Supporting successful clozapine treatment
Authors:   , Beex-Oosterhuis Marieke Martine 
Published: May 2023

The overall objective of this thesis is to support successful clozapine treatment, by firstly expanding the knowledge on the predictability of early clozapine discontinuation, secondly investigating the necessity of clozapine discontinuation due to (intended) pregnancy, and thirdly expanding the knowledge on therapeutic drug monitoring (TDM) of clozapine in light of once-daily (QD) dosing and protein binding, as well as in light of possible pitfalls in the interpretation of these TDM results.
In chapter 2.1 a prediction model was developed for unsuccessful clozapine treatment one year after the drug was first dispensed by a community pharmacy. Unsuccessful clozapine treatment was defined as the absence of current insurance claims for clozapine treatment 365 days after the index date. In 20.4% clozapine treatment was unsuccessful 1 year after the index date. Unsuccessful treatment was more common among outpatient starters than among inpatient starters. The number of variables needed to predict as much as 30% or 68% of the variability in unsuccessful clozapine treatment was too large for a simple prediction model.
Disproportionality in case safety reports on adverse pregnancy outcomes between clozapine and other antipsychotics (OAP) used during pregnancy was determined in chapter 3.1. Overall, no signal of disproportionate reporting associating clozapine with the studied adverse pregnancy outcomes was found. Chapter 3.2 provides a critical appraisal of the available evidence related to the safety of clozapine for schizophrenia during pregnancy and lactation. Data on perinatal clozapine exposure are of limited quality and quantity. Data thus far do not support that clozapine is teratogenic, increases the risk of stillbirth, abortion, or foetal disorders, nor that it increases the risk of delivery complications or premature birth. Information about clozapine exposure through breast milk is scarce.
In chapter 4.1, we determined whether the pharmacokinetics of clozapine and norclozapine with QD use are similar to twice-daily (BID) use. Dosing regimen did not affect any of the pharmacokinetic parameters of clozapine and norclozapine. Clozapine concentrations sampled in the morning with QD use are markedly different from its trough concentrations and higher than if the same daily dose had been used in two divided doses. The implications of this on clozapine’s therapeutic window at QD dosing is yet unknown.
In chapter 4.2, we investigated whether protein binding of clozapine and norclozapine becomes saturated at higher concentrations. Secondly, we investigated the correlation between unbound clozapine and norclozapine fractions and alpha-1 acid glycoprotein concentrations. Clozapine and norclozapine concentrations correlated well with its unbound concentrations. The dosing regimen did not affect the relation between total clozapine and norclozapine concentrations and its unbound fractions. A moderate (clozapine) and small (norclozapine) correlation were found between AGP-concentrations and unbound fractions of clozapine and norclozapine.
Chapter 4.3 describes the hurdles to be taken when developing a method for quantification of the unbound concentrations of clozapine and norclozapine in serum, using ultrafiltration (UF). This study demonstrates that the choice of the ultrafilter is a crucial part of the development of a method to measure unbound concentrations using UF. Adequate control of the factors influencing the NSA is essential, as well as factors influencing the stability of the protein-drug complex.
The study in chapter 4.4 assessed whether clozapine concentrations measured in plasma collected with tubes containing ethylenediaminetetraacetic (EDTA) and lithium-heparin (LH) as anticoagulants are comparable to clozapine concentrations measured in serum. The use of LH-derived plasma samples for therapeutic drug monitoring of clozapine may lead to different clinical interpretations than when using serum samples. Therefore, interchangeable use of LH-derived plasma and serum samples to measure clozapine levels in clinical practice is not recommended.
In chapter 5, the findings of this thesis were put into a broader perspective.