Therapeutic drug monitoring (TDM) helps optimize drug dosing by measuring blood concentrations. For antipsychotics, TDM is crucial in understanding the balance between efficacy and toxicity. While venous blood sampling is standard, it is invasive and distressing for patients with needle anxiety. Capillary microsampling, using a simple finger prick, offers a less invasive alternative that enables self-collection, reduces hospital visits, and improves patient experience. In the Capillary Olanzapine Sampling Method validation Study (COSMOS) study we aim to validate capillary microsampling for olanzapine compared to venipuncture.
The validated microsampling method will be implemented in the Toward precision dosing of olanzapine in anorexia nervosa (TORPEDO) study. Anorexia nervosa (AN) is a severe eating disorder with high mortality, affecting over 5,600 people in the Netherlands, with 1,300 new cases annually. Recovery is often prolonged, with only half of patients fully recovering within 10 years. Olanzapine is commonly prescribed to manage severe anxiety and obsessive compulsions, but limited pharmacokinetic data in AN patients often leads to cautious low dosing, potentially resulting in subtherapeutic treatment and delayed recovery. This study will investigate olanzapine pharmacokinetics in AN and non-AN patients (adolescents and young adults) to optimize dosing strategies, improving efficacy while minimizing side effects. We will analyze plasma levels at steady state and their correlation with side effects, including extrapyramidal symptoms, cardiac abnormalities, sedation, and metabolic changes.

Clozapine is the preferred treatment for resistant schizophrenia, reducing symptoms, hospitalization, and mortality but causing serious side effects. Therapeutic drug monitoring helps balance efficacy and risk. Due to significant interindividual variability (IIV), identical doses yield different exposures, necessitating an understanding of IIV's causes to optimize dosing. This study developed a pharmacokinetic model and assessed covariate effects on pharmacokinetics. A retrospective analysis of clozapine plasma concentrations from 32 patients at the Central Institute of Mental Health (June 2020–October 2021) was conducted using a point-of-care whole blood test. Pharmacokinetic analysis via NONMEM evaluated covariates including sex, age, smoking, caffeine intake, serum creatinine, liver enzymes, fluvoxamine coadministration, metabolic ratios, and CYP1A2 genotypes.
A one-compartment model with first-order absorption best described the data. The estimated distribution volume (V) was 905 L, and clearance (CL) was 44.4 L/h. Including sex and fluvoxamine use reduced CL variability by 8.9% and 7.8%, respectively. Female patients had 50% lower CL than males, and fluvoxamine users had a 25.5% reduction. These findings help explain clozapine's IIV and could improve personalized dosing strategies.

Introduction: Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations.
Areas covered: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented.
Expert opinion: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.

Background: Lithium is as a cornerstone treatment for bipolar disorder, effective across both acute and maintenance phases. Long-term use of lithium is linked to a significant reduction in suicide risk. Despite its well-established efficacy, the use of lithium is underutilized, especially in the younger population, mainly due to the presumed risk of developing chronic kidney disease. However, the data on lithium's safety in younger populations is limited, with a notable scarcity of pharmacokinetic and pharmacodynamic (PK/PD) studies and age-specific dosing guidelines.
Methods: This study details a comprehensive population PK/PD analysis using data from Phase I (an 8 week, open-label, randomized, escalating-dose study) and Phase II (a 16 week, open-label, long-term effectiveness trial) of the CoLT1 study. This includes lithium concentration-time profiles at both single dose and steady state, and trough concentrations, Neurological Rating Scale (NRS) scores, Neurological Examination for Lithium (NELi), thyroid function (TSH, T3, and T4), and renal function measured over 24 weeks. While steady-state PK profiles, trough concentrations, and effectiveness scores over this period have been published, the relationship between these PK profiles, trough concentrations, and the longitudinal safety data has yet to be analyzed.
Discussion: This is the first study to evaluate the safety parameters of lithium in children and adolescents. With access to the COLT1 data, we will expand on their findings by undertaking a comprehensive pharmacokinetic/pharmacodynamic (PK/PD) analysis. Our findings aim to clarify the safety profile of lithium in paediatric populations, providing crucial insights that could refine therapeutic strategies and enhance patient outcomes.

Background: Variation in sampling time impacts interpretation of clozapine levels that is presently done via a blood sample collection. Saliva is a non-invasive and convenient sample source for therapeutic drug monitoring (TDM) and has the additional benefit of containing only free fraction of clozapine, which might provide a stronger association with clozapine efficacy and side effects. This study aimed to examine the utility of saliva for clozapine TDM when compared against plasma.
Methods: Blood and saliva samples were collected in a single visit from 155 patients on clozapine. Clozapine levels were assayed using high-performance liquid chromatography with ultraviolet/visible detection (HPLC-UV). CYP1A2 metabolising status and known non-genetic factors influencing clozapine plasma levels were assessed. Side effects of clozapine, i.e. hypersalivation, sedation, constipation and QTc prolongation were assessed.
Results: Clozapine was detected in 151 (97.4%) saliva samples. Significant correlations were observed between plasma and saliva levels of clozapine (rs = 0.577, p < 0.001). In the multivariate model, CYP1A2 induction status, antidepressant use and sampling time were significantly associated with plasma clozapine levels. In saliva, CYP1A2 induction status was the sole factor associated with clozapine levels. Of the four clozapine side effects assessed, only QTc prolongation was significantly associated with both plasma and saliva clozapine concentrations.
Conclusion: Our study provides preliminary support for the use of saliva for monitoring of clozapine levels and patient adherence. In addition, our findings underscore the importance of CYP1A2 induction status and antidepressant use as key influencers of clozapine levels, contributing to more informed prescribing practices.

White blood cell monitoring is an essential part of clozapine treatment protocols worldwide in order to handle the risk of clozapine-related agranulocytosis. However, other types of clozapine-related adverse reactions may lead lethality in clozapine-treated patients. Protocols and package inserts worldwide provide no instructions for preventing clozapine-related adverse reactions other than agranulocytosis, such as myocarditis or pneumonia during clozapine titrations. Here we present an international guideline with authors from 50 countries/regions as an effort to personalise clozapine titration schedules for adult inpatients. This protocol is based on three innovative aspects: (1) personalised titration, (2) C-reactive protein (CRP) measures, as an index of immunological reaction to clozapine, and (3) dose predictions based on plasma or serum levels. This clozapine titration guideline recommends measuring clozapine and CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, to prevent adverse reactions that could lead to clozapine discontinuation.