Clozapine Concentrations Research Articles

Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish.

The present study examined the bioconcentration of 2 basic pharmaceuticals: verapamil (a calcium channel blocker) and clozapine (an antipsychotic compound) in 2 fresh water fishes, fathead minnow and channel catfish. In 4 separate bioconcentration factor (BCF) experiments (2 chemicals × 1 exposure concentration × 2 fishes), fathead minnow and channel catfish were exposed to 190 μg/L and 419 μg/L of verapamil (500 μg/L nominal) or 28.5 μg/L and 40 μg/L of clozapine (50 μg/L nominal), respectively. Bioconcentration factor experiments with fathead consisted of 28 d uptake and 14 d depuration, whereas tests conducted on catfish involved a minimized test design, with 7 d each of uptake and depuration. Fish (n = 4-5) were sampled during exposure and depuration to collect different tissues: muscle, liver, gills, kidneys, heart (verapamil tests only), brain (clozapine tests only), and blood plasma (catfish tests only). Verapamil and clozapine concentrations in various tissues of fathead and catfish were analyzed using liquid chromatography-mass spectrometry. In general, higher accumulation rates of the test compounds were observed in tissues with higher perfusion rates. Accumulation was also high in tissues relevant to pharmacological targets in mammals (i.e. heart in verapamil test and brain in the clozapine test). Tissue-specific BCFs (wet wt basis) for verapamil and clozapine ranged from 0.7 to 75 and from 31 to 1226, respectively. Tissue-specific concentration data were used to examine tissue-blood partition coefficients.

Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey.

BackgroundClozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men.MethodsWe investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness.ResultsMean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27–0.79) mg/L] compared with men [0.44 (0.26–0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0–45.3)] for females compared with 32.5 (25.2–41.0) for males. Overall, BMI increased by 0.7 kg/m2 over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose ≤6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (χ2 = 18.6, p < 0.0001).ConclusionsWe have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism.

The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis.

Clozapine, an atypical antipsychotic agent, is highly effective in treatment-resistant schizophrenia; however, its major side effect is constipation. Instead of laxatives, rhein is a pharmacologically active component found in Rheum palmatum L., a medicinal herbal remedy for constipation. The purpose of this study is to determine whether rhein impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of clozapine in brain when used to relieve clozapine-induced constipation. Here, we have investigated not only the PK of clozapine in blood but also the effects of rhein on the PK of clozapine in blood and in brain extracellular fluid together with the PD effects on neurotransmitters in extracellular fluid. The concentrations of clozapine and norclozapine in biologic samples were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat medial prefrontal cortex (mPFC) produced by clozapine were assayed by high-performance liquid chromatography-electrochemical detection. The results demonstrate that the clozapine PK was nonlinear. Pretreatment with rhein for 7 days increased the total blood concentration of clozapine, but significantly reduced the unbound clozapine concentrations in the mPFC by approximately 3-fold. Furthermore, 7 days of rhein pretreatment thoroughly abolished the efflux of dopamine and its metabolite (3,4-dihydroxyphenylacetic acid) and altered the profile of homovanillic acid, another metabolite of dopamine, in the mPFC. In conclusion, rhein was found to substantially decrease clozapine and norclozapine concentrations in the mPFC dialysate, and this is accompanied by lower concentrations in the neurotransmitters in the same biophase. These findings suggest that a detailed clinical study for drug-drug interactions is recommended.

Factors predicting use of laxatives in outpatients stabilized on clozapine.

Constipation is a common and sometimes fatal side effect of clozapine treatment. In this study, we aimed to identify factors associated with clozapine-induced constipation. Data on 202 outpatients stabilized on clozapine treatment were collected. Of these, 71 patients (35%) had a current prescription for laxatives (a proxy for the presence of constipation). Mean clozapine dose was 400.4 mg/day in those prescribed laxatives and 390.1 mg/day in those not prescribed laxatives (p = 0.67), while mean clozapine plasma concentration was 0.53 mg/l and 0.49 mg/l, respectively (p = 0.29). Patients using laxatives had on average 29% higher norclozapine concentrations (mean = 0.34 mg/l) than those who did not use laxatives (mean = 0.27 mg/l; p = 0.046). Laxative use was more common in female patients (49.1%) than male patients (29.1%; p < 0.01). Prescribers should be vigilant for constipation at any dose or plasma concentration of clozapine and should be mindful that male patients may be undertreated. Norclozapine concentrations may predict clozapine-induced constipation.

Inflammation and psychotropic drugs: the relationship between C-reactive protein and antipsychotic drug levels.

In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient. The aim of this study was to find out whether elevated serum levels (≥5mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone. Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5mg/l) and pathological (>5mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis. Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0% (clozapine), 11.9% (quetiapine), and 24.2% (active moiety of risperidone), respectively. In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.

Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine.

Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia. Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity. The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains. This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.

Clozapine Induced EEG Abnormalities and the Serum Concentration of Clozapine in Japanese Patients with Schizophrenia

Introduction Clozapine-induced electroencephalography (EEG) abnormalities are common. It has been reported that clozapine-induced EEG abnormalities occur in a dose-dependent manner and correlate with the serum concentration of clozapine (C-CLZ). However, the oppositional results were also reported. Objectives The objective of this study was to investigate the relationship between serum level of clozapine and EEG abnormalities. Methods Twenty-eight patients were recruited in this study, but five patients were excluded because clozapine was discontinued before post-treatment EEG measurement or measurement of C-CLZ. Ultimately, 23 patients (6 males, 17 females) with an average age of 35 years were enrolled. The subjects were divided into EEG normal and abnormal group. C-CLZ and the serum concentration of metabolite of clozapine (N-CLZ) were measured. The correlation between C-CLZ and daily dose of CLZ (D-CLZ), N-CLZ and D-CLZ were evaluated in each group. C-CLZ per D-CLZ (C/D), N-CLZ per D-CLZ (N/D) and the ratio of C-CLZ to N-CLZ (C/N) were compared between the two groups. Results 74 serum levels were measured. All patients had normal baseline EEGs, and 10 patients later showed EEG abnormalities. There were a significant correlation between C-CLZ and D-CLZ (EEG normal: rs 0.58, p Conclusion There was no relationship between the serum concentration of clozapine and EEG abnormalities.

Nor-clozapine Plasma Concentration/daily Clozapine Dose Ratio (Ncz/d): an Index of Response to Clozapine Treatment.

The present study investigated relationships between plasma concentrations of clozapine (CZ) and nor-clozapine (NCZ), clozapine metabolic index (NCZ/CZ), nor-clozapine plasma concentration/daily clozapine dose ratio (NCZ/D) and response to clozapine treatment in schizophrenic patients. Twelve treatment-resistant schizophrenic patients, recruited for this study, were treated with clozapine for six weeks. Our sample was composed by 4 males and 8 females aged 35-52 years recruited at the Department of Psychiatry, University of Naples SUN. The diagnosis of schizophrenia was established according to ICD-10 criteria (9 paranoid type and 3 residual type) and with history of illness from more than ten years, resistant to treatments with other typical and atypical antipsychotics. All the patients in this study were treated with clozapine, valproic acid, lorazepam or delorazepam. Patient health improvement was assessed before (T0) and after six weeks of clozapine therapy (T6), using the Brief Psychiatric Rating Scale (BPRS). Plasmatic clozapine and nor-clozapine concentrations were determined by high-performance liquid chromatography (HPLC). Analyses of variance (ANOVA) and χ 2 -test (SPSS 19) were used to find correlations between the different studied parameters and the BPRS scores. No significant correlations between CZ, NCZ, NCZ/CZ and clinical health improvement in BPRS scores among our schizophrenic patients were found; however, a significant correlation (p

Occurrence of selected pharmaceuticals in water and sediment of Umgeni River, KwaZulu-Natal, South Africa.

Selected pharmaceuticals including antibiotics, antipyretics, a stimulant, an antiepileptic and an antipsychotic drug were determined in wastewater, surface water and sediment along the Umgeni River which is the main source of water to Durban City in KwaZulu-Natal, South Africa. Samples were analysed using high-performance liquid chromatography coupled to a mass spectrometer (HPLC-MS/MS) after clean up and pre-concentration by solid phase extraction (SPE). At the wastewater treatment plant outlet, the antipyretic ibuprofen was detected in concentrations up to 12.94μg/L and 15.96ng/g in wastewater and bio-solids, respectively. The antipsychotic clozapine was detected in concentrations up to 14.43μg/L and 18.75ng/g in wastewater and bio-solids, respectively. Other pharmaceuticals namely sulfamethazine, sulfamethoxazole, erythromycin, metronidazole, trimethoprim, acetaminophen, caffeine and carbamazepine were also detected but in lower concentration compared to clozapine and ibuprofen (<10μg/L or 10ng/g). Clozapine and ibuprofen were detected at high concentrations in the surface water and sediment of Umgeni River. The highest concentration of clozapine (78.33μg/L) was detected at the business park, while that for ibuprofen (62.0μg/L) was detected at the point where a tributary, Msunduzi, joins Umgeni. Metronidazole was only detected in sediment, and caffeine (2243.52ng/g) was detected at the highest concentration in the sediment at the blue lagoon sampling site. The antibiotic sulfamethoxazole was also detected in appreciable amounts up to 507.34ng/g in the sediment at the Msunduzi tributary sampling site. The data collected implies that while insufficiently treated wastewater contributes to surface water contamination, human activities also contribute appreciably to the pharmaceutical loading of River Umgeni.

Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

To assess (1) the variance of plasma clozapine levels; (2) the relative importance of sex, smoking habits, weight, age, and specific genetic variants of cytochrome P450 1A2 (CYP1A2), uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4), and multidrug resistance protein 1 (MDR1) on plasma levels of clozapine; and (3) the relation between plasma clozapine levels, fasting glucose levels, and waist circumference. There were 113 patients on clozapine treatment recruited from psychosis outpatient clinics in Stockholm County, Sweden. Patients had genotype testing for single nucleotide polymorphisms: 2 in MDR1, 3 in CYP1A2, and 1 in UGT1A4. Multiple and logistic regression were used to analyze the relations. There was a wide variation in plasma concentrations of clozapine (mean = 1,615 nmol/L, SD = 1,354 nmol/L), with 37% of the samples within therapeutic range (1,100-2,100 nmol/L). Smokers had significantly lower plasma clozapine concentrations than nonsmokers (P ≤ .03). There was a significant association between the rs762551 A allele of CYP1A2 and lower plasma clozapine concentration (P ≤ .05). Increased fasting glucose level was 3.7-fold more frequent in CC and CA genotypes than AA genotype (odds ratio = 0.27; 95% confidence interval, 0.10-0.72). There was no significant relation between higher fasting glucose levels, larger waist circumference, and higher clozapine levels. It is difficult to predict plasma clozapine concentration, even when known individual and genetic factors are considered. Therefore, therapeutic drug monitoring is recommended in patients who are treated with clozapine.

An Electrochemical Micro-System for Clozapine Antipsychotic Treatment Monitoring

Clozapine is the most effective antipsychotic medication for schizophrenia, but it is underutilized because of the inability to effectively monitor its treatment efficacy and side effects. In this work, we demonstrate the first analytical micro-system for real-time monitoring of clozapine serum levels. An electrochemical lab-on-a-chip is developed and integrated with a catechol-chitosan redox cycling system. The microfabricated device incorporates 4 electrochemical reaction chambers with the capability of analyzing microliter-volume samples. Integration of the catechol-chitosan film amplifies the clozapine oxidative signal and improves the signal-to-noise ratio, which addresses sensitivity and selectivity challenges. Optimization of the redox cycling system fabrication parameters and analysis of various electrochemical techniques and data processing approaches is implemented to maximize clozapine detection performance. The device is tested with buffer samples containing clozapine and demonstrates a sensitivity of 54μCmLcm−2μg−1 and a limit-of-detection of 0.8μgmL−1, a sensing performance similar to a counterpart macro-scale benchtop system. Importantly, the feasibility to differentiate between 0.33μgmL−1 and 3.27μgmL−1 clozapine concentrations in human serum without any preceding dilution or filtering procedures is demonstrated, a significant step towards utilizing point-of-care testing micro-systems for schizophrenia treatment management. With these micro-systems, we envision more effective and safe treatment that will enable fewer visits to the clinicians, decrease costs and patient burden.

Genome-wide association study of lymphoblast cell viability after clozapine exposure.

Clozapine is an antipsychotic drug with proven efficacy in treatment-resistant schizophrenia but also known to induce potentially lethal agranulocytosis (CIA) in 1% of patients. Genetic factors are likely to play a role in the molecular basis of CIA. We explored an in vitro system to study the genetic susceptibility of CIA. Cell viability was measured in 90 lymphoblast cell lines exposed to a series of increasing concentrations of clozapine for 48 hr. Quantitative trait measures of cell viability as well as area under the survival curve were used in a linear mixed model for genome-wide association analyses. The estimated heritability of clozapine-induced cell viability reduction in these cell lines is h2=0.76. No genome-wide significant association was observed after correction for multiple testing. Two independent loci with nominal evidence of association were observed at 30× clinical clozapine concentration: rs2709505 (P=1.41×10(-8)) in an intron of MDFIC and rs10457252 (P=1.79×10(-8)) located in a gene desert at chromosome 6q21. We identified one locus (rs1293970) near PRG4 that was consistently associated for all separate concentration analyses at P<5×10(-5). PRG4 encodes hemangiopoietin, a growth stimulator for hematopoietic stem cells. No evidence was observed for involvement of the MHC region. Our results demonstrate that clozapine-induced viability reduction in lymphoblast cell lines is a heritable, polygenic trait. Thus, in vitro models of CIA might be a useful tool for future discovery of genetic risk factors, although larger sample sizes will be required to unambiguously identify these loci.

Comparative study of relative bioavailability between two formulations containing Clozapine 100 mg in patients with schizophrenia

This study aimed to evaluate the bioequivalence between two products containing Clozapine 100 mg (testing product: LifalClozapina® from Lifal – Industrial Pharmaceutical Laboratory of Alagoas S/A and the reference product: Leponex® from the Novartis Biociencias S/A. Laboratories) in 40 volunteers. The study was open, randomized, cross-over type, in a state of equilibrium, with two periods (two sequences) in which volunteers were given, in each period, the testing formulation or the reference formulation. The relative bioavailability of the formulations following oral administration was evaluated based on statistical comparisons of relevant pharmacokinetic parameters obtained from blood samples in a 24 hours period. The concentration of Clozapine was measured using an appropriate and valid analytical method. The pharmacokinetic measures used were: Cmin and Cmax, and ASCt. The mean differences (± SD) between reference and testing were: 0.1615 ± 0.3404 (ng/mL); -0.0969 ± 0.4131 (ng/mL); and 0.9143 ± 3.9941 (ng*h/mL). The confidence intervals for medium bioequivalence met the limits determined by the National Agency of Sanitary Surveillance (ANVISA) of 80 to 125%, and both medications were considered bioequivalent. Thus, the testing and reference products are considered interchangeable.

Clozapine serum concentrations in dopamimetic psychosis in Parkinson's disease and related disorders.

Psychotic symptoms in Parkinson's disease (PD) caused by dopamimetic treatment are a relevant clinical problem. As clozapine does not cause extrapyramidal side effects, it is suitable for treatment of dopamimetic psychosis. The main aim of the present study was (1) to establish an indication-specific recommendation for therapeutic reference range of clozapine among patients with dopamimetic psychosis in PD and related disorders. Secondary goals were (2) to test whether clozapine therapy is safe and calculable despite pharmacokinetic changes expected in the study population and (3) to assess influencing variables on clozapine serum levels. We carried out a retrospective chart review of patients suffering from dopamimetic psychosis as well as Lewy body dementia treated with clozapine. We extracted demographic and clinical data as well as results from therapeutic drug monitoring that was carried out via high-performance liquid chromatography in order to analyse clozapine and norclozapine serum concentrations. n = 35 patients could be identified and were included in the study. Mean age was 72.4years. Clozapine treatment for patients with dopamimetic psychosis in PD and related disorders seems to be safe and calculable. Mean clozapine serum concentration was 77.9ng/ml (SD 63.4ng/ml). Clozapine dose is significantly correlated with serum clozapine concentration (r = 0.35; R (2) = 0.122). Women showed lower clozapine serum concentrations although they received higher weight-corrected clozapine doses. We suggest an orienting indication-specific therapeutic reference range of 15-141ng/ml among PD patients with dopamimetic psychosis. Therapeutic drug monitoring is recommended and might help to minimize the risk of adverse events by screening for unexpectedly high serum concentrations of clozapine.

Factors associated with subjective side-effects during clozapine treatment

Objective: Clozapine is associated with subjectively unpleasant or clinically serious side-effects, which may affect treatment adherence. The aims of the study were to explore the association of clozapine+ norclozapine serum concentration and other factors with subjective side-effects in schizophrenia patients. Methods: In this cross-sectional study, 237 patients with a diagnosis of schizophrenia, schizo-affective or other non-organic psychoses completed the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), a self-report scale measuring side-effects of antipsychotics and a clinical questionnaire. Clozapine+ norclozapine serum concentration of 190 patients was measured. Of the patients 80 (33.7%) were on antipsychotic combination therapy. Results: Higher clozapine+ norclozapine concentrations were associated with the depression–anxiety factor of LUNSERS and antipsychotic combination treatments were associated with sympatichotonia–tension factor. Younger patients reported sedation more often than older patients. Conclusion: According to the present results, high clozapine concentrations were associated with depression–anxiety symptoms, but the causality remains unknown.

Prediction of brain clozapine and norclozapine concentrations in humans from a scaled pharmacokinetic model for rat brain and plasma pharmacokinetics.

BackgroundClozapine is highly effective in treatment-resistant schizophrenia, although, there remains significant variability in the response to this drug. To better understand this variability, the objective of this study was to predict brain extracellular fluid (ECF) concentrations and receptor occupancy of clozapine and norclozapine in human central nervous system by translating plasma and brain ECF pharmacokinetic (PK) relationships in the rat and coupling these with known human disposition of clozapine in the plasma.MethodsUnbound concentrations of clozapine and norclozapine were measured in rat brain ECF using quantitative microdialysis after subcutaneous administration of a 10 mg/kg single dose of clozapine or norclozapine. These data were linked with plasma concentrations obtained in the same rats to develop a plasma–brain ECF compartmental model. Parameters describing brain ECF disposition were then allometrically scaled and linked with published human plasma PK to predict human ECF concentrations. Subsequently, prediction of human receptor occupancy at several CNS receptors was based on an effect model that related the predicted ECF concentrations to published concentration-driven receptor occupancy parameters.ResultsA one compartment model with first order absorption and elimination best described clozapine and norclozapine plasma concentrations in rats. A delay in the transfer of clozapine and norclozapine from plasma to the brain ECF compartment was captured using a transit compartment model approach. Human clozapine and norclozapine concentrations in brain ECF were simulated, and from these the median percentage of receptor occupancy of dopamine-2, serotonin-2A, muscarinic-1, alpha-1 adrenergic, alpha-2 adrenergic and histamine-1 for clozapine, and dopamine-2 for norclozapine were consistent with values reported in the literature.ConclusionsA PK model that relates clozapine and norclozapine disposition in rat plasma and brain, including blood–brain barrier transport, was developed. Using allometry and published human plasma PK, the model was successfully translated to predict clozapine and norclozapine concentrations and accordant receptor occupancy of both agents in human brain. These predicted exposure and occupancy measures at several receptors that bind clozapine may be employed to extend our understanding of clozapine’s complex behavioral effects in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/1479-5876-12-203) contains supplementary material, which is available to authorized users.

Population Pharmacokinetic/Pharmacodynamic Model of Clozapine for Characterizing the Relationship Between Accumulated Exposure and PANSS Scores in Patients With Schizophrenia

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. 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, E(max), 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. 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 E(max) model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E(max) 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. 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.

Can valproic acid be an inducer of clozapine metabolism?

Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.

Olanzapine and clozapine induce glucose metabolism dysregulation in differentiated murine myocyte (LB360)

Clozapine and olanzapine are atypical antipsychotics (AAPs) that are commonly prescribed for managing not only psychosis such as schizophrenia and bipolar disorder but also non‐psychotic disorders these days as alternatives to the typical antipsychotics such as fluphenazine. Those atypical antipsychotics are believed to have fewer side effects than typical antipsychotics do, but still have adverse effects associated with metabolic dysregulation that often leads to metabolic syndromes such as type 2 diabetes and related disease. To investigate the mechanism of impairing glucose and lipid metabolism, we examined the glucose and lipid metabolism in drug‐treated murine myocytes (C2C12 cells, ATCC CRL‐1772). We examined the PI3/Akt signaling pathway that are related to glucose transport and glycogen synthesis as several preliminary studies found AAPs directly cause impaired glycemic control and insulin resistance. C2C12 myoblasts were differentiated by adding 2% (v/v) horse serum in DMEM medium after confluence. Cells were treated with the same concentration of clozapine, olanzapine, and fluphenazine at 20 μM. The amount of glucose uptake was estimated by measuring intracellular glucose contents. Level of mRNA and protein expression of the glucose metabolism related enzymes were measured by real time PCR and Western Blot analysis, respectively.

5:15 PM NOVEL GENETIC RISK VARIANTS FOR CLOZAPINE-ASSOCIATED NEUTROPENIA

Clozapine is a uniquely effective antipsychotic, but is very toxic in clozapine-naïve subjects. A 34-year-old male patient in a mental health facility, who was not prescribed clozapine, took 350 mg clozapine obtained from another patient at night. He was found dead the next morning. The presence of cardiomegaly related to obesity may have increased the risk of suffering an acute cardiac event after ingestion of clozapine. The medication prescribed to the patient was not thought to have contributed to the fatal outcome. Post mortem femoral blood clozapine and norclozapine concentrations were 0.48 and 0.20 mg/L, respectively. By way of comparison, audit of 104,127 plasma samples (26,796 patients) assayed for therapeutic drug monitoring purposes 1993–2007, showed plasma clozapine 0.35 mg/L or more in 57.5% samples (8.4% 1 mg/L or more). Those involved in the investigation of clozapine-associated deaths need to be aware that that death in an adult may occur after a single ‘therapeutic’ dose. A diagnosis of fatal clozapine poisoning cannot be made solely on the basis of a post mortem blood clozapine measurement.