfort of side effects such as sedation, orthostatic hypotension and
hypersalivation over the day, without assigning restrictions to a maximum dose.
Accordingly, in the Netherlands there seems to be a shift towards OID dosing of
clozapine at the end of the day. Though an OID regimen may be beneficial for
drug adherence, benefits regarding relief of side effects have not been proven
yet. Moreover, all the available pharmacokinetic studies with clozapine are
based on the twice-a-day (BID) regimen, as is the established clozapine
threshold concentration for effect (0.30-0.35mg/l). However, in practice the
same clozapine plasma reference concentrations, are used to guide therapy for
both single and divided dose schedules, but it is not known whether this is
legitimate or not.

The aim of this study is to assess the differences in the pharmacokinetic
properties of clozapine and norclozapine when clozapine is used OID or BID in
psychiatric patients, examining both clozapine and norclozapine concentrations
and its unbound fractions and total concentrations. Ultimately, the knowledge
of the full pharmacokinetic profile will facilitate in developing an evidence
based therapeutic window for clozapine when used OID. Additionally, we will
explore the influence of dose frequency on the impact and frequency of
clozapine*s side effects in relation with the clozapine plasma concentration
found in this study, using the UKU (Udvalg for Kliniske Undersogelser)
ratingscale.

This is a multicentre, non-randomised, open label study, using a limited
sampling strategy and population pharmacokinetic analyses.

The study will be conducted among psychiatric in- and outpatients receiving
clozapine therapy OID or BID as part of their regular treatment. Thus, patients
are not designated to any investigational treatment nor to any dosing regimen
different from their normal treatment. In participants using clozapine OID in
total 9 (or 10) blood samples will be drawn at the study day (7 (or 8) for
clozapine and norclozapine analysis and 2 for analysis of co-variates). All
samples will be taken within 12 hours after the start of the study day, using
the Venflon multiple sample sleeve, allowing collection of numerous samples
through a single venepuncture and thereby reducing the number of venapunctures.
A physician trained and competent in blood sampling will be installed at the
study location for drawing blood at specified time points. He/she will also
monitor both psychiatric and somatic signs of the participants in order to
detect any psychiatric or somatic discomfort, stress or other disturbing signs
during the study day.