Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder: Linking blood levels to weight gain and effectiveness.

AIMS: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side-effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side-effects and drug effectiveness. METHODS: Twenty-four children and adolescents (15 males, 9 females) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side-effects and drug effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed-effects models. RESULTS: For both aripiprazole and dehydro-aripiprazole, one-compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations best predicted higher BMI z-scores (P < .001) and higher Hb1Ac levels (P = .03) during follow-up. No significant association was found between sum concentrations and effectiveness. CONCLUSIONS: Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems.

Relationship of Prolactin Concentrations to Steady-State Plasma Concentrations of Aripiprazole in Patients With Schizophrenia.

BACKGROUND: Aripiprazole is regarded as the first-line antipsychotic medication. Long-term aripiprazole therapy can cause hypoprolactinemia, which may result from its activity as a dopamine agonist. However, there is little information on hypoprolactinemia and steady-state aripiprazole concentrations. METHODS: The subjects included 66 male and 177 female patients diagnosed with schizophrenia who were treated with aripiprazole. The plasma concentrations of aripiprazole and dehydroaripiprazole and the plasma concentration of prolactin were measured using high-performance liquid chromatography and enzyme immunoassay, respectively. A prolactin concentration of <5 ng/mL was defined as hypoprolactinemia. RESULTS: Fifty-two of the 66 male patients (79%) and 58 of the 177 female patients (33%) had hypoprolactinemia. There were significant inverse correlations between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.447, P < 0.001) and the active moiety (aripiprazole plus dehydroaripiprazole) (rs = -0.429, P < 0.001) in men. In women, significant inverse correlations were also found between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.273, P < 0.01) and the active moiety (rs = -0.275, P < 0.01). CONCLUSIONS: These findings suggest that lower prolactin levels are, to some extent, associated with higher plasma drug concentrations in male and female patients with schizophrenia treated with aripiprazole.

The action of aripiprazole and brexpiprazole at the receptor level in singultus.

The hiccup (Latin singultus) is an involuntary periodic contraction of the diaphragm followed by glottic closure, which can be a rare side effect of aripiprazole. In contrast to the structurally closely related aripiprazole, brexpiprazole was not associated with this particular adverse drug reaction. Having two very similar drugs that differ in their ability to induce hiccups represents a unique opportunity to gain insight into the receptors involved in the pathophysiology of the symptom and differences in clinical effects between aripiprazole and brexpiprazole. The overlap between maneuvers used to terminate paroxysmal supraventricular tachycardia and those employed to terminate bouts of hiccups suggests that activation of efferent vagal fibers can be therapeutic in both instances. Recent work seems to support a pivotal role for serotonin receptors in such vagal activation. It is unlikely that a unique receptor-drug interaction could explain the different effects of the examined drugs on hiccup. The different effect is most likely the consequence of several smaller effects at more than one receptor. Brexpiprazole is a highly affine (potent) α2C antagonist and, therefore, also an indirect 5-HT1A agonist. In contrast, aripiprazole is a partial 5-HT1A agonist (weak antagonist) and an HT3 antagonist. Activation of 5-HT1A receptors enhances vagal activity while HT3 blockade reduces it. Vagus nerve activation is therapeutic for hiccups. A definitive answer continues to be elusive.

pH-Independent Dissolution and Enhanced Oral Bioavailability of Aripiprazole-Loaded Solid Self-microemulsifying Drug Delivery System.

The present study pursued the systematic development of a stable solid self-emulsifying drug delivery system (SMEDDS) of an atypical antipsychotic drug, aripiprazole (APZ), which exhibits poor aqueous solubility and undergoes extensive p-glycoprotein efflux and hepatic metabolism. Liquid SMEDDS excipients were selected on the basis of solubility studies, and the optimum ratio of surfactant/co-surfactant was determined using pseudo-ternary phase diagrams. The prepared formulations were subjected to in vitro characterization studies to facilitate the selection of optimum liquid SMEDD formulation containing 30% Labrafil® M 1944 CS, 46.7% Cremophor® EL and 23.3% PEG 400 which were further subjected to solidification using maltodextrin as a hydrophilic carrier. The optimized solid SMEDDS was extensively evaluated for stability under accelerated conditions, dissolution at various pH and pharmacokinetic profile. Solid-state attributes of the optimized solid SMEDDS indicated a marked reduction in crystallinity of APZ and uniform adsorption of liquid SMEDDS. Stability study of the solid SMEDDS demonstrated that the developed formulation retained its stability during the accelerated storage conditions. Both the optimized liquid and solid SMEDDS exhibited enhanced dissolution rate which was furthermore independent of the pH of the dissolution medium. Oral bioavailability studies in Sprague-Dawley rats confirmed quicker and greater extent of absorption with solid SMEDDS as evident from the significant reduction in Tmax in case of solid SMEDDS (0.83 ± 0.12 h) as compared with commercial tablet (3.33 ± 0.94 h). The results of the present investigation indicated the development of a stable solid SMEDDS formulation of APZ with enhanced dissolution and absorption attributes.

Understanding variability in the pharmacokinetics of atypical antipsychotics - focus on clozapine, olanzapine and aripiprazole population models.

Antipsychotic medicines are widely used for the management of psychotic symptoms regardless of the underlying diagnosis. Most atypical antipsychotics undergo extensive metabolism prior to excretion. Various factors may influence their pharmacokinetics, particularly elimination, leading to highly variable drug concentrations between individual patients following the same dosing regimen. Population pharmacokinetic approach, based on nonlinear mixed effects modeling, is a useful tool to identify covariates explaining pharmacokinetic variability, as well as to characterize and distinguish unexplained residual and between-subject (interindividual) variability. In addition, this approach allows the use of both sparsely and intensively sampled data. In this paper, we reviewed the pharmacokinetic characteristics of clozapine, olanzapine and aripiprazole, focusing on a population modeling approach. In particular, models based on a nonlinear mixed effects approach performed by NONMEM® software in order to identify and quantify sources of pharmacokinetic variability are presented. Population models were identified through systematic searches of PubMed and sixteen studies were selected. Some of the factors identified that significantly contribute to variability in elimination among clozapine, olanzapine, and aripiprazole are demographic characteristics, body weight, genetic polymorphism, smoking and in some cases drug interactions. Scientific research based on pharmacometric modeling is useful to further characterize sources of variability and their combined effect.

Pathological Concentration of C-reactive Protein is Correlated to Increased Concentrations of Quetiapine, But Not of Risperidone, Olanzapine and Aripiprazole in a Naturalistic Setting.

INTRODUCTION: Infections can alter drug clearance, but the impact of inflammation-induced changes is still not well known. The aim of the investigation was to examine the effect of pathological C-reactive protein (CRP) values (≥0.5 mg/dL) and leukocyte count on the metabolism of 4 different atypical antipsychotics. METHODS: Steady-state serum concentrations of individual patients under therapy with risperidone (n=45), aripiprazole (n=30), olanzapine (n=24), and quetiapine (n=166) were retrospectively analyzed during a period of inflammation by Spearman's Rho correlation analysis. Mann-Whitney U test was applied for comparison of patients with serum concentrations above and below the upper limit of the therapeutic reference range of each target drug with regard to CRP concentration and leukocyte count. Linear regression analysis was applied to correct for confounding parameters age and sex. RESULTS: Pathological concentrations of CRP were significantly associated with elevated values of C/D of quetiapine (n=166, Spearman's Rho: r=0.269, p<0.001; linear regression: p<0.001). Among patients with quetiapine serum concentrations below 500 ng/mL, CRP concentrations were significantly (p=0.006) lower compared to patients with quetiapine concentrations above 500 ng/mL. A trend for a positive correlation between CRP and serum concentration was found for olanzapine (n=24, Spearman's Rho: r=0.385, p=0.063; linear regression: p=0.086). CONCLUSION: During a period of inflammation in patients taking quetiapine, according to our results, attention in dosing strategies is required to prevent toxic plasma concentrations.

Association between aripiprazole pharmacokinetics and CYP2D6 phenotypes: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: The FDA has provided recommendations for aripiprazole use in CYP2D6 poor metabolizers (PMs); however, PMs make up <1% of the Asian population and no recommendation has been provided for intermediate metabolizers (IMs), who comprise a considerable proportion of the Asian population (64%-70% occurrence of CYP2D6*10). This study aimed to investigate the characteristics of aripiprazole metabolism in IMs and other phenotypes by conducting the first meta-analysis of the association among CYP2D6 phenotypes and aripiprazole pharmacokinetics (PK). METHODS: We searched four electronic databases for studies published through February 2018, investigating the association between aripiprazole and CYP2D6 gene polymorphisms. Gene polymorphism information was extracted, and CYP2D6 phenotypes were determined according to a unified classification standard. The associations between three aripiprazole PK-related outcomes and CYP2D6 phenotype were analysed. Meta-analyses were used to compare ultra-rapid metabolizers (UMs) vs extensive metabolizers (EMs), EMs vs IMs and IMs vs poor metabolizers (PMs) for each outcome. The aripiprazole serum concentration funnel plot and the Egger's and Begg's tests were used to assess publication bias. RESULTS AND DISCUSSION: Altogether, 10 studies were included in this analysis (n = 649). Aripiprazole serum concentration differed significantly between EMs and IMs (EM vs IM pooled SMD: -0.383; 95% CI: -0.735 to -0.031, P = 0.03 < 0.05), but not between IMs and PMs (IM vs PM pooled SMD: -0.425; 95% CI: -0.933 to 0.082, P = 0.10 > 0.05). However, aripiprazole plus dehydroaripiprazole serum level did not significantly differ among EMs, IMs and PMs (EM vs IM pooled SMD: -0.285; 95% CI: -0.724 to 0.154, P = 0.20 > 0.05; IM vs PM pooled SMD: -0.302; 95%CI: -0.810 to 0.205, P = 0.24 > 0.05). Overall, aripiprazole serum level and the sum level of aripiprazole plus dehydroaripiprazole in different phenotypes followed the trend UMs < EMs < IMs < PMs, whereas dehydroaripiprazole serum level followed the trend UMs < EMs > IMs > PMs. WHAT IS NEW AND CONCLUSION: Aripiprazole serum concentration differed significantly between EMs and IMs, but not between PMs. Whether this has clinical significance requires further evaluation by randomized trials.

Clinical Use of Dopamine Modulators as Third-Generation Antipsychotic Agents.

When dopamine was identified as a primary target for schizophrenia, the dopamine antagonists, now referred to as first-generation antipsychotics, were added to our pharmacopeia. In the 1990s, with the discovery of risperidone and clozapine, the mechanism of dopamine receptor antagonism was paired with serotonin receptor antagonism to give rise to second-generation antipsychotics. A decade later these mechanisms were further refined to selective dopamine receptors antagonism and serotonin receptors antagonism and agonism to create a modulation or stabilization of dopamine nerve firing in differential ways. This new wave may be referred to as the third generation. The current article reviews the pharmacodynamics and pharmacokinetics of these dopamine modulators. [Journal of Psychosocial Nursing and Mental Health Services, 57(2), 7-11.].

Pharmacokinetic Evaluation of a 1-Day Treatment Initiation Option for Starting Long-Acting Aripiprazole Lauroxil for Schizophrenia.

BACKGROUND: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation. We report findings from a phase 1 study investigating a nanocrystalline milled dispersion of AL (ALNCD) as a potential 1-day initiation regimen. The 1-day initiation regimen is designed to enable rapid achievement of plasma aripiprazole concentrations that are comparable with the 21-day oral initiation regimen. Here, a 6-month pharmacokinetic study compared 2 different initiation regimens for starting AL. METHODS: Patients were randomized 1:1:1:1 to receive 1 of 4 treatments consisting of the 1-day (single ALNCD injection + one 30-mg dose of oral aripiprazole on day 1 only) or the 21-day (15-mg daily dose of oral aripiprazole for 21 days) initiation regimen, each combined with a starting AL dose of either 441 mg or 882 mg. RESULTS: In total, 133/161 patients completed the study. The pharmacokinetic profile of the 1-day initiation regimen was comparable to the 21-day initiation regimen; both achieved aripiprazole concentrations in the therapeutic range within 4 days and remained in a comparable concentration range during treatment initiation. Common adverse events (≥5.0%) were injection-site pain, headache, increased weight, insomnia, dyspepsia, and anxiety. Nine akathisia events occurred (4 events in 4 patients and 5 events in 2 patients in the 1-day and 21-day initiation regimen groups, respectively). CONCLUSIONS: The 1-day initiation regimen resulted in plasma aripiprazole concentrations consistent with the 21-day initiation regimen. Therefore, a single dose of ALNCD with a single 30-mg oral dose of aripiprazole provides an alternative initiation regimen for starting AL.

Determination of plasma concentration reference ranges for oral aripiprazole, olanzapine, and quetiapine.

BACKGROUND: Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient. AIMS: The aim of this study was to develop "reference ranges" for oral aripiprazole, olanzapine, and quetiapine to allow clinicians to understand expected variability in patients treated with APS. The reference ranges were constructed to account for different oral doses, sampling times, and variability both between, and within, subjects. METHODS: Population pharmacokinetic models were used to simulate plasma concentrations over time under different doses and population demographics. The references were validated against external data both numerically and graphically. RESULTS: Reference ranges for oral aripiprazole, olanzapine, and quetiapine were derived and successfully validated against the external data. The 80% reference range for aripiprazole following a 2-mg oral dose was 14.7-41.6 ng/mL 0-4 h post dose and 10.6-37.1 ng/mL 20-24 h post dose. These ranges increased to 221-624 ng/mL 0-4 h post dose following administration of a 30-mg dose, and 159-557 ng/mL 20-24 h post dose. The 80% reference range 0-4 h post dose was 22.5-67.1 ng/mL following a 15-mg dose once daily of oral olanzapine, and 179-768 ng/mL following a 150-mg dose once daily of oral quetiapine. CONCLUSIONS: Comparing individual patients' APS levels with reference ranges, along with a full clinical assessment, could provide important insights to help a clinician optimize APS therapy.

Efficacy and safety of aripiprazole for the treatment of schizophrenia: an overview of systematic reviews.

PURPOSE: To conduct an overview to summarize the efficacy and safety of aripiprazole for the treatment of schizophrenia. METHODS: A literature search was performed in PubMed, the Cochrane Library, LILACS, and the Centre for Reviews and Dissemination, for articles published until March 31, 2017. We included systematic reviews with meta-analyses of randomized controlled trials assessing the efficacy, and/or the safety of aripiprazole, for patients with schizophrenia. Two authors independently performed the study selection, data extraction, and quality assessment. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and the Risk of Bias in Systematic Review (ROBIS) tool were used to appraise the quality of evidence and the risk of bias in the reviews, respectively. RESULTS: Fourteen studies fulfilled the inclusion criteria. Aripiprazole showed efficacy similar to that of both typical and atypical antipsychotic drugs (except olanzapine and amisulpride). Aripiprazole caused significantly lower weight gain and alterations in glucose and cholesterol levels, as compared to clozapine, risperidone, and olanzapine. In addition, aripiprazole caused significantly fewer general extrapyramidal side effects, less use of antiparkinsonian drugs, and akathisia, compared with typical antipsychotic drugs and risperidone. The overall quality of evidence in the reviews ranged from "very low" to "moderate," principally because of the risk of bias of original trials, inconsistency, and imprecision in the outcomes. According to the ROBIS tool, there are four reviews with "high" risk of bias and five with "unclear" risk of bias. CONCLUSIONS: Aripiprazole exhibited efficacy similar to that of other antipsychotic drugs and a better safety profile than that of typical (i.e., less some extrapyramidal side effects) and atypical (i.e., less metabolic changes) antipsychotic drugs.

Enhancement of In Vivo Efficacy and Oral Bioavailability of Aripiprazole with Solid Lipid Nanoparticles.

Aripiprazole (ARP), a second-generation or atypical antipsychotic, is poorly soluble and undergoes extensive hepatic metabolism and P-glycoprotein efflux which lead to reduced in vivo efficacy and increased dose-related side effects. To enhance in vivo efficacy and oral bioavailability of aripiprazole, aripiprazole-loaded solid lipid nanoparticles (SLNs) were developed using tristearin as solid lipid. Tween 80 and sodium taurocholate were used as surfactants to prepare SLNs using microemulsification method. SLNs were characterized for particle size, zeta potential, entrapment efficiency, and crystallinity of lipid and drug. In vitro release studies were performed in water containing 0.5% sodium dodecyl sulfate. Pharmacodynamic evaluation was carried out in laca mice using dizocilpine-induced schizophrenic model where behavioral evaluation revealed better in vivo efficacy of SLNs. Pharmacokinetics of aripiprazole-loaded SLNs after oral administration to conscious male Wistar rats was studied. Bioavailability of aripiprazole was increased 1.6-fold after formulation of aripiprazole into SLNs as compared to plain drug suspension. The results indicated that solid lipid nanoparticles can improve the bioavailability of lipophilic drugs like aripiprazole by enhancement of absorption and minimizing first-pass metabolism.

Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia.

BACKGROUND: Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS: Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. FINDINGS: The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. CONCLUSIONS: This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Prediction of an Optimal Dose of Aripiprazole in the Treatment of Schizophrenia From Plasma Concentrations of Aripiprazole Plus Its Active Metabolite Dehydroaripiprazole at Week 1.

BACKGROUND: It has been suggested that a plasma trough concentration of aripiprazole plus its active metabolite, dehydroaripiprazole of 225 ng/mL is a threshold for a good therapeutic response in the treatment of acutely exacerbated patients with schizophrenia. The present study investigated whether or not an optimal dose of aripiprazole could be predicted from these concentrations at week 1. METHODS: The subjects were 26 inpatients with schizophrenia, who received aripiprazole once a day for 3 weeks. The daily doses were 12 mg for the first week and 24 mg for the next 2 weeks. No other drugs except biperiden and flunitrazepam were coadministered. Blood samples were taken at weeks 1 and 3 after the treatment. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. RESULTS: There was a significant linear relationship between the plasma concentrations of aripiprazole plus dehydroaripiprazole at weeks 1 (x) and 3 (y) (P < 0.001). Regression equation was y = 2.580x + 34.86 (R = 0.698). Based on the equation, a nomogram to estimate an optimal dose of aripiprazole could be constructed. CONCLUSIONS: The present study suggests that an optimal dose of aripiprazole for the treatment of patients with schizophrenia can be predicted from the plasma concentrations of the sum of the 2 compounds at week 1.

Aripiprazole Nanocrystal Impregnated Buccoadhesive Films for Schizophrenia.

Aripiprazole is an atypical antipsychotic drug approved worldwide for treatment of acute and long term schizophrenia in adults. Increasingly atypical antipsychotics are playing a key role in the management of schizophrenia. The aim of the present study was to design a mucoadhesive dosage form for buccal delivery of aripiprazole which could provide a rapid drug delivery to the systemic circulation. Nanocrystals of aripiprazole were prepared by nano-precipitation using acid-base neutralization. These nanocrystals were then incorporated into buccoadhesive chitosan films. All the drug loaded films were found to smooth, non-tacky possessing high mechanical strength. Films were characterized for crystallinity of drug, surface pH, thickness, folding endurance, swelling behavior, mucoadhesive strength, drug release and ex-vivo permeation across rabbit cheek mucosa. In-vitro drug release studies indicated distinctly higher drug release from nanocrystal loaded films, FAPZ 13 and FAPZ 14. Permeation studies indicated a higher flux from films FAPZ 14 (442.34 ± 51.08 µg/cm2/h, P < 0.0001) when compared to film FAPZ 12. These promising results indicate that the developed nanocrystal loaded buccal films FAPZ 14 have the potential to provide a faster availability of aripiprazole and the buccoadhesive films offer promising option to patients with schizophrenia especially for geriatric patients.

Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol.

PURPOSE: Therapeutic drug monitoring (TDM) of antipsychotics can aid in therapy optimization, explaining adverse effects or non-response. One reason for therapeutic failure or adverse effects is caused by genetic variations in the cytochrome P450 drug-metabolizing genes. The aim of this study was to evaluate the impact of CYP2D6 polymorphisms on steady-state serum concentrations of antipsychotics metabolized by CYP2D6, taking into account the co-medication with CYP2D6 inhibitors. METHODS: Serum and EDTA samples were collected from 82 psychiatric patients. After a liquid-liquid extraction, serum samples were analyzed using an ultra-high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for quantification of the antipsychotics. CYP2D6 genotyping was performed using the Luminex xTAG® CYP2D6 Kit v3 (Luminex Corporation). Patients were divided into five phenotype subgroups by calculation of the activity score (AS): poor metabolizers (PM; AS 0), intermediate metabolizers (IM; AS 0.5-1), extensive metabolizers with slow activity (EM-s; AS 1-1.5), extensive metabolizers with fast activity (EM-f; AS 2), and ultra-rapid metabolizers (UM; AS >2). The influence of the phenotypes on the concentration-to-dose and metabolite-to-parent ratios was evaluated. RESULTS: Overall, 6.1 % UM (n = 5), 25.6 % EM-f (n = 21), 46.3 % EM-s (n = 38), 1.2 % EM-s/EM-f (n = 1), 6.1 % IM (n = 5), and 14.6 % PM (n = 12) were found, taking co-administration of strong and moderate CYP2D6 inhibitors into account (phenoconversion). It was demonstrated that CYP2D6 polymorphisms affect the serum concentrations of aripiprazole (n = 18), haloperidol (n = 11), risperidone (n = 20), and zuclopenthixol (n = 6), while no influence was seen on the paliperidone serum concentrations (n = 31). CONCLUSIONS: Even with a small number of patients per antipsychotic, the importance of CYP2D6 genotyping was still clearly stated. This study illustrates the high potential of combining TDM and CYP2D6 genotyping in clinical practice.

Therapeutic drug monitoring of second-generation antipsychotics in pediatric patients: an observational study in real-life settings.

PURPOSE: Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels. METHODS: Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables. RESULTS: Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9%) but lower intra-patient (34.2%) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1%, while the intra-patient variability was much lower (29.3%). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01). CONCLUSION: Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.

The effect of resveratrol on pharmacokinetics of aripiprazole in vivo and in vitro.

1. The objective of this study were to investigate the effect of orally administered resveratrol on the pharmacokinetics of aripiprazole (APZ) in rat, and the inhibitory effects of resveratrol on APZ dehydrogenation activity in liver microsomes and human cytochrome P450 3A4 and 2D6. 2. Twenty-five healthy male Sprague-Dawley rats were randomly divided into five groups: A (control group), B (multiple dose of 200 mg/kg resveratrol), C (multiple dose of 100 mg/kg resveratrol), D (a single dose of 200 mg/kg resveratrol) and E (a single dose of 100 mg/kg resveratrol). A single dose of 3 mg/kg APZ administered orally 30 min after administration of resveratrol. In addition, CYP2D6*1, CYP3A4*1, human and rat liver microsomes were performed to determine the effect of resveratrol on the metabolism of APZ in vitro. 3. The multiple dose of 200 or 100 mg/kg resveratrol significantly increased the AUC and Cmax of APZ. The resveratrol also obviously decreased the CL, but without any significant difference on t1/2 in vivo. On the other hand, resveratrol showed inhibitory effect on CYP3A4*1, CYP2D6*1, human and rat microsomes, the IC50 of resveratrol was 6.771, 87.87, 45.11 and 35.59 µmol l(-1), respectively. 4. Those results indicated more attention should be paid when APZ was administrated combined with resveratrol.

Population pharmacokinetics of aripiprazole in healthy Korean subjects.

OBJECTIVE: Aripiprazole is widely used to treat schizophrenia and bipolar disorder. This study aimed to develop a combined population pharmacokinetic model for aripiprazole in healthy Korean subjects and to identify the significant covariates in the pharmacokinetic variability of aripiprazole. METHODS: Aripiprazole plasma concentrations and demographic data were collected retrospectively from previous bioequivalence studies that were conducted in Chonbuk National University Hospital. Informed consent was obtained from subjects for cytochrome P450 (CYP) genotyping. The population pharmacokinetic parameters of aripiprazole were estimated using nonlinear mixed-effect modeling with first-order conditional estimation with interaction method. The effects of age, sex, weight, height, and CYP genotype were assessed as covariates. RESULTS: A total of 1,508 samples from 88 subjects in three bioequivalence studies were collected. The two-compartment model was adopted, and the final population model showed that the CYP2D6 genotype polymorphism, height and weight significantly affect aripiprazole disposition. The bootstrap and visual predictive check results were evaluated, showing that the accuracy of the pharmacokinetic model was acceptable. CONCLUSIONS: A population pharmacokinetic model of aripiprazole was developed for Korean subjects. CYP2D6 genotype polymorphism, weight, and height were included as significant factors affecting aripiprazole disposition. The population pharmacokinetic parameters of aripiprazole estimated in the present study may be useful for individualizing clinical dosages and for studying the concentration-effect relationship of the drug.

[Pharmacokinetics and safety of aripiprazole long-acting injection, following multiple deltoid administrations in schizophrenia patients in Japan].

Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 µg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.