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.