Pharmacokinetics Of Olanzapine Research Articles

Population pharmacokinetics of olanzapine in pediatric patients with psychiatric disorders

ABSTRACT Objective To develop and validate a population pharmacokinetic (PPK) model of oral olanzapine in pediatric Chinese patients in order to individualize therapy in this population. Methods A total of 897 serum concentrations from 269 pediatric patients taking oral olanzapine (ages 8 to 17 years) were collected. Demographic parameters, biological characteristics and concomitant medications were investigated as covariates. The data was analyzed using a nonlinear mixed-effects modeling approach. Bootstrapping (1000 runs), normalized prediction distribution error (NPDE), and external validation of 62 patients were employed. Simulations were performed to explore the individualized dosing regimens in various situations. Results The one-compartment model with first-order absorption and elimination had an apparent clearance (CL/F) of 10.38 L/h, a distribution volume (V/F) of 9.41 L/kg and an absorption rate constant (Ka) fixed at 0.3 h−1. The equation was CL∕F (L∕h) = 10.38 × (body weight∕60)0.25 ×1.33 (if male) × 0.71 (if co-occurrence of infection) × 0.51 (if co-therapy with fluvoxamine) × 1.27 (if co-therapy with sertraline) × 1.43 (if co-therapy with valproate). The final model had satisfactory stability, robustness, and predictive ability. The results from a simulation suggested the oral olanzapine doses required for male and female pediatric patients weighing between 40-60 kg without co-medication were 10–15 mg/day and 7.5-10 mg/day, respectively, and dosage adjustments should be based on sex and body weight; and co-administrated with valproate, sertraline, or fluvoxamine. Conclusion This model may help individualize optimum dosing of oral olanzapine for pediatric patients.

Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F=15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10mg may be sufficient to achieve the therapeutic range of olanzapine. Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

Review: Influence of the CYP450 Genetic Variation on the Treatment of Psychotic Disorders.

Second-generation antipsychotic metabolism is mainly carried out by the CYP450 superfamily, which is highly polymorphic. Therefore, knowing the influence of the different known CYP450 polymorphisms on antipsychotic plasmatic levels and, consequently, the biological effect could contribute to a deeper knowledge of interindividual antipsychotic treatment variability, prompting possible solutions. Considering this, this state of the art review aimed to summarize the current knowledge about the influence of the diverse characterized phenotypes on the metabolism of the most used second-generation antipsychotics. Forty studies describing different single nucleotide polymorphisms (SNPs) associated with the genes CYP1A2, CYP2D6, CYP3A4, CYP3A5, and ABCB1 and their influence on pharmacokinetics of olanzapine, clozapine, aripiprazole, risperidone, and quetiapine. Most of the authors concluded that although significant differences in the pharmacokinetic parameters between the different phenotypes could be observed, more thorough studies describing pharmacokinetic interactions and environmental conditions, among other variables, are needed to fully comprehend these pharmacogenetic interactions.

Population Pharmacokinetics of Olanzapine and Samidorphan When Administered in Combination in Healthy Subjects and Patients With Schizophrenia.

A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2‐compartment disposition model with first‐order absorption and elimination and a lag time for absorption adequately described concentration‐time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5′‐diphospho‐glucuronosyltransferase–mediated direct glucuronidation and cytochrome P450 [CYP]‐mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5′‐diphospho‐glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.

What to Do About Missed Doses? A Retrospective Study of Olanzapine in the Elderly.

BackgroundSchizophrenia is characterized by a high disease burden. Olanzapine is a common drug used in antipsychotic medication. Little is known about the population pharmacokinetics of olanzapine in elderly patients. Missed doses are a common and unavoidable issue during the treatment of psychiatric diseases, especially in elderly patients. This study aimed to identify what an elderly person should do if doses are inadvertently missed.MethodsData were collected from 140 elderly psychiatric patients (aged ≥65 years) who received olanzapine therapy. Olanzapine concentrations were determined by high pressure liquid chromatographic tandem mass spectrometry (HPLC-MS/MS) and a population-based approach was used to quantify the characteristics of elderly patients. A non-linear mixed-effects model was used for data analysis. Simulations based on the final model were applied to predict situations involving a single missed dose or three consecutive missed doses under several remedial regimens.ResultsA total of 474 samples from 140 elderly patients were included in the therapeutic drug monitoring (TDM) data analysis. A one-compartment model, with no significant covariates, was developed to describe the population pharmacokinetics of olanzapine in elderly patients. The population predicted systematic clearance (CL/F) and volumes of distribution (V/F) were 18 L/h and 785 L, respectively. The simulation demonstrated that in a missed dose situation, elderly patients should take the regular dose immediately; the refill dose used at the second remedial time point depends on the length of the time delay.ConclusionHere, we used a simulation to provide a remedial regimen for missed doses of olanzapine in the elderly population. Our simulation can provide valuable suggestions for individualized therapy in elderly patients.

Using physiologically-based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet.

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically‐based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once‐daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady‐state total systemic exposures by 1.1‐, 1.5‐, and 1.6‐fold, respectively, for olanzapine, and by 1.2‐, 1.9‐, and 2.3‐fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies.

The gut microbiome influences the bioavailability of olanzapine in rats

BackgroundThe role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics. MethodsIn this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone. FindingsThe bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone. InterpretationAlistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted. FundingThis research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).

Application of Physiologically Based Pharmacokinetic Modeling to Predict the Effect of Renal Impairment on the Pharmacokinetics of Olanzapine and Samidorphan Given in Combination.

BackgroundA combination of the antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of patients with schizophrenia or bipolar I disorder. The effect of severe renal impairment on the pharmacokinetics of olanzapine and samidorphan after a single oral dose of OLZ/SAM was evaluated in a clinical study. Complementary to the clinical findings, physiologically based pharmacokinetic modeling was used to assess the effects of varying degrees of renal impairment on the pharmacokinetics of olanzapine and samidorphan.MethodsA physiologically based pharmacokinetic model for OLZ/SAM was developed and validated by comparing model-simulated data with observed clinical data. The model was applied to predict changes in olanzapine and samidorphan pharmacokinetics after administration of OLZ/SAM in subjects with mild, moderate, and severe renal impairment relative to age-matched controls with normal renal function.ResultsThe model predicted 1.5- and 2.2-fold increases in olanzapine and samidorphan area under the plasma concentration–time curve (AUC), respectively, after a single dose of OLZ/SAM in subjects with severe renal impairment vs controls, which was consistent with results from the clinical study. Application of the model prediction indicated increases in steady-state olanzapine AUC of 1.2-, 1.5-, and 1.6-fold, and samidorphan AUC of 1.4-, 1.8-, and 2.2-fold, in subjects with mild, moderate, and severe renal impairment, respectively, relative to healthy controls.ConclusionsPhysiologically based pharmacokinetic modeling extended the findings from a clinical study in severe renal impairment to other untested clinical scenarios; these data could be of interest to clinicians treating patients with renal impairment.

Population pharmacokinetics of olanzapine in children.

The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.

Therapeutic Drug Monitoring of Olanzapine and Cytochrome P450 Genotyping in Nonsmoking Subjects.

The relationship between a daily dose of olanzapine, its serum concentration, and the genotype of young nonsmoking men treated for schizophrenia or schizophreniform disorder was investigated in day-to-day clinical practice. Pharmacogenetics was also examined for the selected patients. A total of 49 participants were recruited as in-patients at the Mental Health Research Center (Moscow, Russia). Inclusion criteria were patients who had been diagnosed with schizophrenia or schizoaffective disorder (following DSM-IV guidelines) and were being treated with OLZ. A prospective, observational, open-study design was implemented. In line with the literature, patients were only included if they attained steady-state OLZ concentrations lasting for at least 8 days. A liquid chromatographic-tandem mass spectrometric method was developed for analyzing OLZ in human serum. The single cytochrome P450 polymorphisms were genotyped using an amplifier real-time polymerase chain reaction system following standard protocols. Evidence indicating that CYP2D6 polymorphism has a significant (P = 0.046) effect on the pharmacokinetics of olanzapine was obtained, confirming the beneficial effects of therapeutic drug monitoring (TDM) for olanzapine. TDM should therefore be used as a standard care during olanzapine therapy. TDM is also useful in assessing adherence and may have a role in limiting olanzapine dosage geared at minimizing the risk of long-term toxicity.

Severe Bradycardia Following Initiation of Low-Dose Olanzapine in A Patient with Anorexia Nervosa

Abstract BACKGROUND: Low-dose Olanzapine has been used clinically for over a decade in anorexia nervosa (AN) patients failing standard treatment in order to decrease anxiety and facilitate weight gain. While Olanzapine has been generally well tolerated, large scale data regarding safety and side-effects in AN patients is lacking. OBJECTIVES: To examine possible association between severe bradycar-dia and Olanzapine use in AN patients. DESIGN/METHODS: Case study and literature review. RESULTS: We present a case of severe bradycardia (HR 18) following initiation of low-dose Olanzapine in a 16 year old female admitted to our inpatient ward with AN and bradycardia during sleep.To our best knowl-edgeno other case studies of severe bradycardia in AN patients treated with Olanzapine have been published to date.We relate our case to findings from available literature that examines potential association between bradycardia and Olanzapine. We point to challenges with obtaining larger scale data on Olanzapine safety and side-effects in AN patients. CONCLUSION: There areinherent cardiac risks associated with treatment of AN patients. Existing literature in patients with diagnosis other than AN suggests there may be inter-individual differences in pharmacoki-netics of Olanzapine and that bradycardia may be a possible adverse effect of Olanzapine even at a low dose. Caution should be used in initiating Olanzapine in AN patients with baseline bradycardia.

Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers

Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15mg with fosamprenavir/ritonavir would lead to a similar area under the concentration–time curve (AUC) compared with olanzapine 10mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (Cmax) and apparent elimination half-life (t1/2) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93–1.08), 1.32 (1.18–1.47) and 0.68 (0.63–0.74), respectively. Fosamprenavir/ritonavir 700/100mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.

Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects

The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug-metabolizing enzymes, transporters, or receptors. The aim of this study was to identify genetic markers predictive of pharmacokinetics, pharmacodynamics, and adverse effects of olanzapine. Sixty-three healthy volunteers receiving a single 5-mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine. All genetic variants were analyzed by PharmaChip, but DRD2 Taq1A polymorphism was determined by real-time polymerase chain reaction. Olanzapine was measured using high-performance liquid chromatography combined with tandem mass spectrometry. The relationship of gender and polymorphisms with olanzapine pharmacokinetics, the change in prolactin levels, and the incidence of adverse effects were evaluated by multiple regression analysis. The pharmacokinetics of olanzapine was influenced by polymorphisms in CYP3A5, GSTM3, and GRIN2B. Prolactin levels were affected by gender and polymorphisms in DRD2 and 5-HTR2A. Polymorphisms in CYP2C9, TPMT, UGT1A1, MDR1, and 5-HTR2A were related to some adverse effects of olanzapine. Several polymorphisms can explain differences in the pharmacokinetics, pharmacodynamics, and safety of olanzapine in healthy subjects. Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established.

Oral Olanzapine Disposition in Adolescents with Schizophrenia or Bipolar I Disorder

Olanzapine is an atypical antipsychotic approved for the treatment of adults and adolescents (aged 13 -17 years) with schizophrenia or bipolar I disorder (manic or mixed episodes). To characterize the pharmacokinetics of olanzapine in adolescents, to estimate the sources of variability, and to identify significant co-variates. In addition, olanzapine pharmacokinetic parameters in adolescents were compared with those in adults to guide appropriate dosing recommendations for adolescent patients. A population pharmacokinetic modeling study was performed. The majority of pharmacokinetic data for the model came from a multicenter, open-label study in which 4.5 weeks of oral olanzapine 2.5-20 mg once daily was administered to a total of 105 patients aged 13-17 years (41.1-148 kg) who had a diagnosis of schizophrenia or bipolar I disorder. Four blood samples at steady state were obtained from each patient. Olanzapine concentrations in plasma were determined using a validated high-performance liquid chromatography method with electrochemical detection. Similar data from 11 adolescents from three previous studies were also included. A pharmacokinetic model was developed and the potential effects of patient characteristics (sex, bodyweight, age, ethnic origin) were investigated using a nonlinear mixed effects modeling program. The distributions of pharmacokinetic parameters for olanzapine in adolescents were compared with those previously reported in adults (n = 912, diagnosis of schizophrenia, olanzapine 5-20 mg/day) using the Kolmogorov-Smirnov 2-sample test. A visual predictive check was performed using Monte Carlo simulations on an external validation dataset. The pharmacokinetics of oral olanzapine in adolescent patients were described by a one-compartment pharmacokinetic model. The typical model estimates were 13.6 L/h (70 kg female patient) for oral clearance (CL/F) and 899 L for oral volume of distribution (V/F). Interpatient variability (40.5% for CL/F, 65.4% for V/F) and residual error (27%) were moderate. Bodyweight and sex had a significant influence on CL/F, which was lower in patients with lower weights and approximately 30% higher in males than females. Olanzapine exposure was typically 27% higher in adolescents versus adults. Approximately 77% of adolescents and adults had comparable CL/F values and 69% had comparable V/F values. The pharmacokinetics of oral olanzapine in adolescent patients are similar to those in adults, and are linear in the dosage range of 2.5-20 mg/day. Given the small magnitude of co-variate effects and the interpatient variability, dose adjustments based on bodyweight or sex are not necessary in adolescents.

Pharmacokinetics of olanzapine in Chinese male schizophrenic patients with various smoking behaviors

Tobacco consumption has been recognized as a factor mediating the interindividual variations in olanzapine's pharmacokinetics and pharmacodynamics. The primary objective of this study was to describe the dose effect of smoking on the dose–plasma concentration relationship and the pharmacokinetics of oral olanzapine in male schizophrenic patients using high-performance liquid chromatography coupled with electrochemical detector. Twenty-seven male schizophrenic inpatients were recruited and were stratified into the following groups according to smoking behaviors: non-smokers ( n = 9), light-smokers (1–4 cigarettes per day; n = 9), and heavy-smokers (≥ 5 cigarettes per day; n = 9). Plasma olanzapine concentrations were determined up to 120 h following a single oral dose of 10 mg olanzapine. The pharmacokinetic parameters were calculated by the non-compartment method using WinNonlin software. Results show that there was a significant correlation among non-smokers ( n = 9; 0.79; p = 0.01) or combined with light-smokers ( n = 18; 0.62; p < 0.01) between peak plasma olanzapine concentrations ( C max ) and their individual dose-corrected by body weight, but this correlation did not appear in heavy-smokers. There were no significant differences between non-smokers and light-smokers except for significant decreased AUC 0→120 by 45.1% in light-smokers. The mean C max and the mean area under the plasma concentration–time curve from time zero to 120 h (AUC 0→120) of the heavy-smoking patients was 9.3 ± 4.3 ng/ml (65.2% reduction compared to the non-smokers) and 302.4 ± 167.8 h ng/ml (67.6% reduction compared to the non-smokers), respectively. In summary, a daily consumption of 5 cigarettes is probably sufficient for induction of olanzapine metabolism. Smoking cessation is recommended for olanzapine therapy to have better prediction for therapeutic dosages particularly in heavy-smokers. Compared to non-smokers, heavy-smokers therefore require a 50–100% increase in olanzapine doses. Therapeutic drug monitoring will need to be considered when schizophrenic patients change their smoking behaviors.

A 16 WEEK RANDOMIZED DOUBLE-BLIND, DOUBLE-DUMMY TRIAL OF SUBLINGUALLY DISINTEGRATING OLANZAPINE VS. STANDARD OLANZAPINE TABLETS IN PATIENTS WHO GAINED WEIGHT DURING OLANZAPINE

Tobacco consumption has been recognized as a factor mediating the interindividual variations in olanzapine's pharmacokinetics and pharmacodynamics. The primary objective of this study was to describe the dose effect of smoking on the dose–plasma concentration relationship and the pharmacokinetics of oral olanzapine in male schizophrenic patients using high-performance liquid chromatography coupled with electrochemical detector. Twenty-seven male schizophrenic inpatients were recruited and were stratified into the following groups according to smoking behaviors: non-smokers (n = 9), light-smokers (1–4 cigarettes per day; n = 9), and heavy-smokers (≥ 5 cigarettes per day; n = 9). Plasma olanzapine concentrations were determined up to 120 h following a single oral dose of 10 mg olanzapine. The pharmacokinetic parameters were calculated by the non-compartment method using WinNonlin software. Results show that there was a significant correlation among non-smokers (n = 9; 0.79; p = 0.01) or combined with light-smokers (n = 18; 0.62; p < 0.01) between peak plasma olanzapine concentrations (Cmax) and their individual dose-corrected by body weight, but this correlation did not appear in heavy-smokers. There were no significant differences between non-smokers and light-smokers except for significant decreased AUC0→120 by 45.1% in light-smokers. The mean Cmax and the mean area under the plasma concentration–time curve from time zero to 120 h (AUC0→120) of the heavy-smoking patients was 9.3 ± 4.3 ng/ml (65.2% reduction compared to the non-smokers) and 302.4 ± 167.8 h ng/ml (67.6% reduction compared to the non-smokers), respectively. In summary, a daily consumption of 5 cigarettes is probably sufficient for induction of olanzapine metabolism. Smoking cessation is recommended for olanzapine therapy to have better prediction for therapeutic dosages particularly in heavy-smokers. Compared to non-smokers, heavy-smokers therefore require a 50–100% increase in olanzapine doses. Therapeutic drug monitoring will need to be considered when schizophrenic patients change their smoking behaviors.

Sex, Race, and Smoking Impact Olanzapine Exposure

Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.

Long-Term Therapeutic Drug Monitoring of Risperidone and Olanzapine Identifies Altered Steady-State Pharmacokinetics

Conflicting therapeutic drug monitoring (TDM) results have been reported for risperidone and olanzapine. This study set out to examine the long-term pharmacokinetics of risperidone and olanzapine in a locked skilled nursing facility where medication administration was controlled by nursing staff. TDM was performed in a long-term treatment protocol for risperidone and olanzapine in 67 refractory chronic schizophrenic patients in a locked, skilled nursing facility. TDM was performed 632 times in the risperidone group of 34 patients and 563 times in the olanzapine group of 33 patients. The logarithm of plasma concentrations were analysed through time by piecewise linear mixed model regressions adjusted for the logarithm of dose. We found risperidone plasma concentration/dose ratio (C/D) accumulation peaks of 49% at 2 months (from baseline concentration) and 9-hydroxy-risperidone and total moiety C/D accumulation peaks of 66% and 55% above the 2-month level at 6 months, which are somewhat similar to those found in our prior study that included a subset of data points analysed here. The risperidone conversion to 9-hydroxy-risperidone by cytochrome P450 (CYP) 2D6 suggests CYP2D6 inhibition or DNA down-regulation in the first 2 months. Olanzapine showed a C/D accumulation peak at 4 months of 31% above baseline, and a slower increase to 47% above baseline at 18 months with no clear plateau. We identified five potential perturbations in the pharmacokinetics of risperidone and olanzapine that could potentially lead to adverse drug reactions. These long-term effects would not be captured by a standard 5-day pharmacokinetic TDM developmental testing model for antipsychotics, and a new model for characterizing variation in C/D by time course is therefore proposed. The time course of the accumulations identified suggests that both CYP inhibition and DNA regulatory mechanisms may be involved in the metabolism of these drugs. Long-term TDM can optimize treatment with risperidone and olanzapine and antipsychotics in general.

Serum Levels of Olanzapine in a Non-Fatal Overdose

Olanzapine is a widely used second generation antipsychotic drug. Case reports of intoxications have been published, but reports in the literature of non-fatal intoxications of olanzapine containing repeated measurements of serum levels are scarce. Therefore, this case of non-fatal olanzapine intoxication is presented, in which 19 blood samples were drawn during 2 weeks. The highest (initial) measured value was estimated at 800 pg/L. This patient ingested 550 mg of olanzapine resulting in clinical signs of intoxication, including seizures. Because the patient was found the day after the intoxication, the initial concentration had probably been higher. The pharmacokinetics of olanzapine has been described as linear and dose-proportional throughout the therapeutic dosing range. Large overdoses, however, have been described to show non-linear pharmacokinetics. In this study's series of serum concentrations, a two-phase elimination was seen, with an initial elimination half-life of about 24 h during the first 3 days, followed by a second phase with a half-life of about 2.5 days. The patient in this case recovered completely. Because the elimination time after intoxication can be considerably longer than expected, it is recommended that the patient's serum concentrations after intoxication be monitored.

Determination of Olanzapine in rat brain using liquid chromatography with coulometric detection and a rapid solid-phase extraction procedure

A sensitive and selective method was developed for the determination of the antipsychotic drug Olanzapine levels in rat brain tissue, based on HPLC with electrochemical detection. The analyses were carried out on a C8 reversed phase column (150 mm × 4.6 mm, 5 μm), using a mobile phase composed of methanol and a phosphate buffer (44.0 mM, pH 3.5), containing triethylamine (21:79, v/v), flowing at 1.2 mL min −1. A high sensitivity coulometric detection analytical cell containing two flow-through low volume working electrodes was used: electrode 1 was set at +0.350 V and electrode 2 at −0.200 V. Olanzapine, administered to rats in different doses or in different times, was extracted from tissue homogenate of either the whole brain or specific areas (cortex, hyppocampus, nucleus striatum) with a rapid solid phase extraction procedure (SPE) on Oasis HLB cartridges. The method provided a high extraction yield of Olanzapine and internal standard (2-methylolanzapine) from brain tissue homogenate with absolute recovery values higher than 90.0%. The detector response was linear over a concentration range of 0.2–100.0 ng mL −1 of Olanzapine. The limit of quantification (LOQ) was 0.2 ng mL −1. Precision results, expressed by the intra-day and the inter-day relative standard deviation values, were satisfactory, better than 4.6%. Accuracy was satisfactory as well. This method proved to be suitable for the analysis of Olanzapine in rat brain tissues and for the study of distribution and pharmacokinetics of Olanzapine in rat brain after a single treatment with the antipsychotic drug.