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Introduction: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19 , CYP2D6 , CYP3A4 , and ABCB1 , and its effect on these outcomes., Methods: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects., Results: Eleven cis- SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain ( q =0.027) and serum concentrations of ESC adj ( q <0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESC adj concentrations. CITs did not indicate that these effects were epigenetically mediated., Discussion: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored., Competing Interests: Dr. Benicio N. Frey has no conflicts to disclose. Dr. Roumen V. Milev has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE Pharmaceuticals, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes of Health Research (CIHR), Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute (OBI), and Ontario Mental Health Foundation (OMHF). Dr. Sagar V. Parikh has received research support or consulting income from Aifred, Assurex (Myriad), Janssen, Mensante, Otsuka, Sage, and Takeda. Dr. Stefanie Hassel has no conflicts of interest to disclose. Dr. Pierre Blier received honoraria for participation in advisory boards, giving lectures, and/or expert consultation from Allergan, Bristol Myers Squibb, Janssen, Lundbeck, Otsuka, Pierre Fabre Medicaments, Pfizer and Sunovion; he received grants from Allergan, Janssen, and Lundbeck/Otsuka. Dr. Faranak Farzan received funding from Michael Smith Foundation for Health Research, Natural Sciences and Engineering Research Council of Canada Discovery, and Canadian Institutes of Health Research. Dr. Raymond W. Lam has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Abbvie, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Boehringer-Ingelheim, Canadian Institutes of Health Research (CIHR), Canadian Network for Mood and Anxiety Treatments, Carnot, Healthy Minds Canada, Janssen, Lundbeck, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute (OBI), Otsuka, Pfizer, Unity Health, and VGH-UBCH Foundation. Dr. Gustavo Turecki has received an Investigator-initiated grant from Pfizer Canada, and honoraria from Bristol-Meyers Squibb Canada and Janssen Canada. Dr. Susan Rotzinger has received grant funding from the Ontario Brain Institute (OBI), and Canadian Institutes of Health Research (CIHR), and holds a patent Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Dr. Stefan Kloiber has received honorarium for past consultation from EmpowerPharm. Dr. Sidney H. Kennedy has received research funding or honoraria from the following sources: Abbott, Alkermes, Allergan, Bristol-Myers Squibb (BMS), Brain Canada, Canadian Institutes for Health Research (CIHR), Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute (OBI), Ontario Research Fund (ORF), Otsuka, Pfizer, Servier, Sunovion and holds stock in Field Trip Health. Dr. Daniel J. Müller reports to be a co-investigator on two pharmacogenetic studies where genetic test kits were provided as in-kind contributions by Myriad Neuroscience. All other authors report no conflicts of interest related to this work., (Thieme. All rights reserved.)

Aripiprazole once-monthly (AOM) exhibits an important interindividual pharmacokinetic variability with significant implications for its clinical use. CYP2D6 and CYP3A4 highly contributes to this variability, as they metabolize aripiprazole (ARI) into its active metabolite, dehydroaripiprazole (DHA) and the latter into inactive metabolites. This study aims to evaluate the effect of CYP2D6 and CYP3A4 polymorphisms in combination and the presence of concomitant inducers and inhibitors of this cytochromes on ARI and DHA plasma concentrations in a real clinical setting. An observational study of a cohort of 74 Caucasian patients under AOM treatment was conducted. Regarding CYP2D6, higher concentrations were found for active moiety (ARI plus DHA) (AM) (67 %), ARI (67 %) and ARI/DHA ratio (77 %) for poor metabolizers (PMs) compared to normal metabolizers (NMs). No differences were found for DHA. PMs for both CYP2D6 and CYP3A4 showed a 58 % higher AM and 66 % higher plasma concentration for ARI compared with PMs for CYP2D6 and NMs for CYP3A4. In addition, PMs for both CYP2D6 and CYP3A4 have 45 % higher DHA concentrations than NMs for both cytochromes and 41 % more DHA than PMs for CYP2D6 and NMs for CYP3A4, suggesting a significant role of CYP3A4 in the elimination of DHA. Evaluating the effect of CYPD26 and CYP3A4 metabolizing state in combination on plasma concentrations of ARI, DHA and parent-to-metabolite ratio, considering concomitant treatments with inducers and inhibitor, could optimize therapy for patients under AOM treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (C max ) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for C max ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899 aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval., (© 2024 Otsuka Pharmaceutical Development & Commercialization, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Aim: The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients., Background: It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabo-lism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported., Objective: The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A) , and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients., Methods: All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis., Results: The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2 *F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2 *C genotype. The absence of the A allele of CYP1A2 *F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis., Conclusion: The findings of this study suggest that the CYP1A2 *F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To investigate the relationship between plasma aripiprazole (ARI) and its metabolite dehydroaripiprazole (DARI) concentrations and prolactin (PRL) levels in Chinese children and adolescents. Methods: This was a retrospective cross-sectional study and the data were collected at Beijing HuiLongGuan Hospital, a Beijing City owned psychiatric hospital, between January 1 and December 31, 2021. Fifty-two child and adolescent inpatients (17 males, 35 females) aged 13-18 years and received ARI regardless of diagnosis were included. The steady-state ARI and DARI plasma concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. The serum PRL levels were measured by chemiluminescence immunoassay. Results: The plasma concentrations of ARI, DARI, and the total of ARI and DARI were negatively correlated with serum PRL levels in female children and adolescents. Approximately 15% of child and adolescent inpatients treated with ARI exhibited subnormal PRL serum levels. Conclusions: The results suggest that in addition to regularly monitoring PRL levels, therapeutic drug monitoring for ARI and its main metabolite DARI can help to mitigate the adverse medical consequences associated with PRL reduction. Thus, clinicians should consider the ARI-induced reduction of PRL levels when prescribing ARI to child and adolescent patients, particularly among females.

To assess the bioequivalence of 2 formulations of aripiprazole orally disintegrating tablets and to monitor their safety and tolerability in Chinese subjects, a single-site, open-label, randomized, 2-preparation, single-dose, 2-period crossover design was conducted. All 60 subjects were randomly divided into the fasting group and the fed group. Blood samples were collected at scheduled times after a single oral dose of orodispersible tablets containing 10 mg of aripiprazole. In the fasting state, the geometric mean ratios (90% confidence intervals [CIs]) of the test/reference formulation were 92.22%-100.20% for the area under the concentration-time curve (AUC) from time zero to the last measured concentration (AUC 0-t ), 91.73%-100.14% for the AUC from administration to infinite time (AUC 0-∞ ), and 98.52%-112.52% for the maximum plasma concentration (C max ). In the fed state, AUC 0-t , AUC 0-∞ , and C max were 92.23%-100.20%, 91.73%-100.14%, and 95.91%-105.13%, respectively. The 90%CIs of the test/reference AUC ratio and C max ratio were within the acceptance range of 80.00%-125.00% for bioequivalence. Neither the maximum peak plasma concentration (t max ) nor the terminal elimination half-life (t 1/2 ) showed any significant difference. No serious adverse events) were encountered during the study. The test and reference formulations were bioequivalent under both fasting and fed conditions and were found to be safe and tolerated., (© 2021, The American College of Clinical Pharmacology.)

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., Competing Interests: N. Yasui-Furukori was a speaker for Otsuka Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Dainippon-Sumitomo Pharmaceutical Co., and MSD Co. K. Shimoda received research support from Novartis Pharma K.K., Dainippon-Sumitomo Pharma Co., Astellas Pharma Inc., Meiji Seika Pharma Co., Ltd., Eisai Co., Ltd., Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., and Takeda Pharmaceutical Co., Ltd., and honoraria from Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical K.K., Shionogi & Co., Ltd., Dainippon-Sumitomo Pharma Co., Daiichi Sankyo Co., and Pfizer Inc. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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) α 2C antagonist and, therefore, also an indirect 5-HT 1A agonist. In contrast, aripiprazole is a partial 5-HT 1A agonist (weak antagonist) and an HT 3 antagonist. Activation of 5-HT 1A receptors enhances vagal activity while HT 3 blockade reduces it. Vagus nerve activation is therapeutic for hiccups. A definitive answer continues to be elusive., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Published by IMR Press.)

Background: Pharmacogenetics study was added into 2 bioequivalence trials of aripiprazole. The correlation between CYP2D6 polymorphisms and aripiprazole pharmacokinetics (PK) was analyzed. Materials & methods: A total of 140 subjects were included. A total of 26 CYP2D6 gene alleles were detected. The plasma concentration of aripiprazole was measured by liquid chromatography-tandem mass spectrometry. SPSS Statistics 21 was used to analyze the correlation between CYP2D6 polymorphisms and aripiprazole PK parameters. Results: All of the four PK parameters were significantly influenced by CYP2D6 rs1058164 and rs28371699 . t 1/2 and area under the concentration-time curve exhibited significant difference between CYP2D6 extensive metabolizers and intermediate metabolizers. Conclusion: Aripiprazole PK was greatly influenced by CYP2D6 . Attention should be paid to the possible dose adjustment for CYP2D6 intermediate metabolizer population when the drug is used in Chinese patients.

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 T max 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.

Background: Aripiprazole lauroxil (AL) is a long-acting injectable antipsychotic approved for treatment of schizophrenia in adults. Approved AL doses and dosing regimens include 441 mg monthly, 662 mg monthly, and 882 mg monthly or every 6 weeks (q6wk), as well as the most recently approved dose, 1064 mg, administered every 2 months., Objective: Pharmacokinetics, safety, and tolerability of an AL regimen with a dose interval of every 2 months (1064 mg) were compared with two other regimens available as monthly and q6wk options., Methods: This study evaluated pharmacokinetics of AL given at a higher dosage strength (1064 mg) and at a longer dose interval (every 8 weeks [q8wk]) than previously studied. Patients with schizophrenia or schizoaffective disorder entering this 44-week, phase I, open-label, multicenter study had no recent exposure to aripiprazole and were maintained on other oral antipsychotics throughout the study. Patients were randomized to one of three AL dose regimens for 24 weeks (four 1064-mg injections [q8wk], five 882-mg injections [q6wk], or seven 441-mg injections [q4wk], with the last AL exposure at week 24). Oral aripiprazole was prohibited. Patients were followed for an additional 20 weeks to assess terminal aripiprazole plasma concentrations and ongoing safety. Plasma concentration samples were obtained at regular intervals to provide pharmacokinetic data for the duration of AL exposure and to measure persistence of plasma aripiprazole concentrations after AL discontinuation., Results: Eligible patients received AL 1064 mg q8wk (n = 35), 882 mg q6wk (n = 34), or 441 mg q4wk (n = 35). Overall, 103/104 (99.0%) patients were taking concomitant non-aripiprazole oral antipsychotic medications during the study. All three AL dose regimens provided continuous exposure to aripiprazole. Mean aripiprazole concentrations from the 1064-mg q8wk regimen were comparable to the 882-mg q6wk regimen and higher than the 441-mg q4wk regimen. Overall incidence by group of any adverse events (AEs) throughout the study was 68.6% (1064 mg q8wk), 50.0% (882 mg q6wk), and 65.7% (441 mg q4wk). The most common AE across regimens was injection-site pain (range 8.6%-11.4%). Serious AEs were reported by eight patients (all but one [increased psychosis in one patient, 441-mg q4wk group] considered unrelated to study drug). Discontinuations due to AEs were reported for 2.9%, 11.8%, and 5.7% of patients receiving the 8-, 6-, and 4-week regimens, respectively. AEs of akathisia, dyskinesia, and dystonia occurred in 2.9%, 8.6%, and 5.7% of patients in the 1064-mg q8wk group, 8.8%, 0%, and 2.9% in the 882-mg q6wk group, and 8.6%, 0%, and 0% in the 441-mg q4wk group, respectively., Conclusions: AL 1064 mg q8wk provided continuous exposure to aripiprazole throughout the 8-week dosing interval and had a safety profile consistent with the 4- and 6-week regimens. These findings were used to support FDA approval of the 1064-mg dose administered every 2 months., Registration: Clinicaltrials.gov: NCT02320032.

Aripiprazole (ARP) is an antipsychotic drug approved for the treatment of schizophrenia. It is poorly water-soluble and undergoes extensive hepatic metabolism and P-gp efflux, which lead to poor bioavailability and increased dose-related side effects. This study focuses on the preparation of mixed micelles (MM) to enhance the aqueous solubility, oral bioavailability, and blood-brain barrier permeation of ARP. For this purpose, Soluplus and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected for micelle preparation (ARP-MM). Micelles with borneol as penetration enhancer were also considered (ARP-B-MM). The optimized formulations have sizes of ca 50 nm, defined in distilled water, narrow size distribution (polydispersity index ≤0.1), and high encapsulation efficiency (greater than98%). Both formulations can be freeze-dried without losing their chemical-physical characteristics and are stable during storage for three months. The mixed micelles resulted stable in enzyme free-simulated gastric fluid (SGF, pH 1.2), simulated intestinal fluid (SIF, pH 6.8), and in serum. The in vitro ARP release was evaluated in the same biorelevant media, (SGF and SIF), and it disclosed that both micelles can give prolonged drug release. Furthermore, ARP solubility is greatly increased when loaded into mixed micelles. The absorption and efflux of ARP-loaded micelles were studied in vitro, employing two artificial membranes (Parallel Artificial Membrane Permeability Assay for the intestinal, PAMPA-GI, and the blood-brain barrier, PAMPA-BBB), to simulate the intestinal and brain epithelium, and the brain microvascular endothelial cell line hCMEC/D3. ARP-MM and ARP-B-MM increase the effective permeability of ARP by a factor of about three in the case of PAMPA-GI and about two for PAMPA-BBB. Furthermore, the P-gp mediated efflux was decreased by about six times in the case of ARP-MM and by about four times in the case of ARP-B-MM, compared to unformulated ARP. Finally, both ARP-loaded mixed micelles ameliorate the bioavailability of ARP, as demonstrated by the increase of the pharmacokinetic parameters, such as Cmax, AUC 0-24h, and t1/2., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique has attracted intense interest in the visualization of drug distribution in tissues. Its capability to spatially resolve individual molecules makes it a unique tool in drug development and research. However, low drug content and severe ion suppression in tissues hinder its broader application to resolve drug tissue distribution, especially small molecule drugs with a molecular weight below 500 Da. In this work, an integrated tissue pretreatment protocol was developed to enhance the detection of central nervous system drugs in the mouse brain using MALDI MSI. To evaluate the protocol, brain sections from mice dosed intraperitoneally with donepezil, tacrine, clozapine, haloperidol, and aripiprazole were used. The tissue sections were pretreated serially by washing with ammonium acetate solution, incubation with trifluoroacetic acid vapor, and n -hexane washing before MALDI MSI. Compared with the untreated sample, the signal intensities for the test drugs increased by 4.7- to 31.5-fold after pretreatment. Besides the enhancement of signal intensity, fine optimization of pretreatment time and washing solvents preserved the spatial distribution of target drug molecules. The utility of the developed protocol also provided tissue-specific distribution for five drugs which were well resolved when imaged by MALDI MS.

Aripiprazole treatment in schizophrenic patients was previously associated with lower or normalized prolactin levels. Genetic variants in cytochrome P450 (CYP) (CYP2D6), dopamine receptor (DRD2, DRD3) and serotonin receptor (HTR2A, HTR2C) genes were previously associated with antipsychotic-induced hyperprolactinaemia. Our aim was to evaluate whether aripiprazole affects prolactin secretion and its relationship with pharmacogenetics. Thirty-one healthy volunteers receiving a 10-mg single oral dose of aripiprazole were genotyped for 12 polymorphisms in CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by qPCR. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by HPLC-MS/MS. Prolactin concentrations of the 31 volunteers taking aripiprazole and 12 volunteers receiving ibuprofen were determined by ELISA. Prolactin concentrations after ibuprofen intake were considered as control, since it is known to cause no effect. Prolactin concentrations were slightly higher in the aripiprazole group compared to the ibuprofen group. All prolactin pharmacokinetic parameters were higher in females than in males. CYP2D6 poor and intermediate metabolizers had notably higher prolactin C max and AUC 0-12 than normal and ultrarapid metabolizers. The DRD3 rs6280 polymorphism affected prolactin levels: volunteers carrying Ser/Ser genotype had significantly lower prolactin levels than volunteers carrying the Gly allele. Furthermore, HTR2C rs3813929 C/C homozygotes had significantly lower prolactin levels than T allele carriers. Nevertheless, aripiprazole did increase prolactin levels compared to ibuprofen., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

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.

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., Competing Interests: J. Deckert is the co-recipient of a grant of the Bavarian State Government to BioVariance and an investigator in a European grant to P1Vital. M. Scherf-Clavel, A. Weidner, A. Menke, and S. Unterecker have no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The polymorphic CYP2D6 enzyme metabolises the antipsychotic drugs risperidone and aripiprazole to their active metabolites, 9OH-risperidone and dehydroaripiprazole. The aim of this study was to quantify the effect of CYP2D6 genetic variability on risperidone and aripiprazole exposure and treatment in a large patient population., Methods: We retrospectively obtained patient data from a routine therapeutic drug monitoring database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between Jan 1, 2005, and Oct 15, 2018. Individuals included in our analyses were CYP2D6-genotyped patients treated with risperidone or aripiprazole. Inclusion criteria for measurement of pharmacokinetic parameters (drug and metabolite serum concentrations) were oral administration of risperidone or aripiprazole, information known about prescribed daily dose and comedications, and aged older than 18 years. Exclusion criteria included polypharmacy with drugs known to be CYP2D6 inhibitors or CYP3A4 inducers or inhibitors. Treatment failure was analysed in all patients treated with risperidone or aripiprazole without these criteria. The first endpoint in our analysis was the metabolism of risperidone to 9OH-risperidone and aripiprazole to dehydroaripiprazole, estimated by the log-transformed ratio between the concentrations of metabolite and parent drug (ie, the metabolic ratio for risperidone [9OH-risperidone]/[risperidone] and the metabolic ratio for aripiprazole [dehydroaripiprazole]/[aripiprazole]). Endpoint two was measurement of drug exposure, quantified by the dose-normalised sum of parent drug and active metabolite serum concentrations (ie, active moiety). The third endpoint of treatment failure was measured as the number of patients switched from risperidone or aripiprazole to another antipsychotic drug within 1 year after the last therapeutic drug monitoring analysis of risperidone or aripiprazole. Patient subgroups were defined by CYP2D6 genotype-determined metaboliser status: poor metabolisers, intermediate metabolisers, normal metabolisers, and ultrarapid metabolisers. ANOVA was used to assess the differences in metabolic ratios, active moieties, and daily doses between individual metaboliser categories, and risperidone and aripiprazole therapeutic failures were compared by logistic regression using the normal metaboliser subgroup as a reference., Findings: 1288 risperidone-treated patients and 1334 aripiprazole-treated patients were included in the study, of whom 725 (56%) risperidone-treated and 890 (67%) aripiprazole-treated patients were eligible for the pharmacokinetic analyses. CYP2D6 genotype significantly changed risperidone and aripiprazole metabolism resulting in an approximately 1·6-times and 1·4-times increase in risperidone and aripiprazole active moiety exposure in poor and intermediate metabolisers compared with normal metabolisers, respectively (odds ratios [OR] for the risperidone dose-normalised active moiety concentration 1·568, 95% CI 1·401-1·736, and 1·373, 1·213-1·532; and for the aripiprazole dose-normalised active moiety concentration 1·585, 1·447-1·724, and 1·476, 1·263-1·688, respectively; p<0·0001 for all). Compared with doses for normal metabolisers, clinicians reduced daily doses of risperidone and aripiprazole administered to poor metabolisers by 19% (95% CI 5-35, p=0·010) and 15% (95% CI 1-28, p=0·033) respectively. The incidence of switching from risperidone to another antipsychotic was increased in ultrarapid metabolisers (OR 2·934, 95% CI 1·437-5·989, p=0·003) and poor metabolisers (1·874, 1·128-3·112, p=0·015); by contrast, the incidence of switching from aripiprazole to another antipsychotic was not significantly related to CYP2D6 metaboliser status., Interpretation: CYP2D6 genotype had a substantial clinical effect on risperidone and aripiprazole exposure and on the therapeutic failure of risperidone. Pre-emptive CYP2D6 genotyping would be valuable for individualising risperidone and aripiprazole dosing and treatment optimisation., Funding: H2020 program U-PGx, The Swedish Research Council, the Swedish Brain foundation, and the South-Eastern Norway Regional Health Authority., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© 2018 John Wiley & Sons Ltd.)

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.]., (Copyright 2019, SLACK Incorporated.)

Dietary supplements and foods can interact with various drugs, leading to possible clinical concerns. This study aimed to investigate the effect of orally administered sinapic acid (SA) on the pharmacokinetics of aripiprazole (APZ) in rats and its possible modulatory effects on hepatic cytochrome P450 (CYP3A2 and CYP2D6) expression in the liver tissues. Single dose and multiple dose parallel groups of wistar rats were categorized into six groups (n = 6 each) which abstained from food for 12 h prior to the experiment, while water was allowed ad libitum. The investigation was carried out for single dose: Group I was treated with normal saline orally for 15 days (normal control). Group II was administered normal saline orally for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group III received SA (20 mg/kg p.o.) for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group IV was treated with SA (20 mg/kg p.o.) for 15 days. For the multiple dose study, Group I was treated with normal saline orally for 15 days (normal control); Group II received APZ (3 mg/kg p.o.) daily for 15 days; Group III was administered with SA (20 mg/kg p.o.) and APZ (3 mg/kg p.o.) for 15 days and Group IV received SA (20 mg/kg p.o.) for 15 days. The group I and IV were kept common in single and multiple dose groups. After last APZ dose, plasma samples were collected and APZ concentrations were determined using an UPLC-MS/MS technique. The pharmacokinetic parameters were calculated using a non-compartmental analysis. The concomitant administration of APZ with SA (as single or multiple dose) resulted in an increase in APZ absorption and a decrease on its systemic clearance. This was associated with a reduction in CYP3A2 and CYP2D6 protein expressions by 33-43% and -71-68% after the single and multiple co-administration, which are two enzymes responsible of the metabolism of APZ. Therefore, a reduction in the metabolic clearance appears to be the mechanism underlying the drug interaction of dietary supplement containing SA with APZ. Therefore, the concomitant administration of SA and APZ should be carefully viewed. Further investigations are required to assess the clinical significance of such observations in humans., (Copyright © 2018. Published by Elsevier Taiwan LLC.)

This work describes the preparation of aripiprazole sustained-release microcrystals for intramuscular injection, through recrystallization, drying, wet grinding, and solidification steps, which had a great impact on the product quality. Here, we evaluated the crystal form of the drug in each step by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and fourier transform infrared spectroscopy (FT-IR), demonstrating that there is no change in the crystal form of aripiprazole monohydrate (H1) during grinding and freeze-drying. Microscopy and scanning electron microscopy (SEM) data showed that freeze-drying had no effect on the morphology of milled H1, and thermal gravimetric analysis (TGA) results showed that the freeze-dried formulation had acceptable water content. In particular, in this study, a similarity factor fitting was applied to determine the similarity of the particle size cumulative distribution curve, and the similarity factor value (99.00) showed that there was no change in the particle size distribution before and after freeze-drying. A two-chamber transmembrane method was used to investigate the in vitro release of the aripiprazole sustained-release microcrystal (ALSI) and commercial preparations (Abilify Maintena®). The similarity factor fitting of in vitro release profiles and drug cumulative release curves in vivo yielded similarity factor values of 98.00 and 95.43, respectively, indicating similar in vitro release and in vivo bioavailability of rats between the ALSI and Abilify Maintena®. A single-dose administration could produce long-term effects for a month. For a microcrystalline suspension, in addition to the conventional quality control indicators, the similarity of the cumulative particle size distribution, the in vitro release profile, and the similarity of the drug release percentage in vivo can be used to reflect product quality and process control., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Pupillometry is used for the detection of autonomic dysfunction related to numerous diseases and drug administration. Genetic variants in cytochrome P450 ( CYP2D6, CYP3A4), dopamine receptor ( DRD2, DRD3), serotonin receptor ( HTR2A, HTR2C) and ATP-binding cassette subfamily B ( ABCB1) genes were previously associated with aripiprazole response., Aims: Our aim was to evaluate if aripiprazole affects pupil contraction and its relationship with pharmacokinetics and pharmacogenetics., Methods: Thirty-two healthy volunteers receiving a 10 mg single oral dose of aripiprazole were genotyped for 15 polymorphisms in ABCB1, CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by reverse transcription polymerase chain reaction. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pupil examination was performed by automated pupillometry., Results: Aripiprazole caused pupil constriction and reached the peak value at C max . HTR2A rs6313 T allele carriers and HTR2C rs3813929 C/T subjects showed higher maximum constriction velocity and maximum pupil diameter. Besides, Gly/Gly homozygotes for DRD3 rs6280 showed significantly lower maximum constriction velocity values. A/G heterozygotes for DRD2 rs6277 showed higher total time taken by the pupil to recover 75% of the initial resting size values. CYP2D6 intermediate metabolisers showed higher area under the curve, C max and T 1/2 than extensive metabolisers. ABCB1 G2677T/A A/A homozygotes had greater T 1/2 in comparison with C/C homozygotes. ABCB1 C3435T T allele carriers and C1236T C/T subjects showed greater area under the curve than C/C homozygotes., Conclusions: Aripiprazole affects pupil contraction, which could be a secondary effect through dopamine and serotonin receptors. Pupillometry could be a useful tool to assess autonomic nervous system activity during antipsychotic treatment.

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.

Introduction: Bipolar disorder is a severe, chronic psychiatric disorder with a need for long-term treatment. Patient nonadherence is frequent and poses a major problem in maintenance therapy. Aripiprazole once-monthly long-acting injectable (AOM LAI) is a recently US Food and Drug Administration-approved treatment option for maintenance therapy that could be of great value. Areas covered: This paper reviews the pharmacokinetic, efficacy and safety data for AOM LAI in bipolar disorder. Expert opinion: AOM LAI is a safe and efficacious treatment option in the maintenance therapy of bipolar I disorder. However, further research is still needed to determine the position of AOM LAI relative to other available treatment options.

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.

BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (AL NCD ) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of AL NCD , AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice., Methods: In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model., Results: Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single AL NCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay., Conclusions: Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. AL NCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC 0-t , C max and t 1/2 of aripiprazole were higher and clearance of aripiprazole, AUC 0-t of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC 0-t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC 0-t of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC 0-t (p = 0.039) and C max of dehydro-aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC 0-t of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Nonadherence to antipsychotic medications for the treatment of schizophrenia is a widely recognized concern, leading to poorer clinical outcomes and higher treatment costs. Long-acting injectable (LAI) antipsychotics offer an extended dosing interval option for patients, although the current options may require an oral overlap at initiation. Aripiprazole lauroxil is an LAI that offers multiple dosing options but requires oral treatment overlap during initiation for the first 21 consecutive days. As an alternative to oral overlap, a novel nano-crystalline milled dispersion delivery system of aripiprazole lauroxil was recently approved as a one-day regimen to be added to aripiprazole lauroxil treatment.

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.

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.

A sensitive and selective LC-MS/MS method for determination of the prodrug aripiprazole lauroxil (AL) and the three metabolites (N-hydroxymethyl aripiprazole [NHA], aripiprazole [ARP], and dehydro aripiprazole [DHA]) in plasma was developed using ARP-d 8 as an internal standard. The analytes were determined on an AB Sciex Triple Quad™ 4500 system using positive ion electrospray ionization and selected multiple reaction monitoring mode. Solid phase extraction was applied for sample preparation for AL, ARP, and DHA, and protein precipitation for NHA. Chromatographic separation was performed on an Agilent Eclipse XDB-CN column (100 × 2.1 mm i.d., 3.5 μm) using the mobile phase of water and acetonitrile (25:75, v/v) containing 0.1% formic acid with a flow rate of 0.5 mL/min. The linear ranges for AL, NHA, ARP, and DHA were 0.5-50 ng/mL, 1.0-50 ng/mL, 0.5-50 ng/mL, and 0.05-5.0 ng/mL, respectively. The average recovery in the plasma sample was stable and reproducible. The precision and accuracy of the intra- and inter-run were within assay variability criteria limits. The developed method was suitable for in vitro biotransformation studies in plasma and animal pharmacokinetic studies after intramuscular injection of AL formulations., (Copyright © 2018. Published by Elsevier B.V.)

Background: Aripiprazole lauroxil (AL) is an FDA-approved treatment for schizophrenia. AL is a non-ester prodrug of aripiprazole that results in extended systemic release of aripiprazole after intramuscular (IM) administration. This Phase-1 study evaluated the pharmacokinetics (PK) and safety of a new AL dose (1064 mg)* for 2-month dose intervals. The study also evaluated 4- and 6-week dose intervals of AL at the 441 mg and 882 mg doses, respectively., Methods: A total of 139 patients diagnosed with schizophrenia and stabilized on a first-line antipsychotic (other than aripiprazole) were randomized to one of 3 dose/dose-interval groups: a 4-week interval of AL 441 mg (n = 35), a 6-week interval of AL 882 mg (n = 34), and an 8-week interval of AL 1064 mg IM injection (n = 70). After randomization, AL assignment was open label and administered as gluteal injections over 24 weeks. The total number of injections over this time period was related to the interval: 7 injections for the 441 mg group, 5 for the 882 mg group, and 4 for the 1064 mg group. PK and safety assessments occurred every 2 weeks and extended for an additional 20 weeks after the last injection. Patients continued their prior antipsychotic throughout, such that the safety (but not the PK) findings also reflect a second antipsychotic co-prescribed with AL., Results: PK findings: administration of AL 1064 mg every 8 weeks and AL 882 mg every 6 weeks provided continuous exposure to aripiprazole. Compared with the AL 441 mg every 4 weeks group, the longer dose-interval groups had consistently higher plasma concentrations for the entirety of the 6- and 8-week dose intervals for the 882 mg and 1064 mg dose groups. Safety findings: the overall safety profile of the group randomized to the 8 week/1064 mg combination was comparable to the 6 week/882 mg and 4 week/441 mg groups. The most common adverse event (AE) for all groups was injection-site reaction (pain). There was no apparent dose-AE signal for extrapyramidal symptoms, akathisia, sedation, or weight gain. In particular, there was no other safety signal identified with the longest interval/highest-dose AL group of 8 weeks/1064 mg., Conclusion: AL allows for a range of dose/dose-interval combinations. The PK results from this study show that a dosing interval of every 8 weeks for the 1064 mg dose resulted in aripiprazole concentrations within the established therapeutic window for AL. There was no safety signal directing any particular concern to any of the three doses/dose intervals studied. All patients continued their primary antipsychotics without any apparent tolerability issue arising from the addition of the AL injections. The results of this study show that 1064 mg AL may be suitable for a 2-month dose interval. The three doses/dose intervals studied have the potential to help clinicians and patients expand their choice of AL treatment to best meet the needs of the individual patient.

Background: Hypernatremic dehydration is well described in exclusively breastfed neonates, although life-threatening complications are rarely reported., Materials and Methods: The present article describes a case of severe hypernatremic dehydration in a previously healthy term neonate. Other published cases of severe complications of hypernatremic dehydration are discussed., Results: The exclusively breastfed neonate described had severe hypernatremic dehydration because of inadequate milk intake, with disseminated intravascular coagulation and right lower limb gangrene that required amputation of all five toes and surgical debridement of the metatarsals. The usual etiology of hypernatremic dehydration in this age group is insufficient breast milk intake. Here, the infant's mother was treated for bipolar disorder with lamotrigine 250 mg orally once daily, aripiprazole 15 mg orally once daily, and sertraline 100 mg orally once daily., Conclusions: Awareness of these complications should prompt close follow-up of the infant with poor weight gain. The role of maternal medication as a risk factor for hypernatremic dehydration among exclusively breastfed infants needs to be further explored.

Background: Aripiprazole lauroxil (AL) is a long-acting injectable medication approved for the treatment of schizophrenia. Current AL regimens are 441 mg, 662 mg, and 882 mg administered monthly (every 4 weeks [q4wk]), or 882 mg administered every 6 weeks (q6wk)., Objective: We examined the feasibility of a 2-month (every 8 weeks [q8wk]) dosing interval of AL in a phase I open-label pharmacokinetic study investigating AL 1064 mg administered q8wk for 24 weeks, followed by 20 weeks of safety and pharmacokinetic measurements (ClinicalTrials.gov ID: NCT02320032). Second, a population pharmacokinetic model (referred to as the 2MPopPK model) was generated using data collected from the present trial, as well as data obtained from earlier studies., Methods: The phase I study included patients with schizophrenia or schizoaffective disorder maintained on an oral antipsychotic (n = 140) who were assigned to one of three groups: AL 441 mg q4wk, AL 882 mg q6wk, or AL 1064 mg q8wk, with a total of seven, five, or four injections administered, respectively. No oral aripiprazole lead-in supplementation was administered and patients continued on maintenance oral antipsychotics. Pharmacokinetic samples were collected at various time points during the 24-week study period and the 20-week follow-up period. Plasma concentrations obtained from the phase I study were analyzed using non-compartmental methods. Additionally, the data were combined with data collected from prior studies to develop the 2MPopPK model., Results: Following the final injection of AL in the phase I study, maximum aripiprazole concentrations were achieved 24.4-35.2 days after the last dose and persisted for the duration of the study. The mean C avg,ss values were 125.8 ng/ml, 131.1 ng/ml, and 140.7 ng/ml for the 441 mg q4wk, 882 mg q6wk, and 1064 mg q8wk doses, respectively. The mean elimination half-life of aripiprazole following the last dose was 53.9 days for the 1064 mg dose, 55.1 days for the 882 mg dose, and 57.2 days for the 441 mg dose. The 2MPopPK dataset included 14,524 aripiprazole concentrations from 700 patients with schizophrenia. The duration of absorption of aripiprazole was estimated as 43 days (95% confidence interval [CI] 42-45 days), which was preceded by a 3.2-day lag time (95% CI 3.0-3.5 days) for a total duration of input into the systemic circulation of 46 days following intramuscular administration of AL. Multiple-dose simulations showed that the 1064 mg q8wk regimen provides aripiprazole concentrations within the concentration range associated with 441 mg and 882 mg q4wk doses previously demonstrated to be efficacious in a phase III study., Conclusion: These data from the phase I study and the 2MPopPK model support the suitability of using the AL 1064 mg dose as a 2-month (q8wk) dose interval option for the treatment of 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.

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.

Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep-wake cycle, emotional lability, delusional thinking, and language and thought disorders. Delirium results from neurotransmitter imbalances involving several neurotransmitters such as dopamine, glutamate, norepinephrine, acetylcholine, gamma-aminobutyric acid, and serotonin. Untreated delirium causes significant morbidity and mortality. Nonpharmacologic and pharmacologic approaches treat delirium. Current pharmacologic management of delirium involves using agents such as haloperidol or second-generation antipsychotics. Third-generation atypical antipsychotic drugs have emerged as a potential choice for delirium management. Aripiprazole is a third-generation antipsychotic with a dopamine receptor-binding profile distinct from other second-generation antipsychotics. Aripiprazole acts as partial agonist at dopamine D 2 and 5-hydroxytryptamine (5-HT) 1A receptors, stabilizing the dopamine receptor leading to improvement in symptoms. The article reviews the pharmacology, pharmacodynamics, metabolism, and evidence of clinical efficacy for this new antipsychotic agent. This article explores possible roles in palliative care.

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.

Risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole are antipsychotic drugs approved for treating various psychiatric disorders, including schizophrenia. The objective of this randomized, parallel-group, open-label study was to compare finger-stick-based capillary with corresponding venous whole-blood and plasma concentrations for these drugs after administration of a single dose to healthy volunteers. All whole-blood and plasma drug concentrations were measured with validated liquid chromatography-tandem mass spectrometry methods. Capillary and venous concentrations (both in plasma and whole blood) were in close agreement, although a time-dependent difference was observed, most obviously for olanzapine and paliperidone, with slightly higher capillary versus venous drug concentrations during the first hours after administering a single dose. The observed difference between capillary and venous plasma drug concentrations is expected not to be relevant in clinical practice, considering the wide window of therapeutic concentrations and the wide range of drug concentrations in the patient population for a given dose. Based on these results, finger-stick-based capillary drug concentrations have been shown to approximate venous drug concentrations., (© 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Quantification of blood levels of antipsychotic drugs may be useful for managing medication therapy. This open-label, parallel-group study was performed to compare finger-stick-based capillary with corresponding venous plasma concentrations for risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole and their major metabolites after repeated dosing in patients with schizophrenia or related illnesses. Finger-stick-based capillary and venous blood samples were collected at various times within a dosing interval. All drug concentration measurements in the derived plasma samples were performed with validated liquid chromatography-tandem mass spectrometry methods. Finger-stick-based capillary and venous plasma drug concentrations after repeated dosing were generally similar. Olanzapine capillary plasma concentrations, however, were on average approximately 20% higher than venous concentrations, with a trend for a relatively greater difference occurring shortly after dosing. In addition, smaller capillary-venous differences were observed for extended-release and long-acting intramuscular formulations and for aripiprazole, a drug with a long half-life, compared with drugs administered as an immediate-release formulation (risperidone, olanzapine). After repeated dosing, plasma derived from finger-stick-based blood was observed to be predictive of the venous concentrations. Capillary sampling may be an appropriate alternative to venous sampling to readily evaluate systemic drug concentrations., (© 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

In the present investigation, a Quality by Design strategy was applied for formulation and optimization of aripiprazole (APZ) loaded PCL nanoparticles (APNPs) using nanoprecipitation method keeping entrapment efficiency (%EE) and particle size (PS) as critical quality attributes. Establishment of design space was done followed by analysis of its robustness and sensitivity. Characterization of optimized APNPs was done using DSC, FT-IR, PXRD and TEM studies and was evaluated for drug release, hemocompatibility and nasal toxicity. PS, zeta potential and %EE of optimized APNPs were found to be 199.2±5.65nm, -21.4±4.6mV and 69.2±2.34% respectively. In vitro release study showed 90±2.69% drug release after 8h. Nasal toxicity study indicated safety of developed formulation for intranasal administration. APNPs administered via intranasal route facilitated the brain distribution of APZ incorporated with the AUC0→8 in rat brain approximately 2 times higher than that of APNPs administered via intravenous route. Increase in Cmax was observed which might help in dose reduction along with reduction in dose related side effects. The results of the study indicate that intranasally administered APZ loaded PCL NPs can potentially transport APZ via nose to brain and can serve as a non-invasive alternative for the delivery of APZ to brain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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.

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.

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.

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that 'kinetic context', as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.

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.

Introduction: Patient non-adherence increases the risk for relapse and the long-term care of schizophrenia. Long-acting injectable (LAI) antipsychotics can decrease this risk by ensuring adherence. An extended formulation, aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM LAI), received regulatory approval in the year 2013 for the treatment of schizophrenia. AOM LAI is the first dopamine D2 partial agonist available in a long-acting formulation for the treatment of schizophrenia., Areas Covered: This review covers data on the efficacy and tolerability/safety of AOM LAI. AOM LAI is a lyophilized powder of aripiprazole, with an elimination half-life of 29.9 - 46.5 days, allowing for a 4-week injection interval. Antipsychotic efficacy was documented in a 12-week double-blind trial (n = 340) and in two maintenance-of-effect trials: a 38-week trial (n = 662) and a 52-week trial (n = 403). The side effect profile is similar to that of oral aripiprazole. Adverse events (≥5% and at least twice that for placebo) were typically mild or moderate and did not lead to discontinuation: increased weight, akathisia, injection site pain and sedation. The 400 mg dose is tolerated by >90% of patients. Injection does not require additional training of health personnel or post-injection observation., Expert Opinion: AOM LAI is an efficacious and well-tolerated antipsychotic treatment for schizophrenia.