Clozapine Drug–Drug Interactions and Individualized Dosing in Bipolar Disorder: A Model-Informed Precision Dosing Approach

Introduction

Bipolar disorder (BD) is a mental illness characterized by alternating episodes of mania (or hypomania) and depression. It is a highly recurrent and complex condition with diverse clinical manifestations. During the manic phase, individuals experience elevated mood, rapid thinking, increased activity, along with grandiose delusions, impulsive behaviors, or reduced need for sleep. In the depressive phase, symptoms include low mood, loss of interest, decreased energy, and in severe cases, suicidal tendencies.^1–5 In terms of etiology, BD involves the interaction of multiple factors, mainly including genetic factors, neurobiological mechanisms, environmental and psychological factors, biological rhythm disorders, metabolic abnormalities, etc.^6–10 According to data from the World Health Organization (WHO), the overall global incidence rate of BD has reached 2.4%.¹¹ With the development of modern society, BD is showing an increasing trend.

The treatment methods for BD mainly include lifestyle adjustment, physical therapy, psychological therapy, drug therapy, etc, among which drug therapy is the main treatment method for BD.^12,13 Clozapine is a dibenzodiazepine class. It has a strong blocking effect on the 5-hydroxytryptamine (5-HT2A) receptor and dopamine (DA1) receptor in the brain, and also has a blocking effect on the dopamine (DA4) receptor, but a weak blocking effect on the dopamine (DA2) receptor. In addition, it has anti-choline (M1), anti-histamine (H1) and anti-A-adrenergic receptor effects. Extrapyramidal reaction and delayed dyskinesia are mild, generally do not cause elevated prolactin in the blood, can directly inhibit the ascending activation system of the brainstem reticular structure, have a powerful sedative-hypnotic effect, indications include schizophrenia and bipolar disorder, including refractory schizophrenia that is ineffective to conventional antipsychotic drugs, additionally it significantly improves positive symptoms (such as hallucinations and delusions) and some negative symptoms (such as apainess), and can reduce the risk of suicide for patients with BD.^14–18 More and more evidences indicate that clozapine can benefit patients with BD, especially for treatment-resistant cases or severe mood instability, and the frequency of its use in patients with BD is gradually increasing.^19–24

However, clozapine has significant pharmacokinetic differences and large variations among individuals, making it difficult to treat an appropriate dose of clozapine. Clozapine is mainly metabolized by cytochrome P450 (CYP) enzymes in liver cells, among them CYP1A2 and CYP3A4 are the main metabolic enzymes, leading to an increased likelihood of CYP enzyme-mediated drug–drug interactions (DDI). A lower clozapine concentration can affect the efficacy of the drug, while a higher concentration often increases the risk of toxicity. Common adverse reactions of clozapine include weight gain, elevated fasting blood glucose, dyslipidemia, epileptic seizures, neutropenia, myocarditis, and pneumonia, etc, and therapeutic drug monitoring (TDM) is often used to detect the concentration of clozapine to formulate an appropriate dosing plan for the next dose of clozapine, clinically.^25–30 However, since there is no reference TDM concentration when the first dose of clozapine is administered, it brings difficulties to the clinical individualized use of clozapine. Especially when there is potential DDI, it further increases the difficulty of individualized administration of clozapine in patients with BD. Thus, this study aims to explore clozapine DDI and its individualized administration regimens for patients with BD based on model-informed precision dosing (MIPD) technology, and achieve clinical precision medication.

Methods

Enrolled Patients

The BD patients included in this study are retrospectively collected from Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University between July 2020 and January 2025 in electronic medical record, which is approved by the Research Ethics Committee of Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University, where the requirement for written informed consent could be waived since the data are collected retrospectively without patient identifiers. This study adheres to the Declaration of Helsinki. Inclusion criteria: (1) BD patients, (2) clozapine treatment, (3) TDM for clozapine. Exclusion criteria: BD patients with missing clinical medical record data. The data included in this study mainly consist of the patients’ basic indicators, clinical test results, and medication information, etc.

Modeling

This study utilizes one of the main tools of MIPD, namely population pharmacokinetics (PPK) with non-linear mixed effect modeling (NONMEM, version 7, ICON Development Solutions, Ellicott City, MD, USA) software, to investigate the DDI of clozapine in patients with BD. Given trough concentration, we research the absorption phase with a one‐compartment model. During the modeling process, the main parameters included are CL/F, V/F, and Ka, where Ka is fixed at 1.3/h.^31,32

Inter-individual variability is shown in Formula (a):

(a)

A_i is individual parameter. TV(A) is typical individual parameter. η_i is symmetrical distribution.

Random residual variability is shown in Formula (b):

(b)

B_i is observed concentration. C_i is individual predicted concentration. ε₁ is symmetrical distribution.

Relationship between parameters and weight is shown in Formula (c):

(c)

D_i is i-th individual parameter. E_i is i-th individual weight. E_std is standard weight of 70 kg and D_std is typical individual parameter. F is the allometric coefficient: 0.75 for the CL/F and 1 for the V/F.³³

Continuous or categorical covariates parameters are shown in Formulas (d) and (e), respectively:

(d)

G_i is individual parameter. TV(G) is typical individual parameter. Z is parameter to be estimated. H_i is covariate of the i-th individual. H_m is population median for the covariate.

Two-step method is used for constructing covariate model. Constructing covariate model uses two-step method. The objective function value (OFV) are decreased more than 3.84 (P<0.05) and increased more than 6.63 (P<0.01), being deemed to the inclusion and exclusion standard, respectively.

Model Evaluation

Observations vs population predictions, observations vs individual predictions, conditional weighted residuals (WRES) vs population predictions, conditional WRES vs time, observations/Predictions vs time, density vs weighted residuals, quantiles of weighted residuals vs quantiles of normal, visual predictive check (VPC) of model are used to evaluate the final clozapine PPK model in BD patients. In addition, bootstrap way is used to repeated random sampling with replacement from the raw data base with 1,000 repetitions with different random sampling. The medians and 2.5th–97.5th percentiles of the results from bootstrap are used for comparing with final model parameters.

Simulation

Monte Carlo simulation (number of interactions is 1000) is adopted to recommend the optimal administration regimen. The simulation scenarios are divided into three types: (i) Patients with BD who are not combined with zopiclone or zolpidem tartrate. (ii) Patients with BD who are combined with zopiclone. (iii) Patients with BD who are combined with zolpidem tartrate. Every type is simulated with 1000 virtual BD patients using 5 weight groups (40, 60, 80, 100, 120 kg) and 10 dose groups (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/kg/day), respectively. The therapeutic window is 350–800 ng/mL, and the toxicity threshold is set at 1000 ng/mL.^34–37

Results

Patient Information

Fifty-one BD patients are included to analyze, among which 21 men and 30 women, aged 21.04–70.12 years old, and weighted 45.00–108.00 kg. Demographic data of BD patients and concomitant medication information are shown in Tables 1 and 2, respectively. Drug combination in BD patients include acarbose capsule, alprazolam tablet, amisulpride tablet, aripiprazole orally disintegrating tablet, aripiprazole tablet, atorvastatin calcium tablet, buspirone hydrochloride tablet, clonazepam tablet, diazepam injection, enteric-coated aspirin tablet, haloperidol injection, lamotrigine tablet, lithium carbonate extended-release tablet, lithium carbonate tablet, lorazepam tablet, magnesium valproate sustained-release tablet, metformin hydrochloride tablet, metoprolol succinate extended-release tablet, omeprazole enteric-coated capsule, perospirone hydrochloride tablet, phenhyxol hydrochloride tablet, propranolol hydrochloride tablet, risperidone tablet, sodium valproate sustained-release tablet, sodium valproate tablet, zolpidem tartrate, zopiclone tablet.

Table 1 Demographic Data of Bipolar Disorder Patients with Clozapine (n = 51)

Table 2 Drug Combination in Bipolar Disorder Patients with Clozapine (n = 51)

Modeling

In the final result, zopiclone, zolpidem tartrate with clozapine have DDI. Final clozapine MIPD model in BD patients is shown in Formulas (f) and (g):

(f)

ZOP, ZOL are zopiclone, and zolpidem tartrate, respectively. When BD patients take ZOP or ZOL, ZOP or ZOL is assigned the value of 1, otherwise ZOP or ZOL is 0.

Evaluation

Visual evaluation of final clozapine MIPD model in BD patients is shown in Figure 1, individual plots are shown in Figure 2, and bootstrap validation is shown in Table 3, indicating that clozapine model is accurate and reliable. Figure 3 is the clearance rate of clozapine in patients with BD. Meanwhile, when patients with BD are combined with zopiclone or zolpidem tartrate, the clearance rates of clozapine in patients with BD decrease by 44.9% or 35%, respectively.

Table 3 Parameter Estimates of Clozapine Final Model and Bootstrap Validation in Bipolar Disorder Patients

Figure 1 Model evaluation. (A) Observations vs population predictions. (B) Observations vs individual predictions. (C) Conditional weighted residuals (WRES) vs population predictions. (D) Conditional WRES vs time. (E) Observations/Predictions vs time. (F) Density vs weighted residuals. (G) Quantiles of weighted residuals vs quantiles of normal. (H) Visual predictive check (VPC) of model.

Figure 2 Individual plots. Abbreviations: ID, patient ID number; DV, measured concentration values; IPRED, individual predictive values; PRED, population predictive values.

Figure 3 The clearance rates of clozapine in patients with bipolar disorder. a: patients with bipolar disorder are not combined with zopiclone or zolpidem tartrate. b: patients with bipolar disorder are combined with zopiclone. c: patients with bipolar disorder are combined with zolpidem tartrate.

Recommended Dose

The simulated clozapine concentrations in patients with BD who are not combined with zopiclone or zolpidem tartrate, the simulated clozapine concentrations in patients with BD who are combined with zopiclone, and the simulated clozapine concentrations in patients with BD who are combined with zolpidem tartrate are shown in Figures 4–6, respectively. The probability for achieving the target concentrations of clozapine in patients with BD is shown in Figure 7, where Figure 7A–C are patients with BD who are not combined with zopiclone or zolpidem tartrate, patients with BD who are combined with zopiclone, patients with BD who are combined with zolpidem tartrate, respectively. When patients with BD have no combined medication of zopiclone or zolpidem tartrate, the recommended doses of clozapine for patients at 40–45 kg, 45–60 kg, 60–78 kg, 78–106 kg, and 106–120 kg are 10 mg/kg/day, 9 mg/kg/day, 8 mg/kg/day, 7 mg/kg/day, and 6 mg/kg/day, respectively. When patients with BD are combined with zopiclone, the recommended doses of clozapine for patients at 40–60 kg and 60–120 kg are 4 mg/kg/day and 3 mg/kg/day, respectively. When patients with BD are combined with zolpidem tartrate, the recommended doses of clozapine for patients at 40–52 kg and 52–120 kg are 5 mg/kg/day and 4 mg/kg/day, respectively. The recommended doses are shown in Table 4. Furthermore, this study simulates the probability to exceed the upper limit of the safe concentrations, which is shown in Figure 8A–C are patients with BD who are not combined with zopiclone or zolpidem tartrate, patients with BD who are combined with zopiclone, patients with BD who are combined with zolpidem tartrate, respectively. The detailed probability to exceed the upper limit of the safe concentrations can be seen in Table 4.

Table 4 Initial Dosage Recommendation of Clozapine in Patients with Bipolar Disorder

Figure 4 The simulated clozapine concentrations in patients with bipolar disorder who are not combined with zopiclone or zolpidem tartrate. (A) Bipolar disorder patients with 40 kg. (B) Bipolar disorder patients with 60 kg. (C) Bipolar disorder patients with 80 kg. (D) Bipolar disorder patients with 100 kg. (E) Bipolar disorder patients with 120 kg.

Figure 5 The simulated clozapine concentrations in patients with bipolar disorder who are combined with zopiclone. (A) Bipolar disorder patients with 40 kg. (B) Bipolar disorder patients with 60 kg. (C) Bipolar disorder patients with 80 kg. (D) Bipolar disorder patients with 100 kg. (E) Bipolar disorder patients with 120 kg.

Figure 6 The simulated clozapine concentrations in patients with bipolar disorder who are combined with zolpidem tartrate. (A) Bipolar disorder patients with 40 kg. (B) Bipolar disorder patients with 60 kg. (C) Bipolar disorder patients with 80 kg. (D) Bipolar disorder patients with 100 kg. (E) Bipolar disorder patients with 120 kg.

Figure 7 Probability for achieving the target concentrations of clozapine in patients with bipolar disorder. (A) Patients with bipolar disorder who are not combined with zopiclone or zolpidem tartrate. (B) Patients with bipolar disorder who are combined with zopiclone. (C) Patients with bipolar disorder who are combined with zolpidem tartrate.

Figure 8 Probability for exceeding the upper limit of safe concentrations in patients with bipolar disorder. (A) Patients with bipolar disorder who are not combined with zopiclone or zolpidem tartrate. (B) Patients with bipolar disorder who are combined with zopiclone. (C) Patients with bipolar disorder who are combined with zolpidem tartrate.

Discussion

DDI refers to the synergistic effect produced when patients use multiple drugs simultaneously or sequentially. It may enhance the therapeutic effect or alleviate adverse reactions, or it may reduce the therapeutic effect or cause unexpected toxicity.³⁸ This interaction can be divided into two categories: enhanced efficacy (including improved therapeutic effect and increased toxicity) and weakened efficacy (including decreased therapeutic effect and reduced toxicity). In terms of mechanism, it can be divided into pharmacokinetic and/or pharmacodynamic interactions. The pharmacokinetic interactions of medicine mainly result from the mutual interference of drugs in the absorption, distribution, metabolism and excretion links. Recent studies have confirmed that pharmacokinetic DDI can significantly alter the administration process of antipsychotic drugs in patients,^39–44 which affects the clinical therapeutic effect. Therefore, individualized drug administration regimens need to be considered in clinical drug administration. To explore the pharmacokinetic effects of combined medication on clozapine in patients with BD and further screen for potential DDI factors, this study conducts relevant explorations using MIPD.

MIPD integrates individual differences of patients, drug characteristics and disease information through mathematical modeling to guide personalized dose adjustment, so as to improve therapeutic effect and reduce adverse reactions.^45,46 Especially in the exploration of drug-related effects, MIPD has significant advantages. MIPD overcomes the limitations of traditional DDI clinical trials in terms of sample size, cost control, and coverage of special populations through sparse data modeling, multi-dimensional covariate integration, and dynamic simulation techniques. It is particularly suitable for interaction analysis and precise medication intervention in complex medication scenarios. Among them, the PPK model is one of the mainstream research methods of MIPD and is currently an important tool used in clinical research for DDI.^47–51 Based on this, we explore clozapine DDI and its individualized administration regimens for patients with BD based on MIPD technology, and achieve clinical precision medication.

The present study collects 51 patients with BD treated with clozapine and all the concomitant medication information used in the clinical practice of the patients are included and analyzed. Although the current number of 51 patients included is not very large, this methodological approach for PPK is fully adequate. Many studies with a similar sample size have already been reported. For example, in the study of population pharmacokinetics and dosing optimisation of polymyxin B in patients with severe burns, the sample size is 53.⁵² In the study of population pharmacokinetics and dosing optimization of cefoselis in paediatric patients with haematological malignancies, the sample size is 53.⁵³ In the study of levetiracetam dosing optimization in neurocritical care population: neuro-ARC study, the sample size is 50.⁵⁴ In the study of population pharmacokinetics and pharmacodynamics of meropenem in critically ill patients with renal impairment or on continuous renal replacement therapy, the sample size is 54.⁵⁵ In the study of impact of body weight on mycophenolic acid population pharmacokinetics in paediatric lupus nephritis: a pharmacogenomic integration study, the sample size is 51.⁵⁶ In the study of population pharmacokinetics of pyrazinamide and isoniazid in plasma and cerebrospinal fluid from South African adults with tuberculous meningitis, the sample size is 49.⁵⁷ That is to say, the current sample size of 51 patients is sufficient.

In the final result of present study, zopiclone, zolpidem tartrate with clozapine have DDI. Meanwhile, when patients with BD are combined with zopiclone or zolpidem tartrate, the clearance rates of clozapine in patients with BD decrease by 44.9% or 35%, respectively. Zopiclone and zolpidem tartrate are both commonly used non-benzodiazepine sedative-hypnotic drugs in clinical practice, mainly used to treat insomnia. In the treatment of BD, they are mainly used to improve sleep disorders. Of course, this research result can also be explained. As everyone knows, clozapine is mainly metabolized in the liver through CYP3A4 and CYP1A2.^58–60 In addition, zopiclone and zolpidem tartrate are mainly metabolized by the CYP3A4 enzyme.^61–64 Therefore, zopiclone and zolpidem tartrate may compete CYP3A4 metabolic enzymes, influence clozapine in the clearance rate of patients with BD.

Furthermore, the present study recommends the dose of clozapine in patients with BD in the presence of DDI through Monte Carlo simulation. When patients with BD have no combined medication of zopiclone or zolpidem tartrate, the recommended doses of clozapine for patients at 40–45 kg, 45–60 kg, 60–78 kg, 78–106 kg, and 106–120 kg are 10 mg/kg/day, 9 mg/kg/day, 8 mg/kg/day, 7 mg/kg/day, and 6 mg/kg/day, respectively. When patients with BD are combined with zopiclone, the recommended doses of clozapine for patients at 40–60 kg and 60–120 kg are 4 mg/kg/day and 3 mg/kg/day, respectively. When patients with BD are combined with zolpidem tartrate, the recommended doses of clozapine for patients at 40–52 kg and 52–120 kg are 5 mg/kg/day and 4 mg/kg/day, respectively.

Currently, the research mainly focuses on the DDI in pharmacokinetics. In the future, it is necessary to further explore the DDI impact on symptom control and adverse reactions. Additionally, the TDM data from external validation needs to be further verified to support our conclusions.

Conclusion

The present study explores the DDI of clozapine in patients with BD based on MIPD, and recommends the individualized dosing regimen of clozapine in patients with BD according to concomitant medication. The TDM data from external validation need to be further verified to support our conclusions in the future.