Wen-Biao Li

Serum concentrations of clozapine and norclozapine in the prediction of relapse of patients with schizophrenia

Schizophrenic outpatients (n=102) whose condition had stabilized with clozapine (CLZ) therapy and were being maintained on CLZ were followed for 1 year. Clinical status and concentrations of serum clozapine (CLZ) and its metabolite norclozapine (NCLZ) were evaluated periodically or when relapse occurred. Relapse was defined as a significant exacerbation of psychotic symptoms or hospitalization. Thirty-three patients relapsed and 69 did not. Relapse patients displayed significantly lower serum concentrations of CLZ and a sum of CLZ and NCLZ at endpoint than non-relapses (CLZ: 162 ng/ml vs. 237 ng/ml, p<0.001; CLZ+NCLZ: 225 ng/ml vs. 301 ng/ml, p<0.001). When all subjects were pooled together, a significant inverse correlation was observed between percent increase in the total score on the Brief Psychiatric Rating Scale (BPRS) from baseline and serum levels of CLZ alone (r=0.404, p<0.001) and the sum of CLZ and NCLZ (r=0.364, p<0.001). Relapses and non-relapses were well separated by a threshold CLZ serum concentration of 200 ng/ml with a sensitivity of 73% and a specificity of 80%. The threshold value represented about a 40% lower serum CLZ level than concentration achieved in acute treatment. Survival analysis showed a similarity of the relapse risk over time defined by the CLZ serum threshold and by symptomatic criteria. These results suggest that effective relapse prevention may require maintenance of patients at CLZ serum concentrations above 200 ng/ml and above 60% of the acute-phase level during long-term maintenance treatment of schizophrenia.

The Differential Effects of Steady-State Fluvoxamine on the Pharmacokinetics of Olanzapine and Clozapine in Healthy Volunteers

The combination of atypical antipsychotics and selective serotonin reuptake inhibitors is an effective strategy in the treatment of certain psychiatric disorders. However, pharmacokinetic interactions between the two classes of drugs remain to be explored. The present study was designed to determine whether there were different effects of steady‐state fluvoxamine on the pharmacokinetics of a single dose of olanzapine and clozapine in healthy male volunteers. One single dose of 10 mg olanzapine (n = 12) or clozapine (n = 9) was administered orally. Following a drug washout of at least 4 weeks, all subjects received fluvoxamine (100 mg/day) for 9 days, and one single dose of 10 mg olanzapine or clozapine was added on day 4. Plasma concentrations of olanzapine, clozapine, and N‐desmethylclozapine were assayed at serial time points after the antipsychotics were given alone and when added to fluvoxamine. No bioequivalence was found in olanzapine alone and cotreatment with fluvoxamine for the mean peak plasma concentration (Cmax), the area under the concentration‐time curve from time 0 to last sampling time point (AUC0‐t), and from time 0 to infinity (AUC0‐∞). Under the cotreatment, Cmax of olanzapine was significantly elevated by 49%, with a 32% reduced time (tmax) to Cmax, whereas the Cmax and tmax of clozapine were unaltered. The cotreatment increased the AUC0‐t and AUC0‐∞ of olanzapine by 68% and 76%, respectively, greater than those of clozapine (40% and 41%). The presence of fluvoxamine also prolonged the elimination half‐life (t1/2) of olanzapine by 40% and, to a much greater extent, clozapine by 370% but reduced the total body clearance (CL/F) of clozapine (78%) more significantly than it did for olanzapine (42%). The apparent volume of distribution (Vd) was suppressed by 31% in olanzapine combined with fluvoxamine but was unaltered in the clozapine regimen. A significant reduction in the N‐desmethylclozapine to clozapine ratio was present in the clozapine with fluvoxamine regimen. The effects of fluvoxamine on different aspects of pharmacokinetics of the two antipsychotics may have implications for clinical therapeutics.

Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia

Aim:To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters.Methods:Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors.Results:A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients.Conclusion:Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.

Therapeutic drug monitoring of psychotropic drugs in China: a nationwide survey.

Objective: To understand the status of therapeutic drug monitoring (TDM) of psychotropic drugs in psychiatric facilities in mainland China and to lay the foundation for improvement of TDM in psychiatry. Methods: A cross-sectional survey was conducted with a locally developed questionnaire among psychiatric facilities in which TDM of psychotropic drugs was available. The questionnaire included laboratory situations, implementation of TDM, equipment and analytical methods, internal quality control (IQC), and external quality assessment (EQA). Results: Forty-seven of the 58 delivered questionnaires were collected from the psychiatric facilities involving 26 provinces in mainland China. The response rate was 81.0%. Among all facilities surveyed, lithium was the most common psychotropic drug (68.1% of the laboratories) monitored by TDM, followed by clozapine (44.7%), carbamazepine (25.5%), chlorpromazine (21.3%), norclozapine (19.1%), risperidone (19.1%), paliperidone (17.0%), valproic acid (14.9%), and quetiapine (10.6%). Only 10.2% of the laboratories had recommendations for dose adjustments based on their TDM reports. Others only provided drug concentration results with no clinical recommendations. The analytical methods used included high-performance liquid chromatography, liquid chromatography with tandem mass spectrometric detection, and immunoassay. For lithium, most hospitals used ion-selective electrode methods. IQC and EQA were still in their infancy. Conclusions: This first nationwide survey showed that TDM has been available in a considerable number of psychiatric hospitals across China. Though current equipment and analytical methods meet the TDM need, much improvement is needed, particularly in new analytical method development, interpretation of results, consultation services, and quality control, including IQC and EQA. Guidance or consensus guideline for TDM of psychotropic drugs in the Chinese language is also urgently required.

Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia.

Background: The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log-linear, Emax, and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens. Results: A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine. The decrease in total PANSS score during treatment was best characterized using cumulated clozapine area under the curve (AUC) data in the Emax model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC50 (cAUC50) required to attain half of Emax was 296 mg·L−1·h−1·d−1. The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response but with a slower relief of symptoms in dose titration regimen. Conclusions: The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients.

Relative Bioequivalence Evaluation of Two Oral Atomoxetine Hydrochloride Capsules: A Single Dose, Randomized, Open-Label, 2-Period Crossover Study in Healthy Chinese Volunteers under Fasting Conditions

To evaluate the bioequivalence of a new formulation of atomoxetine hydrochloride (CAS 82248-59-7) capsules (test) and an available branded capsules (reference) after administration of a single 40 mg dose, randomized, open-label, 2-period crossover study was conducted in 22 healthy male Chinese subjects with a 1-week wash-out period. This study was designed for/the Honglin Pharmaceutical Co. Ltd and contracted to be done by the Beijing Anding Hospital in order to satisfy Chinese regulatory requirements to allow marketing of this generic product and performed according to the criteria of SFDA. Blood samples were collected before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detection. A non-compartmental method was used to calculate the pharmacokinetic parameters and evaluate bioequivalence of the 2 formulations. The 90% confidence interval (CI) of the ratios (test/reference) of atomoxetine for AUC0-24, AUC0-∞ and Cmax were 100.9% (93.6-108.8%), 103.1% (95.1-111.7%) and 105.2% (92.8-119.4%), respectively, which fell within the interval of 80-125% and 75-133%. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. From these results it can be concluded that the test formulation of atomoxetine capsules met the regulatory criterion for bioequivalence to the reference formulation.

Development of a population pharmacokinetic model of olanzapine for Chinese health volunteers and patients with schizophrenia

Objective Olanzapine is an atypical antipsychotic drug commonly used for the treatment of schizophrenia. However, there are still many complications associated with the use of olanzapine, and researchers continually strive to improve the handling of data from regular therapeutic drug monitoring (TDM). The objective of this study is to optimise the individualised treatment of olanzapine by establishing a population pharmacokinetics (PopPK) model in Chinese patients with schizophrenia. Methods This study integrates an extensive collection of concentration data from healthy volunteers after a single dose and a less extensive collection of samples from patients undergoing TDM. A PopPK model was developed using non-linear mixed-effects modelling. Potential covariates, including the olanzapine manufacturer and patient gender and age, were assessed during model development. A total of 616 plasma concentration levels from 22 healthy male individuals in China and 458 concentration levels from 112 male and 122 female patients with schizophrenia undergoing TDM at 12 hospitals in China were included in the analysis. The concentration profile could be best described using a two-compartment model with first-order absorption and elimination. Results The absorption rate (Ka) of olanzapine ranged from 2.85 h–1 to 5.39 h–1 for the different formulations. The typical absorption time delay was 0.877 hour. Body weight had a considerable effect on the apparent volume of the centre compartment and showed a power relationship. Conclusions A PopPK model of olanzapine in Chinese patients with schizophrenia was developed in this study. After determining the PK parameters of olanzapine, the results suggested that body weight exhibited a considerable impact effect on VC/F. The impact of subjects and formulations requires further study. The PopPK model established in this study is likely to provide some information for the individualised therapy of olanzapine. Trial registration number ChiCTR-TRC-10000934; Results.

Associations between the DBH gene, plasma dopamine β-hydroxylase activity and cognitive measures in Han Chinese patients with schizophrenia

The dopamine (DA) and norepinephrine (NE) systems modulate cognitive function. Dopamine β-hydroxylase (DβH) converts DA to NE, and its activity is under strong genetic control. This study examines the association of plasma DβH (pDβH) activity, DBH gene polymorphisms (-1021C>T, rs1611115 and 444G>A, rs1108580) and cognitive deficits in Han Chinese patients with schizophrenia. We assessed pDβH activity and cognitive function using the Verbal Fluency Test (VFT), Trail Making Test (TMT) A-B, Stroop color-word test and Wisconsin Card Sorting Test (WCST) in 200 patients with schizophrenia before and after 8weeks of antipsychotic treatment (96 patients completed assessments at baseline and post-treatment). We found that rs1611115 was significantly associated with pDβH activity, and there was strong LD between rs1611115 and rs1108580 polymorphisms. Correlation analysis indicated that pDβH activity correlated nominally with improvement in VFT score after 8weeks antipsychotic treatment. Moreover, there was a significant genotype effect of the rs1108580 on VFT: the VFT score of patients with AA genotype was higher than that of patients with AG/GG genotype either at baseline or the end of 8 weeks after treatment. However, this difference was not observed for rs1611115. Our findings confirm a strong association between genotype at rs1611115 and pDβH activity in Chinese patients with schizophrenia. Our data also suggest the rs1108580 polymorphism may influence some aspects of cognitive function in schizophrenia.