Does dose frequency influence the plasma concentration of clozapine and norclozapine in psychiatric patients in the Netherlands?

Background of the study:

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/1). 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.

Objective of the study:

The aim of this multicentre, non-randomised, open label 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.

Clozapine is highly protein bound and theoretically protein binding can become saturated when higher peak concentrations are reached after once daily (OID) dosing of clozapine. Also higher peak concentrations after OID dosing, could theoretically lead to saturation of clozapine’s metabolic enzymes and thus might alter its linear elimination rate into a non-linear relation, influencing its elimination rate. Finally, since norclozapine has a longer terminal elimination half-life than clozapine, it is possible that the metabolic ratio of clozapine to norclozapine is increased when switching from BID dosing to OID dosing. This underlines the need for a population pharmacokinetic study comparing both total and free clozapine and norclozapine concentrations when clozapine is adminis-tered OID or BID.

-T = 0 hours : trough concentration

-T = 20 minutes: absorption phase begins

-T = 2 hours and 4 hours: maximum concentration (Cmax) is expected to be reached after 1-3 hours

-T = 8 hours: for BID dosing, this time point will be on the slope between the Cmax and the trough concentration

-T = 12 hours: for OID dosing, this time point will be halfway the concentration time curve; for BID dosing, the concentration at t=12 hours is expected to be equal to the concentration at t= 0 hours (trough concentration).

At the study day(s), multiple blood samples will be drawn from the included patients. Sampling times depend on the patient’s clozapine dosing regimen.
In addition, a standardised assessment tool for measuring the side-effects of clozapine will be filled out by the participants during the study day