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1.
Drug Metab Rev ; 52(1): 1-18, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32008418

RESUMO

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.


Assuntos
Antipsicóticos/farmacocinética , Modelos Biológicos , Animais , Aripiprazol/farmacocinética , Clozapina/farmacocinética , Humanos , Dinâmica não Linear , Olanzapina/farmacocinética
2.
Expert Opin Drug Saf ; 19(1): 43-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31770500

RESUMO

Introduction: Clozapine remains the most effective antipsychotic for treatment-refractory schizophrenia. However, ~40% of the patients respond insufficiently to clozapine. Clozapine's effects, both beneficial and adverse, have been proposed to be partially attributable to its main metabolite, N-desmethylclozapine (NDMC). However, the relation of the clozapine to norclozapine ratio (CLZ:NDMC; optimally defined as ~2) to clinical response and metabolic outcomes is not clear.Areas covered: This narrative review comprehensively examines the clinical utility of the CLZ:NDMC ratio to reduce metabolic risk and increase treatment efficacy. The association of the CLZ:NDMC ratio with changes in psychopathology, cognitive functioning, and cardiometabolic burden will be explored, as well as adjunctive treatments and their effects.Expert opinion: The literature suggests a positive association between the CLZ:NDMC ratio and better cardiometabolic outcomes. Conversely, the CLZ:NDMC ratio appears inversely associated with better cognitive functioning but less consistently with other psychiatric domains. The CLZ:NDMC ratio may be useful for predicting and monitoring cardiometabolic adverse effects and optimizing potential cognitive benefits of clozapine. Future studies are required to replicate these findings, which if substantiated, would encourage examination of adjunctive treatments aiming to alter the CLZ:NDMC ratio to best meet the needs of the individual patient, thereby broadening clozapine's clinical utility.


Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Esquizofrenia/tratamento farmacológico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Clozapina/efeitos adversos , Clozapina/análogos & derivados , Clozapina/sangue , Clozapina/farmacocinética , Cognição/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Humanos
3.
Forensic Sci Int ; 307: 110108, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877542

RESUMO

Quetiapine is an atypical antipsychotic drug, frequently found in post-mortem samples. The quantitative determination of active metabolites may help in the interpretation of the potential toxic effects of the parent drug and its role in death. A fully validated LC-MS/MS method was developed for the identification and quantification of quetiapine and two main metabolites (N-desalkylquetiapine and 7-hydroxyquetiapine) in blood, biological fluids and tissues. Then, the distribution of analytes in different matrices was evaluated. LODs of 0.9, 0.3 and 0.3ng/mL were calculated for quetiapine, N-desalkylquetiapine and 7-hydroxyquetiapine respectively; while a LOQ at the concentration of 10.0ng/mL was defined for the three analytes. 13 post-mortem positive real cases have been included in the experiment. The results revealed that quetiapine and N-desalkylquetiapine might undergo a significant post-mortem redistribution, while 7-hydroxyquetiapine is less affected by this factor. N-desalkylquetiapine could be found in blood in relatively high concentrations in comparison to those of quetiapine; therefore, it should be always advisable to measure both the analytes. The analysis of tissues could provide additional data on potential intoxication with quetiapine.


Assuntos
Antipsicóticos/farmacocinética , Mudanças Depois da Morte , Fumarato de Quetiapina/farmacocinética , Tecido Adiposo/química , Adulto , Idoso , Bile/química , Química Encefálica , Cromatografia Líquida , Dibenzotiazepinas/farmacocinética , Feminino , Toxicologia Forense , Humanos , Rim/química , Limite de Detecção , Fígado/química , Pulmão/química , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/química , Baço/química , Espectrometria de Massas em Tandem , Distribuição Tecidual , Adulto Jovem
4.
AAPS PharmSciTech ; 21(1): 27, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858315

RESUMO

The purpose of this study was to develop and evaluate a new formulation of ziprasidone (ZIP) for improved fasted state absorption and sustained drug release. ZIP solid dispersions were produced via spray drying using Soluplus®, an amphiphilic polymer, as the solubility enhancer. Physicochemical analysis proved that ZIP presented at amorphous state in the spray-dried microparticles and the dissolution rate of ZIP from the Soluplus®-ZIP composite microparticles was significantly increased compared with that of the physical mixtures. Commonly used encapsulation materials including Eudragit® RL, Eudragit® S100 and Ethyl Cellulose were incorporated into the solid dispersions to regulate the drug release kinetics. The formulation containing ethyl cellulose provided the most sustained release behaviors. Pharmacokinetic studies in beagle dogs confirmed that there was no significant difference in oral bioavailability of the microparticles under fasted and fed states, and a prolonged Tmax value was simultaneously achieved compared with the commercial ZIP capsules.


Assuntos
Antipsicóticos/administração & dosagem , Celulose/análogos & derivados , Interações Alimento-Droga , Piperazinas/administração & dosagem , Polietilenoglicóis/química , Polivinil/química , Tiazóis/administração & dosagem , Animais , Antipsicóticos/farmacocinética , Disponibilidade Biológica , Celulose/química , Preparações de Ação Retardada , Cães , Piperazinas/farmacocinética , Solubilidade , Tiazóis/farmacocinética
5.
Expert Opin Pharmacother ; 20(17): 2063-2072, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31644326

RESUMO

Introduction: Cariprazine, a D3-preferring, dopamine D2/D3 partial agonist, has efficacy in treating both acute phases of bipolar I disorder (BD-I). It has been approved by the FDA for treatment of acute manic, mixed and depressive episodes associated with BD-I.Areas covered: In this review, the authors discuss the unique pharmacological properties and clinical efficacy profile of cariprazine, and their relevance in the context of routine clinical decision-making for BD-I. For the purpose of this review, the authors searched for clinical trials in BD published in the PubMed, Web of Science, Embase and PsychInfo databases as well as for studies registered in the ClinicalTrials.gov database.Expert opinion: Based on evidence from RCTs in manic and mixed episodes, cariprazine in a dose-range of 3-12 mg is effective for treating acute mania and mixed states associated with BD-I. Importantly, evidence from placebo-controlled trials in bipolar depression suggests that cariprazine is also effective as a monotherapy in treating acute bipolar depression in doses of 1.5-3 mg/day. It is overall well tolerated; however, clinicians need to monitor patients for akathisia.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Piperazinas/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Agonistas de Dopamina/efeitos adversos , Meia-Vida , Humanos , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Resultado do Tratamento
6.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416290

RESUMO

Neuroleptics and antiepileptics are excreted in saliva, which can, therefore, be very useful in determining their concentration in the body. This study presents a method developed to simultaneously identify five neuroleptics-olanzapine, quetiapine, risperidone, aripiprazole, and clozapine-and the antiepileptic carbamazepine together with their metabolites: N-demethyl olanzapine, norquetiapine, 9-OH-risperidone, dehydroaripiprazole, N-desmethylclozapine, and carbamazepine-10,11 epoxide. Chlordiazepoxide was used as the internal standard. Strata-X-C columns were used for isolation of the compounds. Chromatographic analysis was carried out using UHPLC with a diode array detector (DAD). A mixture of acetonitrile and water with the addition of formic acid and 0.1% triethylamine was used as the mobile phase. The developed method was validated by determining the linearity for all analytes in the range 10-1000 ng/mL and the value of R2 > 0.99. Intra- and inter-day precision were also determined, and the relative standard deviation (RSD) value in both cases did not exceed 15%. To determine the usefulness of the developed method, saliva samples were collected from 40 people of both sexes treated with the tested active substances both in monotherapy and in polypragmasy. In all cases, the active substances tested were identified.


Assuntos
Anticonvulsivantes/farmacologia , Antipsicóticos/farmacocinética , Cromatografia Líquida de Alta Pressão , Saliva/metabolismo , Anticonvulsivantes/química , Antipsicóticos/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Reprodutibilidade dos Testes
7.
Expert Opin Pharmacother ; 20(16): 1925-1933, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31431092

RESUMO

Introduction:Treatment-resistant depression (TRD), seldom interchangeably referred to as 'depression inadequately responding to the standard antidepressant drug,' carries a significant burden. The atypical antipsychotics represent a popular augmentation strategy for antidepressant-resistant depression, although their efficacy/safety profiles vary across different agents and presentations of depression. Areas covered: This review appraises the evidence supporting the use of brexpiprazole augmentation for major depressive disorder (MDD) adults showing an inadequate response to standard antidepressants, covering the related regulatory affairs, and essential pharmacology. Expert opinion: Brexpiprazole is a 'third-generation' antipsychotic featuring dopaminergic D2 and serotonergic 5-HT1A partial agonism approved by the U.S. Food and Drug Administration for the treatment of MDD, besides schizophrenia in adults. The clinical trials leading to the extended approval of brexpiprazole rely on the definition of 'inadequate response' to antidepressants, which seems to poorly represent the most severe cases of TRD seen in clinical practice. TRD definitions appraised in the literature are likewise inconsistent and questionable from a clinical-standpoint. Compared to aripiprazole, brexpiprazole has lower D2 intrinsic activity, although the latter features a more potent serotonergic 5-HT2A antagonism. The actual propensity of brexpiprazole to induce akathisia and tardive dyskinesia warrants assessment by ad-hoc designed long-term, controlled trials.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Quinolonas/uso terapêutico , Tiofenos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Tiofenos/efeitos adversos , Tiofenos/farmacocinética
8.
Psychiatr Prax ; 46(5): 287-289, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31269521

RESUMO

Systemic infections are known to alter the metabolism of various drugs via inhibition of the cytochrome P450 family. Here, we report the cases of two patients with schizophrenic psychosis and highly elevated clozapine levels during pulmonary systemic infection, however without experiencing side effects. After antibiotic treatment and temporary reduction of clozapine dosage blood levels of clozapine normalized within a few days. These cases show that clozapine levels may be highly elevated without necessarily causing side effects and that intensified pharmacovigilance should be considered by the clinician in patients with systemic infections.


Assuntos
Clozapina , Pneumonia/metabolismo , Antipsicóticos/farmacocinética , Clozapina/farmacocinética , Alemanha , Humanos , Transtornos Psicóticos/tratamento farmacológico
9.
Expert Opin Drug Metab Toxicol ; 15(8): 619-631, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31271537

RESUMO

Introduction: The comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorders (BDs) is a frequent and severe condition characterized by a chronic course, high suicidal risk and tendency towards chronicity and treatment non-response. It represents a real challenge to psychiatrists, while requiring a careful and appropriate therapeutic management consisting in the combination of serotonergic antidepressants (ADs), such as serotonin reuptake inhibitors (SRIs), with mood stabilizers. This combination, like any other, raises the problems related to drug interactions that may lead to pharmacokinetic and pharmacodynamic changes, resulting in the modification of the pharmacologic effect and safety profile of a given compound. Areas covered: The aim of the present paper was to review the literature on the pharmacokinetic and pharmacodynamic changes resulting from the interactions of the different drugs prescribed in the OCD-BD comorbidity. Expert opinion: The literature data on pharmacokinetic and pharmacodynamic changes due to interactions of drugs commonly prescribed in the treatment of the OCD-BD comorbidity are extremely limited, and the information is inferred by findings gathered in psychiatric patients suffering from other disorders. This represents a gap in psychopharmacology that should be filled by specific studies on this important topic.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Antimaníacos/administração & dosagem , Antimaníacos/farmacocinética , Antimaníacos/farmacologia , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Transtorno Bipolar/complicações , Interações Medicamentosas , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/farmacologia
10.
Int J Clin Pharmacol Ther ; 57(9): 437-444, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31232279

RESUMO

OBJECTIVE: Antipsychotics exhibit different profiles of efficacy and safety in patients with schizophrenia. It has recently been reported that the risk of rehospitalization was the lowest with paliperidone palmitate (PP), a long-acting injectable (LAI), when compared with other LAIs (of zuclopenthixol, perphenazine, and olanzapine). We aimed to investigate whether treating patients with PP was also associated with improved real-life treatment persistence. MATERIALS AND METHODS: We conducted a retrospective observational study of the LAI antipsychotics (LAIAs) dispensed in French retail pharmacies. Treatment persistence was defined as the non-discontinuation of LAIAs for ≥ 5 months after LAIA initiation (and was also analyzed by Kaplan-Meier persistence curves). RESULTS: A total of 4,492 patients were included in the study. The persistence rate was significantly greater for LAI-PP (64.5%) than for either LAI haloperidol decanoate (HD) or LAI risperidone microspheres (R) (46.4% and 35.4%, respectively). Multivariate Cox analyses illustrated that LAIA initiation with HD or R significantly increased the risk of discontinuation when compared with PP. CONCLUSION: PP demonstrated a significantly higher persistence rate than HD or R. Moreover, LAIA initiation with HD or R significantly increased the risk of treatment discontinuation relative to PP. Further comparative studies are required to comprehensively determine whether PP has a better efficacy and/or safety profile than other LAIs.


Assuntos
Antipsicóticos/farmacocinética , Esquizofrenia/tratamento farmacológico , Preparações de Ação Retardada , França , Haloperidol/análogos & derivados , Haloperidol/farmacocinética , Humanos , Injeções , Palmitato de Paliperidona/farmacocinética , Estudos Retrospectivos , Risperidona/farmacocinética
11.
Biol Pharm Bull ; 42(6): 1025-1029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155577

RESUMO

Magnesium oxide (MgO) is a widely used laxative. Because many antipsychotic drugs are lipophilic-basic-compounds, their solubility decreases with increasing pH and changes markedly as the pH of the solution approaches their pKa. It is highly important to clarify the effect of co-administration of MgO on the serum drug concentration for effective, safe, and appropriate medication therapy. However, the relationship between MgO administration and the serum concentration of antipsychotic drugs in patients with schizophrenia has not been reported. Therefore, in the present study, we investigated the effect of MgO administration on the concentration of antipsychotic drugs in the blood of patients with schizophrenia. The serum concentrations of biperiden, zotepine, and risperidone were assayed using an LC/MS system. The correlation between the daily dose of MgO and the relative-drug-concentration (rCp) in each patient was examined. As the MgO dose was increased, the risperidone concentration decreased. The correlation coefficient decreased for risperidone, zotepine, and biperiden, in the same order. To clarify the difference in the suppression potency of MgO on the three drugs, the relationship between the physical properties and the correlation coefficients of each drug was carefully examined. A strong correlation was observed between the pKa and the correlation coefficient. Patients with schizophrenia are often prescribed antipsychotic drugs, which have anticholinergic action and tend to suppress gastric acid secretion. We concluded that basic drug absorption might be suppressed due to an increase in the stomach pH following MgO administration. Therefore, MgO co-administration is better to avoid while taking antipsychotic drugs and anticholinergic drugs.


Assuntos
Antipsicóticos/farmacocinética , Laxantes/farmacologia , Óxido de Magnésio/farmacologia , Esquizofrenia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/sangue , Biperideno/sangue , Biperideno/farmacocinética , Dibenzotiepinas/sangue , Dibenzotiepinas/farmacocinética , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Pessoa de Meia-Idade , Risperidona/sangue , Risperidona/farmacocinética , Esquizofrenia/tratamento farmacológico
12.
Expert Rev Clin Pharmacol ; 12(7): 603-621, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075044

RESUMO

Introduction: This article comprehensively reviews the clinical utility of the serum clozapine/norclozapine (CLO/NCLO) ratio. Areas covered: Fifty-four published studies used this ratio (21 from a PubMed search from onset to 10/21/18 and 33 identified by the authors). To estimate a combined mean of the CLO/NCLO ratio in published studies, a PubMed search on 10/21/18 identified 422 articles leading to 19 included. The systematic review focused on 1) the combined analysis, 2) CYP1A2 activity, 3) clinical response, 4) cognition, and 5) renal function. Expert opinion: Our combined analysis provided a weighted mean CLO/NCLO ratio of 1.73 in 2,317 adult patients from 19 studies, but the range in the studies varied widely from 1.19 to 3.37. No study provided data on variability of the CLO/NCLO ratios within individual patients. The CLO/NCLO ratio is not a measure of CYP1A2 activity and is not associated with clinical response. The association of the CLO/NCLO ratio with cognitive measures is unclear (4 cross-sectional studies were positive and post-hoc analysis of a randomized clinical trial was negative). Future studies must replicate the finding of a case report that gemfibrozil may invert the CLO/NCLO ratio (making it <1), indicating that gemfibrozil inhibits the renal transporter that excretes NCLO.


Assuntos
Antipsicóticos/farmacocinética , Clozapina/análogos & derivados , Monitoramento de Medicamentos/métodos , Adulto , Animais , Clozapina/farmacocinética , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Riv Psichiatr ; 54(2): 43-58, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30985829

RESUMO

Paliperidone is a second-generation antipsychotic drug belonging to the class of benzisoxasole derivatives. Paliperidone is the major active metabolite of risperidone (9-OH-risperidone) and, as such, is comparable to the latter in terms of pharmacodynamic properties. However, due to its peculiar characteristics, paliperidone may be particularly useful in the treatment of schizophrenic patients. In this critical review of the literature the efficacy and tolerability in the short- and in the long-term have been evaluated in patients with schizophrenia. Taking into account the tolerability and efficacy data, together with the use of innovative sustained-release formulation, with a peculiar pharmacokinetic profile that allows single daily administration, paliperidone can be considered a valid option both for the short and the long-term treatment of schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacocinética , Preparações de Ação Retardada , Esquema de Medicação , Humanos , Palmitato de Paliperidona/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Esquizofrenia/metabolismo
14.
Lancet Psychiatry ; 6(5): 418-426, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31000417

RESUMO

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.


Assuntos
Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Citocromo P-450 CYP2D6/genética , Variantes Farmacogenômicos , Transtornos Psicóticos/tratamento farmacológico , Risperidona/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Antipsicóticos/farmacocinética , Aripiprazol/farmacocinética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Transtornos Psicóticos/genética , Estudos Retrospectivos , Risperidona/farmacocinética , Falha de Tratamento , Adulto Jovem
15.
Ther Drug Monit ; 41(3): 348-356, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31025986

RESUMO

BACKGROUND: No comprehensive collection of routine therapeutic drug monitoring data for antipsychotic drugs has been published. METHODS: In this compilation, data on 12 antipsychotics are presented. The drugs included are amisulpride (n = 506), aripiprazole (n = 1610), clozapine (n = 1189), flupentixol (n = 215), haloperidol (n = 390), olanzapine (n = 10,268), perphenazine (n = 1065), quetiapine (n = 5853), risperidone (n = 3255), sertindole (n = 111), ziprasidone (n = 1235), and zuclopenthixol (n = 691). Because only one sample per patient is included, the number of patients equals the number of samples. For each drug, median serum concentrations as well as that of the 10th and 90th percentiles are given for a range of daily doses. Comparisons are made between males and females, between patients younger than 65 years and 65 years and older, and between those treated with a low and a high dose of each drug. The concentration-to-dose (C/D) ratio is the primary variable used in these comparisons. Coefficients of variation (CVs) for the serum concentrations of each drug within and between subjects are presented. RESULTS: In general, the C/D ratios were higher in females than in males, higher in those 65 years and older than in younger subjects, and lower in those treated with higher doses than in those treated with lower doses. CVs between individuals were larger than within subjects, and the CVs were highest for the drugs with short elimination half-lives. CONCLUSIONS: For each antipsychotic drug, the results presented can serve as a reference tool for pharmacokinetic interpretation of the individual patient's serum drug level. The compiled serum concentrations and the C/D ratios can support the physician's decision when individualizing dosing and determining treatment strategies for a specific patient.


Assuntos
Antipsicóticos/sangue , Idoso , Antipsicóticos/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino
16.
Clin Drug Investig ; 39(5): 477-484, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888624

RESUMO

BACKGROUND: A combination of the atypical antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of schizophrenia. The goal of OLZ/SAM is to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain and many associated long-term metabolic consequences. The primary metabolic pathways for olanzapine are direct glucuronidation via uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4 and cytochrome P450 (CYP)-mediated oxidation, mainly by CYP1A2. In contrast, the samidorphan metabolic pathway is mediated predominantly by CYP3A4. OBJECTIVE: The aim of this study was to evaluate the effects of CYP3A4 induction on the single-dose pharmacokinetics of OLZ/SAM in healthy subjects. METHODS: In this phase I, single-center, open-label, two-period study, 24 healthy volunteers received a single oral dose of OLZ/SAM 10/10 (10 mg olanzapine/10 mg samidorphan) on day 1. After a 14-day washout, 600 mg of rifampin (rifampicin), a strong CYP3A4 inducer, as well as an inducer of UGT enzymes and a weak inducer of CYP1A2, was administered once daily on days 15‒21. A single oral dose of OLZ/SAM 10/10 was coadministered with rifampin 600 mg on day 22. Olanzapine and samidorphan pharmacokinetic parameters were determined after OLZ/SAM dosing on days 1 and 22. The geometric mean ratio of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUC∞) for olanzapine and samidorphan in the presence and absence of rifampin, along with its two-sided 90% confidence interval, were derived from a linear mixed-effects model. Safety was monitored throughout the study. RESULTS: Compared with OLZ/SAM alone, coadministration of OLZ/SAM with rifampin decreased the Cmax and AUC∞ of olanzapine by 11% and 48%, and that of samidorphan by 44% and 73%, respectively. OLZ/SAM 10/10 was generally well tolerated in this study. CONCLUSION: Coadministration with rifampin decreased total systemic exposure (based on AUC∞) of olanzapine and samidorphan by 48% and 73%, respectively.


Assuntos
Antipsicóticos/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacocinética , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacocinética , Olanzapina/farmacocinética , Rifampina/farmacocinética , Adulto , Antipsicóticos/administração & dosagem , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Interações Medicamentosas/fisiologia , Quimioterapia Combinada , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Naltrexona/farmacocinética , Antagonistas de Entorpecentes/administração & dosagem , Olanzapina/administração & dosagem , Rifampina/administração & dosagem , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/fisiologia , Adulto Jovem
18.
J Psychosoc Nurs Ment Health Serv ; 57(3): 7-10, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30835795

RESUMO

Long-acting injectable (LAI) antipsychotic medications have been around since the 1960s as alternatives to oral formulations to improve medication adherence. LAIs are similar enough to their corresponding oral formulations to be used interchangeably and have convincing evidence of improving consistency in pharmacotherapy that reduces the rates of relapse and frequency of hospitalization for individuals with psychosis. So why are they not used as often? The current article presents an argument to initiate LAIs early in treatment as a way of establishing consistency in treatment, thereby, potentially improving client outcomes. [Journal of Psychosocial Nursing and Mental Health Services, 57(3), 7-10.].


Assuntos
Antipsicóticos/uso terapêutico , Injeções Intramusculares/métodos , Adesão à Medicação , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacocinética , Preparações de Ação Retardada , Hospitalização , Humanos
19.
Crit Rev Ther Drug Carrier Syst ; 36(2): 137-181, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806211

RESUMO

The parenteral route of administration is preferred over the oral route for treatment of many chronic and life-threatening diseases due to better patient compliance. Long-acting injectables/depot delivery systems are formulations intended for prolonged/sustained drug release over a long period of time ranging from a few days to months. Depot delivery systems enhance product quality by decreasing dosing frequency, simplifying the drug regimen. Parenteral depots reduce the relapse rate of disease and the maintenance phase of therapy, hence improving efficacy and treatment adherence. However, despite being extensively explored in the last seventy years, only a few depot products have been marketed or have reached commercial viability. The introduction of long-acting injectables of any drug took 9 to 10 years after approval of its oral formulation. Mainly the market has been conquered by long-acting injectables for antipsychotic, substance abuse, and hormonal therapy drugs. This article focuses on the preparation of long-acting injectables with special emphasis on challenges associated with formulation. The evolution and current global market trend of various depot formulations are also discussed. Insight is provided into the promising future of long-acting injectables of protein-based drugs as well as multidrug therapy, along with potential uses in the treatment of chronic diseases like HIV, Parkinson's, and Alzheimer's.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Injeções/tendências , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Previsões , Terapia de Reposição Hormonal/métodos , Terapia de Reposição Hormonal/tendências , Humanos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Injeções/métodos
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