Serum Concentrations Of Clozapine Research Articles

Clozapine-Induced Acute Hyperglycemia Is Accompanied with Elevated Serum Concentrations of Adrenaline and Glucagon in Rats.

Clozapine, an atypical antipsychotic agent, has been reported to cause acute hyperglycemia. However, the mechanism of clozapine-induced rapidly developing hyperglycemia is not well elucidated. To clarify the mechanism underlying clozapine-induced acute hyperglycemia, we investigated the effects of single intravenous administration of clozapine on the serum concentrations of glucose and several endogenous substances in rats. Male Wistar rats received an intravenous injection of saline (control) or clozapine 2.5, 5, 10 mg/kg. Blood samples were obtained periodically after clozapine administration to determine the serum concentrations of glucose, adrenaline, glucagon, insulin, corticosterone, and clozapine. The serum concentrations of glucose, adrenaline, and glucagon increased dose-dependently after the administration of clozapine at 2.5-10 mg/kg, and reached maxima at 5 mg/kg of clozapine. The serum concentration of corticosterone increased after the administration of clozapine, but no significant variation was observed with the dosage of clozapine. The concentration of serum insulin increased in a dose-dependent manner after clozapine administration. In conclusion, a single administration of clozapine increased the serum concentration of glucose in rats, and adrenaline and/or glucagon would be associated with clozapine-induced acute hyperglycemia.

Comedication of Valproic Acid Is Associated With Increased Metabolism of Clozapine

Valproic acid and clozapine are drugs commonly used in the treatment of schizophrenic and schizoaffective disorders. Pharmacokinetic interactions of valproic acid with several drugs are well known, yet results concerning the interaction with clozapine are inconsistent. Steady-state dose-corrected serum concentrations of clozapine and its main metabolite norclozapine were retrospectively analyzed in 45 patients receiving both clozapine and valproic acid. Controls were matched for sex, age, smoking, comedication, and inflammatory response. The group receiving comedication with valproic acid showed significantly lower median dose-corrected serum concentrations of norclozapine (0.44 [0.27-0.58] (ng/mL)/(mg/d) vs 0.78 [0.60-1.07] (ng/mL)/(mg/d)) as well as metabolite to parent compound ratios (0.40 [0.36-0.47] vs 0.71 [0.58-0.84]) by approximately 44%. Dose-corrected serum concentrations of clozapine were not significantly lower. The effect of valproic acid was independent of sex and smoking. Comedication with valproic acid accelerated metabolism of clozapine with predominant effects on the degradation of norclozapine. Therapeutic drug monitoring should be applied to guide individual patient responses upon initiation of comedication.

Inflammation and clozapine concentrations

Although clozapine is highly effective in managing patients with treatment‐resistant schizophrenia, it possesses a highly variable pharmacokinetic profile influenced by multiple factors. These variables include altered metabolic status as a result of drug‐drug interactions, as well as patient‐specific factors such as smoking1 and infection.2 The mechanism of infection‐related changes in clozapine pharmacokinetics is thought to be related to release of inflammatory cytokines that act as inhibitors of cytochrome P‐450 enzymes.3,4 Two recent case reports discussed the occurrence of elevated serum clozapine concentrations in patients with inflammatory conditions.5

Effect of clozapine dose and concentration on fasting concentration of appetite regulating peptides

The aim of this study is to analyze whether clozapine serum concentration may affect fasting serum levels of several appetite regulating peptides: CART, PYY(1-36), NPY, AgRP, des-acylated ghrelin, leptin and obestatin. Serum concentration of clozapine and fasting serum levels of des-acylated ghrelin, neuropeptide Y (NPY), agouti-related protein (AgRP), peptide YY (PYY(1-36)), cocaine- and amphetamine-regulated transcript (CART), leptin and obestatin were measured in 30 subjects with schizophrenia on clozapine monotherapy. Leptin concentration was negatively correlated with clozapine dose (r = −0.53, p = 0.002), while NPY concentration was negatively correlated with clozapine concentration (r = −0.55, p = 0.01). Correlations with other peptides were not significant. We cannot conclude that serum concentration of clozapine is directly associated with increased or decreased level of appetite-regulating peptides.

The Glasgow antipsychotic side-effects scale for clozapine in inpatients and outpatients with schizophrenia or schizoaffective disorder

Background: The inconsistency in clinician and patient ratings of clozapine-induced side effects underscore the need to supplement clinician-based estimates of side effects with patient-reported ones.Aims: The main aims of the study are validation of the Glasgow antipsychotic side-effects scale for clozapine (GASS-C) in Serbian inpatients/outpatients with schizophrenia or schizo-affective disorder and recommendations for its future use, based on common and rare clozapine-associated side-effects.Methods: The GASS-C was administered to 95 outpatients/inpatients diagnosed with schizophrenia, schizoaffective, or chronic psychotic disorder.Results: The scale showed good overall reliability, with an internal consistency coefficient of α = 0.84, an average retest coefficient of rho = 0.76, and a Spearman–Brown coefficient of validity of 0.81. Side effects were absent or mild in 64.2% of the patients, moderate in 31.6%, severe in 4.2%; 14% of the subjects considered their symptoms distressing. The most commonly reported side-effects were drowsiness, thirst, frequent urination, and dry mouth. Women reported more side effects than men, and patients not in a relationship reported significantly fewer side effects than patients in a relationship. Results indicate a weak positive correlation (rho = 0.231; p = .025) between severity of side effects and clozapine dose.Conclusions: The GASS-C showed good psychometric characteristics in clinical population of patients on clozapine. In future studies, clozapine serum concentrations should be measured when using the GASS-C to monitor side effects.

Correlation Between Serum Concentrations of N-Desmethylclozapine and Granulocyte Levels in Patients with Schizophrenia: A Retrospective Observational Study.

Clozapine is restricted to use in patients with treatment-refractory schizophrenia due to the risk of a serious drop in absolute neutrophil granulocyte count (ANC). The formation of reactive, unstable metabolites (adducts) has been suggested as a mechanism of clozapine-induced granulocyte decline. These adducts are not detectable in vivo, but stable clozapine metabolites could potentially be indirect pharmacokinetic measures of adduct formation. The present retrospective observational study investigated the correlation between concentrations of N-desmethylclozapine, the major stable clozapine metabolite, and ANC in a real-life population of clozapine-treated patients. Patients were includedfrom a therapeutic drug monitoring service at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between March 2005 and December 2015. Information about clozapine and N-desmethylclozapine steady-state trough concentrations, as well as accompanying measurements of ANC, were collected from the laboratory database. Correlations of serum concentrations of N-desmethylclozapine and clozapine (and their respective ratios) with ANC were investigated by linear mixed-model analysis. Overall, 129 patients with 855 measurements of clozapine/N-desmethylclozapine concentrations and ANC (range 0.9-19×109 cells/L, median 4.6) were included. Concentrations of N-desmethylclozapine, but not clozapine, correlated significantly and positively with ANC (estimated model slope 0.0011×109 cells/L/nM; p=0.002), and the N-desmethylclozapine/clozapine ratio also positively correlated with ANC (p=0.040). N-Desmethylclozapine level and ANC significantly correlated in this real-life population of schizophrenia patients. The positive correlation, which was also present for the metabolic ratio, might reflect reduced clozapine availability for the formation of reactive metabolites potentially affecting granulocyte level. However, as our findings were based on ANC mainly within the reference range, this hypothesis should be studied further in clozapine-treated patients with neutropenia or agranulocytosis.

Potential Role of Patients’ CYP3A-Status in Clozapine Pharmacokinetics

Background:The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy.Methods:Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients’ CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients.Results:The patients’ CYP2C19 or CYP2D6 genotypes and CYP1A2 expression seemed to have no effect on clozapine serum concentration, whereas CYP3A4 expression significantly influenced the normalized clozapine concentration (185.53±56.53 in low expressers vs 78.05±29.57 or 66.52±0.25 (ng/mL)/(mg/kg) in normal or high expressers, P<.0001), in particular that the patients expressed CYP1A2 at a relatively low level. The functional CYP3A5*1 allele seemed to influence clozapine concentrations in those patients who expressed CYP3A4 at low levels. The dose requirement for the therapeutic concentration of clozapine was substantially lower in low CYP3A4 expresser patients than in normal/high expressers (2.18±0.64 vs 4.98±1.40 mg/kg, P<.0001). Furthermore, significantly higher plasma concentration ratios of norclozapine/clozapine and clozapine N-oxide/clozapine were observed in the patients displaying normal/high CYP3A4 expression than in the low expressers.Conclusion:Prospective assaying of CYP3A-status (CYP3A4 expression, CYP3A5 genotype) may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYP3A testing for patients under clozapine therapy.

Effect of Clonazepam Co-Administered with Clozapine on the Serum Clozapine and Norclozapine Concentration of Patients with Schizophrenia: A Retrospective Survey.

BackgroundFor patients with schizophrenia clozapine (CLZ) is sometimes co-prescribed with clonazepam (CLNAZ). However, the impact of administration of CLZ along with CLNAZ on the serum concentration of CLZ and its major metabolite N-CLZ in schizophrenia is not well understood.AimTo investigate the effects of CLNAZ co-medication, patient gender, age and CLZ dosage on serum concentration of CLZ and norclozapine (N-CLZ) in individuals with schizophrenia.MethodsSerum CLZ and N-CLZ concentrations and demographic data were retrospectively analyzed for 341 patients with schizophrenia. We used SPSS 21.0 to perform stepwise regression to analyze the concentration data and demographics. Variables included in the analysis were: serum concentration of CLZ, N-CLZ, and CLZ dosage, gender, age and CLNAZ co-medication.Results(1) CLNAZ co-medication significantly affects serum CLZ and N-CLZ concentration in schizophrenics (p=0.010, p=0.020); (2) CLNAZ co-medication, gender and CLZ dosage significantly affect serum CLZ concentration in patients with schizophrenia (p=0.010, p=0.009, p<0.001). Serum CLZ concentration is negatively correlated with CLNAZ co-medication, and is positively correlated with being female and CLZ dosage; (3) CLNAZ co-medication and CLZ dosage were significantly related to serum N-CLZ concentration in participants (p=0.020, p<0.001). Serum N-CLZ concentration was negatively correlated with CLNAZ comedication, and positively correlated with CLZ dosage.ConclusionCLNAZ co-medication is associated with changes in serum CLZ and N-CLZ concentration. It is indicated that gender and/or CLZ dosage are also related to serum CLZ and N-CLZ concentration. Therapeutic drug monitoring and dosage regulation of CLZ should be performed for patients with schizophrenia who are also taking CLNAZ to maintain a safe and effective serum concentration of CLZ and N-CLZ.

Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice.

Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319mg, 4.9mg/kg) and serum concentration (mean 387ng/ml) of clozapine was found with the variation in dose explaining 30% of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3ng/ml, P=0.018) and moderate ADRs (261.4 vs 416.3ng/ml, P=0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs.

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.

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.

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine

The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. A systematic review of English-language MEDLINE articles was undertaken. Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

A Puzzling Case of Increased Serum Clozapine Levels in a Patient With Inflammation and Infection

A 23-year old male with a history of schizophrenia treated with clozapine 900 mg/d was admitted to the hospital for a gastrointestinal infection. The trough serum concentration of clozapine at admission was 9074 nmole/L, that is, almost 4-fold the upper limit of the reference range. The patients did not report any adverse effects of clozapine. The clozapine concentration 1 month earlier had been 1919 nmole/L, which is well within the reference range. There seems to be 2 different mechanisms explaining the increase in clozapine levels in this patient. First, a downregulation of CYP enzyme activities, which primarily seems to be mediated by interleukin-6, takes place during infection and inflammation. Second, the concentration of the acute phase protein α1-acid glycoprotein (AGP; orosomucoid) increases during infection and inflammation. As approximately 95% of clozapine is bound to AGP, the concentration of clozapine will increase in parallel with the increase in AGP. A therapeutic drug monitoring analysis measures the total drug concentration (ie, the concentration of unbound plus plasma protein bound drug), whereas the concentration of free drug exerts its pharmacological effects. Thus, this second mechanism will, in contrast to the first mechanism, not affect the clinical effect of clozapine. Although the patient was also treated with ciprofloxacin, which has been reported to inhibit the metabolism of clozapine, the clozapine levels did not further increase. This case illustrates the complex interrelationship between serum levels of clozapine and an intercurrent infection treated with potentially interacting antibiotics.

Case Report: The clinical implications of clozapine and cigarette smoking

INTRODUCTION Cigarette smoking is prevalent among psychiatric patients, with rates several times higher than the general population. As an example, up to 80% of schizophrenic patients smoke cigarettes. Clozapine is extensively metabolized by cytochrome P450 isoenzyme 1A2 and polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke are thought to induce CYP 1A2. Therefore concurrent smoking with clozapine can potentially lead to decreased clozapine levels and decreased efficacy, while smoking cessation can potentially lead to increased levels and toxicity. Enzyme induction has been reported to result in a 20 to 40% lower mean clozapine concentration in smokers compared to nonsmokers. We present a case of altered serum drug concentrations in association with changes in smoking status in a patient upon admission to a nonsmoking inpatient psychiatric facility.

Impact of Tobacco Smoking Cessation on Stable Clozapine or Olanzapine Treatment

To examine the pharmacokinetic implications and potential clinical effects of tobacco smoking cessation in patients on stable clozapine or olanzapine treatment. A literature search of MEDLINE (1950-November 2009) and EMBASE (1980-November 2009) was conducted using the search terms smoking, tobacco, cigarette, cannabis, smoking cessation, cytochrome P450, antipsychotic, clozapine, and olanzapine. In addition, reference lists from publications identified were searched manually. English-language articles and human studies were identified, yielding 111 returns. Articles that reported clinical outcomes following smoking cessation were selected. Pharmacokinetic data for these drugs were reviewed and articles that provided relevant background information were also included. Pharmacokinetic studies have demonstrated more rapid clearance of olanzapine and lower clozapine and norclozapine (desmethylclozapine) concentrations in smokers compared to nonsmokers. These studies also found that smokers require higher doses of these agents than nonsmokers. There are case reports of adverse clinical outcomes following smoking cessation in patients being treated with olanzapine and clozapine. Reports that included serum concentrations consistently found elevations following smoking cessation, and dosage reductions of 30-40% were required to achieve pre-cessation concentrations. Worsening psychiatric symptoms, somnolence, hypersalivation, extreme fatigue, extrapyramidal effects, and seizures have all been reported following smoking cessation in this patient group. Pharmacists need to be aware of potential risks associated with smoking cessation in patients stabilized on clozapine or olanzapine. Toxicity as a result of recent smoking reduction or cessation may be a reason for hospital admission. For hospitalized patients, pharmacists should obtain information concerning smoking status, including cessation attempts. Nonspecific signs and symptoms of elevated clozapine or olanzapine concentrations should be considered in relation to clinical status while the patient is hospitalized. Measurement of baseline serum clozapine concentrations and/or empiric dosage adjustment in patients expected to have a prolonged hospital stay with forced smoking cessation may be appropriate.

Determination of clozapine in serum of patients with schizophrenia as a measurement of medication compliance

Although antipsychotic drugs have been effective in reducing symptoms of schizophrenia, issues with adherence to these agents continue to be a barrier to the implementation and delivery of a successful treatment plan. An estimated 25% of patients with schizophrenia are partially adherent or non-adherent within 7–10 days of beginning therapy. There are some ways to evaluate the pharmacotherapy adherence of the patients: evaluation of the disease symptoms and/or the side effects of the drugs, questionnaires to evaluate quality of life, patient attitude toward his (her) drugs and pill counts. Although these methods represent a good option, they are subjective; for example, if the patients lie this leads to false results. Drug monitoring of patients’ biological fluids can be a useful tool to evaluate adherence by relating the serum or plasma levels of drugs with pharmacotherapy compliance. The aim of this study was to determine if serum clozapine levels are a suitable method for evaluating patient adherence to clozapine therapy. Clozapine concentration was determined in serum of 26 volunteer patients who were using this drug as pharmacotheraphy for 6 months to 5 years (steady state conditions at 7–10 days of treatment with the drug). The analysis was done for 6 months, with three samples taken for each patient during this time, relating clozapine serum concentration of lower than therapeutic range with pharmacotherapy non-adherence of patients. Moreover, we compared the evaluation of the pharmacotherapy adherence from serum levels of the drug, with the evaluation of the pharmacotherapy adherence from an indirect tool to evaluate symptoms of disease. Twelve patients were found non-adherent by clozapine serum concentration (46.15%), whereas eight patients were found non-adherent using clinician questionnaire (30.76%). After to evaluate some factors (cigarettes, co-medication, inter-individual variability) that could give different results of adherence from evaluation of serum concentrations and from indirect methods, we can conclude that the clozapine serum concentration is a more objective method of evaluating pharmacotherapy adherence of patients receiving this drug.

The influence of inflammatory reactions on the serum concentration of clozapine

The influence of inflammatory reactions on the serum concentration of clozapine

Determination of pharmacokinetic properties of clozapine and norclozapine in Korean schizophrenia patients

There is a wide interethnic variance in the pharmacokinetic profile of clozapine (CLZ), but the accumulated data are limited to some regional populations. In this study, we investigated the pharmacokinetic profile of CLZ in Korean patients and examined the association between serum CLZ parameters and clinical outcome. We assessed 78 Korean patients with schizophrenia who had been taking CLZ medication for more than 6 months. The patients were classified into three groups (good, moderate, and poor responders) according to their Clinical Global Impressions-Improvement scores. The serum concentrations of CLZ and norclozapine were 610.7+/-368.4 and 314.5+/-163.0 ng/ml (mean+/-SD), respectively, showing a large interindividual variation that was affected by dose, age, smoking habits, and sex by variable degrees. The pharmacokinetic profiles of Koreans were similar to those observed in Asians but quite different from those in Caucasians. Investigation on clinical responses revealed that the good or moderate responders clinically improved at a relatively low serum CLZ levels, whereas the poor responders showed less improvement despite the higher doses and serum levels. The metabolic ratio of the good responders was 0.65+/-0.20, higher than the poor responders (P=0.033). In this study, we identified a pharmacokinetic profile of CLZ in Korean schizophrenia patients and found a wide interindividual difference affected by various factors.