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1.
Artigo em Inglês | MEDLINE | ID: mdl-39237024

RESUMO

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.


Assuntos
Antipsicóticos , Aripiprazol , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Aripiprazol/farmacocinética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Masculino , Feminino , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Quinolonas/farmacocinética , Quinolonas/sangue , Adulto Jovem , Piperazinas/farmacocinética , Piperazinas/sangue , Idoso , Preparações de Ação Retardada/farmacocinética
2.
J Pharm Biomed Anal ; 248: 116322, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38964167

RESUMO

Cystic fibrosis is one of the most common genetic diseases among caucasian population. This disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the CFTR protein. Lumacaftor, elexacaftor, tezacaftor, and ivacaftor were currently used as the treatment to Cystic fibrosis. In this study, we describe a new method for the simultaneous quantification of four molecules: lumacaftor, elexacaftor, tezacaftor, and ivacaftor, alongside two metabolites of ivacaftor, specifically hexyl-methyl ivacaftor and ivacaftor carboxylate by liquid chromatography-tandem mass spectrometry. This method holds significant utility for therapeutic drug monitoring and the optimization of treatments related to CFTR modulators. Molecules were extracted from 100 µL of plasma by a simple method of protein precipitation using acetonitrile. Following extraction, chromatographic separation was carried out by reverse chromatography on a C18 analytical column, using a gradient elution of water (0.05 % formic acid, V/V) and acetonitrile (0.05 % formic acid, V/V). The run time was 7 minutes at a flow rate of 0.5 mL/min. After separation, molecules were detected by electrospray ionization on a Xevo TQD triple-quadrupole-mass-spectrometer (Waters®, Milford, USA). The calibration range were: 0.053-20.000 mg/L for elexacaftor, tezacaftor and lumacaftor, 0.075-14.000 mg/L for ivacaftor, and 0.024-6.500 mg/L for hexyl-methyl ivacaftor and ivacaftor carboxylate. The proposed method underwent throughout validation demonstrating satisfactory precision (inter- and intra-day coefficients of variation less than 14.3 %) and a good accuracy (inter- and intra-day bias ranging between -13.7 % and 14.7 %) for all the analytes. The presented method for the simultaneous quantification of CFTR modulators and their metabolites in human plasma has undergone rigorous validation process yielding good results including strong precision and accuracy for all analytes. This method has been effectively used in routine analytical analysis and clinical investigations within our laboratory.


Assuntos
Aminofenóis , Aminopiridinas , Benzodioxóis , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Indóis , Quinolonas , Humanos , Aminofenóis/sangue , Aminofenóis/farmacocinética , Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Benzodioxóis/sangue , Benzodioxóis/farmacocinética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/sangue , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Monitoramento de Medicamentos/métodos , Indóis/sangue , Indóis/farmacocinética , Espectrometria de Massa com Cromatografia Líquida , Pirazóis/sangue , Pirazóis/farmacocinética , Piridinas , Pirróis/sangue , Pirróis/farmacocinética , Pirrolidinas , Quinolonas/sangue , Quinolonas/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
3.
Ther Drug Monit ; 46(5): 687-691, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38648649

RESUMO

BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.


Assuntos
Antipsicóticos , Leite Humano , Palmitato de Paliperidona , Período Pós-Parto , Fumarato de Quetiapina , Quinolonas , Risperidona , Esquizofrenia , Tiofenos , Humanos , Feminino , Palmitato de Paliperidona/farmacocinética , Palmitato de Paliperidona/uso terapêutico , Adulto , Fumarato de Quetiapina/farmacocinética , Fumarato de Quetiapina/uso terapêutico , Antipsicóticos/farmacocinética , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Gravidez , Risperidona/farmacocinética , Risperidona/sangue , Risperidona/uso terapêutico , Leite Humano/metabolismo , Leite Humano/química , Recém-Nascido , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Tiofenos/farmacocinética , Tiofenos/sangue , Quinolonas/farmacocinética , Quinolonas/sangue , Quinolonas/uso terapêutico , Espectrometria de Massas em Tandem/métodos , Sangue Fetal/química , Sangue Fetal/metabolismo , Complicações na Gravidez/tratamento farmacológico
4.
Clin Biochem ; 90: 40-49, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33539809

RESUMO

OBJECTIVES: Critically ill patients in intensive care unit (ICU) are susceptible to infectious diseases, thus empirical therapy is recommended. However, the therapeutic effect in ICU patients is difficult to predict due to fluctuation in pharmacokinetics because of various factors. This problem can be solved by developing personalized medicine through therapeutic drug monitoring. However, when different measurement systems are used for various drugs, measurements are complicated and time consuming in clinical practice. In this study, we aimed to develop an assay using ultra-high performance liquid chromatography coupled with tandem mass spectrometry for simultaneous quantification of 12 antimicrobial agents commonly used in ICU: doripenem, meropenem, linezolid, tedizolid, daptomycin, ciprofloxacin, levofloxacin, pazufloxacin, fluconazole, voriconazole, voriconazole N-oxide which is a major metabolite of voriconazole, and posaconazole. DESIGN & METHODS: Plasma protein was precipitated by adding acetonitrile and 50% MeOH containing standard and labeled IS. The analytes were separated with an ACQUITY UHPLC CSH C18 column, under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. RESULTS: The method fulfilled the criteria of US Food and Drug Administration for assay validation. The recovery rate was more than 84.8%. Matrix effect ranged from 79.1% to 119.3%. All the calibration curves showed good linearity (back calculation of calibrators: relative error ≤ 15%) over wide concentration ranges, which allowed determination of Cmax and Ctrough. Clinical applicability of the novel method was confirmed. CONCLUSIONS: We have developed an assay for simultaneous quantification of 12 antimicrobial agents using a small sample volume of 50 µL with a short assay time of 7 min. Our novel method may contribute to simultaneous calculation of pharmacokinetic and pharmacodynamic parameters.


Assuntos
Anti-Infecciosos/sangue , Anti-Infecciosos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/farmacologia , Azóis/sangue , Carbapenêmicos/sangue , Ciprofloxacina/sangue , Daptomicina/sangue , Doripenem/sangue , Monitoramento de Medicamentos/métodos , Feminino , Fluconazol/sangue , Fluoroquinolonas/sangue , Humanos , Unidades de Terapia Intensiva , Levofloxacino/sangue , Linezolida/sangue , Masculino , Meropeném/sangue , Staphylococcus aureus Resistente à Meticilina/metabolismo , Pessoa de Meia-Idade , Oxazinas/sangue , Oxazolidinonas/sangue , Quinolonas/sangue , Tetrazóis/sangue , Voriconazol/sangue
5.
Invest New Drugs ; 38(6): 1836-1845, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32578154

RESUMO

LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Quinolonas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Inibidores de Fosfoinositídeo-3 Quinase/sangue , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/farmacocinética , Quinolonas/efeitos adversos , Quinolonas/sangue , Quinolonas/farmacocinética , Critérios de Avaliação de Resposta em Tumores Sólidos , Serina-Treonina Quinases TOR/metabolismo , Tomografia Computadorizada por Raios X
6.
Biopharm Drug Dispos ; 41(6): 268-272, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32557753

RESUMO

Rebamipide is used widely in East Asia for the treatment of gastric ulcers, acute gastritis, and exacerbated chronic gastritis. The objective of this study was to investigate the pharmacokinetic (PK) properties of rebamipide following single oral administration in rats and dogs. Eleven rats and dogs received single oral administrations of rebamipide (35 mg/kg and 100 mg, respectively). Blood samples were collected according to the assigned schedule, and the plasma concentration of rebamipide was determined using liquid chromatography-tandem mass spectrometry. A double-peak phenomenon was observed in the PK profile of rebamipide in rats. In contrast, rebamipide showed a conventional PK profile without double peaks in dogs. The half-life of rebamipide in rats (12.85 ± 7.86 h) was longer than that in dogs (5.62 ± 2.24 h), and the apparent total clearance (Clt /F) of rebamipide in rats (3.32 ± 1.18 L/h) was lower than that in dogs (105.01 ± 42.37 L/h). Simple allometric approaches showed that the correlation between body weight and Clt /F (R2 = 0.9287) among rats, dogs, and humans appeared satisfactory. This finding will help not only in understanding the pharmacology of rebamipide but also in establishing a strategy for in vivo evaluation of novel rebamipide formulations.


Assuntos
Alanina/análogos & derivados , Fármacos Gastrointestinais/farmacocinética , Quinolonas/farmacocinética , Administração Oral , Alanina/sangue , Alanina/farmacocinética , Animais , Cães , Fármacos Gastrointestinais/sangue , Meia-Vida , Masculino , Quinolonas/sangue , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
7.
Clin Pharmacol Drug Dev ; 9(8): 1015-1024, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32237115

RESUMO

Laquinimod, a neuroimmunomodulator, is extensively metabolized by cytochrome P450 (CYP) 3A4, and modulations of CYP3A4 activity may lead to alterations in the pharmacokinetics and/or clinical effects of laquinimod. To determine the drug-drug interaction potential of laquinimod with CYP3A inhibitors and inducers, interaction assessments were conducted in healthy volunteers using single-dose administration of laquinimod before and after multiple dosing of CYP3A inhibitors (ketoconazole, fluconazole, and cimetidine) or a CYP3A4 inducer (rifampin). For ketoconazole, subjects (n = 14) received laquinimod 0.6 mg following 1 day of ketoconazole (400 mg daily) pretreatment, a single concomitant dose, and 28 additional days. For fluconazole, subjects (n = 14) received laquinimod 0.6 mg after a single fluconazole dose of 400 mg followed by 200-mg daily fluconazole administration for 20 additional days. For cimetidine, subjects (n = 14) received laquinimod 0.6 mg following 1 day of cimetidine (800 mg twice daily) pretreatment, a single concomitant dose, and 21 additional days. For rifampin, subjects (n = 14) received laquinimod 0.6 mg following 9 days of rifampin (600 mg daily) pretreatment, a single concomitant dose, and 12 additional days. Coadministration of laquinimod with CYP3A inhibitors, ketoconazole, fluconazole, and cimetidine increased laquinimod area under the plasma concentration-time curve from time zero to infinity by approximately 3.1-, 2.5-, and 1.1-fold, respectively. Coadministration of laquinimod with rifampin decreased laquinimod area under the plasma concentration-time curve from time zero to infinity by 5-fold. These results indicate that coadministration of laquinimod with moderate to strong inhibitors of CYP3A or strong inducers of CYP3A may give rise to significant pharmacokinetic drug interactions.


Assuntos
Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Neuroimunomodulação/efeitos dos fármacos , Quinolonas/farmacocinética , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Indutores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/estatística & dados numéricos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/sangue , Segurança
8.
Drug Des Devel Ther ; 14: 407-415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32095071

RESUMO

BACKGROUND: Dovitinib (TKI 258) is a small-molecule multi-kinase inhibitor for the treatment of different types of cancer. There is currently no validated method for its quantitative determination; therefore, we aimed to develop a reliable method to assay dovitinib. METHOD AND RESULTS: An electrospray ionization tandem mass spectrometry (ESI-MS/MS) method was used to separate dovitinib using an analytical C18 column (50 × 2.1 mm, 1.8 µm) at 25°C. Bosutinib was used as the internal standard (IS). Dovitinib was extracted from mouse plasma using a precipitation procedure. The mobile phase consisted of 10 mM ammonium formate: acetonitrile (68:32, v/v, pH 4.3) run at a rate of 0.3 mL min-1. MS detection was performed in the positive ion mode. Multiple reaction monitoring transitions were 393→337 and 393→309 for dovitinib, and 530→141 and 530→113 for bosutinib. The investigated method was validated as a bio-analytical method based on FDA guidelines. The linearity of the developed method was over the range of 5-500 ng mL,-1 coefficient of determination (r2= 0.9998). The average intra-day recovery and relative standard deviation (RSD) of the quality control (QC) sample were 97.24% and 1.32%, whereas the overall inter-day accuracy and precision were 97.99% and 0.54%, respectively. Dovitinib was stable during sample storage and handling conditions. Furthermore, the dilution integrity of the method was demonstrated by good recovery (97-99%) and RSD values (0.5-0.7%). CONCLUSION: This method was selectively sensitive and exhibited no matrix effect, with an acceptable accuracy and precision according to the FDA guidelines. The developed method could be efficiently used for pharmacokinetic studies of dovitinib.


Assuntos
Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Quinolonas/sangue , Quinolonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Benzimidazóis/química , Calibragem , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolonas/química
9.
Pharm Dev Technol ; 25(5): 625-639, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32031478

RESUMO

To improve the solubility and oral bioavailability of a novel antimalarial agent ELQ-331(a prodrug of ELQ-300), spray-dried dispersions (SDD) and a self-emulsifying drug delivery system (SEDDS) were developed. SDD were prepared with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) polymer carrier and Aeroperl® 300 Pharma and characterized by differential scanning calorimetry, powder X-ray diffraction. For SEDDS, solubility in oils, surfactants, and co-surfactants was determined and ternary phase diagram was constructed to show self-emulsifying area. SEDDS were characterized for spontaneous emulsification and droplet size distribution. The amorphous ELQ-331 SDD improved the solubility to 10× in fast-state simulated intestinal fluid and addition of sodium lauryl sulphate externally to SDDs further improved the solubility to ∼28.5× versus non-formulated drug. SEDDS had good self-emulsifying characteristics with small emulsion droplet sizes and narrow particle distribution. Oral pharmacokinetic studies for SDD and SEDDS formulations were performed in rats. The ELQ-331 rapidly converted to ELQ-300 soon after oral administration in rats. Exposure levels of ELQ-300 were about 1.4-fold higher (based on AUC) in SEDDS than SDD formulations. Poorly soluble drugs like ELQ-331 can be formulated using SDD or SEDDS to improve solubility and oral bioavailability.


Assuntos
Antimaláricos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Pró-Fármacos/química , Quinolonas/química , Administração Oral , Animais , Antimaláricos/administração & dosagem , Antimaláricos/sangue , Disponibilidade Biológica , Estabilidade de Medicamentos , Emulsões , Excipientes/química , Masculino , Estrutura Molecular , Polietilenoglicóis/química , Polivinil/química , Pró-Fármacos/administração & dosagem , Quinolonas/administração & dosagem , Quinolonas/sangue , Ratos Sprague-Dawley , Solubilidade
10.
Eur J Clin Pharmacol ; 76(1): 41-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31637453

RESUMO

PURPOSE: Tailoring medication dosing for the individual patient is complex, and many factors can influence drug exposure. We investigated the effect of age and CYP2D6 genotype on aripiprazole and dehydroaripiprazole exposure in patients using long-acting injectable (LAI) or oral aripiprazole. METHODS: Matched data on serum concentration of aripiprazole and CYP2D6 genotype of patients using oral or LAI aripiprazole were included retrospectively from a therapeutic drug monitoring service. The patients were divided into the following CYP2D6 genotype-defined categories: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs). Linear mixed model analyses were used to evaluate the impact of CYP2D6 genotype on dose-adjusted serum concentrations of the active moiety of aripiprazole+dehydroaripiprazole in relation to age and formulation. RESULTS: We identified 635 patients (mean age = 40.1 years, 9.4% ≥ 65 years, 53.7% females) using LAI (n = 166) or oral formulation (n = 469). The genotype-predicted CYP2D6 phenotype subgroups were 2.4% UMs, 82.0% NMs, 8.0% IMs, and 7.2% PMs. Age did not significantly affect exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (p = 0.071) or oral (p = 0.14) subgroups. Compared with CYP2D6 NMs, PMs and IMs had significantly increased exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (1.7-fold higher, p < 0.001, and 1.5-fold higher, p < 0.001) and oral (1.7-fold higher, p < 0.001, and 1.6-fold higher, p < 0.001) subgroups. CONCLUSIONS: In conclusion, doses should be adjusted according to CYP2D6 genotype when initiating treatment with aripiprazole LAI or tablets, while advanced age do not affect the exposure of the active moiety of aripiprazole treatment regardless of formulation.


Assuntos
Fatores Etários , Aripiprazol/administração & dosagem , Aripiprazol/sangue , Citocromo P-450 CYP2D6/genética , Piperazinas/administração & dosagem , Piperazinas/sangue , Quinolonas/administração & dosagem , Quinolonas/sangue , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais
11.
Biomed Res Int ; 2019: 2612849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781604

RESUMO

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a transient and reversible brain dysfunction, that occurs when the source of sepsis is located outside of the central nervous system; SAE affects nearly 30% of septic patients at admission and is a risk factor for mortality. In our study, we sought to determine whether metabolite changes in plasma could be a potential biomarker for the early diagnosis and/or the prediction of the prognosis of sepsis. METHOD: A total of 31 SAE patients and 28 healthy controls matched by age, gender, and body mass index (BMI) participated in our study. SAE patients were divided into four groups according to the Glasgow Coma Score (GCS). Plasma samples were collected and used to detect metabolism changes by gas chromatography-mass spectrometry (GC-MS). Analysis of variance was used to determine which metabolites significantly differed between the control and SAE groups. RESULTS: We identified a total of 63 metabolites that showed significant differences among the SAE and control groups. In particular, the 4 common metabolites in the four groups were 4-hydroxyphenylacetic acid; carbostyril, 3-ethyl-4,7-dimethoxy (35.8%); malic acid peak 1; and oxalic acid. The concentration of 4-hydroxyphenylacetic acid in sepsis patients decreased with a decrease of the GCS. CONCLUSIONS: According to recent research on SAE, metabolic disturbances in tissue and cells may be the main pathophysiology of this condition. In our study, we found a correlation between the concentration of 4-hydroxyphenylacetic acid and the severity of consciousness disorders. We suggest that 4-hydroxyphenylacetic acid may be a potential biomarker for SAE and useful in predicting patient prognosis.


Assuntos
Biomarcadores/sangue , Metabolômica , Encefalopatia Associada a Sepse/sangue , Sepse/sangue , Idoso , Índice de Massa Corporal , Diagnóstico Precoce , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Escala de Coma de Glasgow , Humanos , Hidroxiquinolinas/sangue , Unidades de Terapia Intensiva , Malatos/sangue , Masculino , Pessoa de Meia-Idade , Ácido Oxálico/sangue , Fenilacetatos/sangue , Prognóstico , Quinolonas/sangue , Sepse/complicações , Sepse/patologia , Encefalopatia Associada a Sepse/complicações , Encefalopatia Associada a Sepse/patologia
12.
J Anal Toxicol ; 43(7): 579-586, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31095699

RESUMO

Quinolone antibiotic residues may pose potential threat to human health. A rapid and sensitive method was developed for the determination of quinolone residues in human serum and urine. After solid phase extraction (SPE) process, eight quinolone residues were analyzed by high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) using ciprofloxacin-d8 as the internal standard. The relative standard deviation of intra-day and inter-day precision for the eight quinolones were less than 7.52% and the accuracies ranged from 95.8% to 103% in human serum, and from 94.1% to 104% in human urine. The extraction recoveries for the eight quinolones varied from 80.2% to 113% in human serum and 83.4% to 117% in human urine. The limit of detection for the eight quinolones was 0.50-1.00 ng/mL. Quinolone antibiotic residues in human serum and urine from 12 volunteers were successfully analyzed with the validated method. The SPE-HPLC-MS/MS method was useful for accurate determination of quinolone antibiotic residues in human body.


Assuntos
Antibacterianos/sangue , Antibacterianos/urina , Resíduos de Drogas/análise , Quinolonas/sangue , Quinolonas/urina , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Análise de Regressão , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
14.
Clin Ther ; 41(3): 505-517.e0, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30819510

RESUMO

PURPOSE: Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone that has been approved for the treatment of community-acquired pneumonia (CAP) in adults. The goals of this study were to evaluate the pharmacokinetic (PK) and population PK parameters of nemonoxacin and to provide the appropriate dose adjustment recommendations for patients with hepatic impairment. METHODS: An open-label, single-dose, parallel group (moderate hepatic impairment group and healthy control group) PK study of nemonoxacin was conducted. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to detect the unchanged nemonoxacin concentration in blood and urine samples. The nonlinear mixed effects modeling tool NONMEN (version 7.3) was used to conduct the population PK analysis. The paired-t test was conducted to compare the PK parameters of the hepatic impairment group and the healthy control group by SPSS (Version 17.0). FINDINGS: Ten subjects for each group were enrolled into the PK study. The PK parameters as well as the plasma concentration-time and logarithmic concentration-time profiles after taking a 500-mg single dose of nemonoxacin showed few differences between the two groups (P > 0.05). The mean areas under the plasma concentration vs. time curve from 0 to 72 h (AUC0-72 h) of the moderate hepatic impairment group and the healthy control group in the nemonoxacin PK study were 58.50 (17.30) mg·h/mL and 49.74 (10.16) mg·h/mL, respectively, giving a mean (SD) AUC0-72 h ratio of 1.15 (0.42) with a 90% CI of 0.91-1.39. A 3- compartment model was considered to be the best model for the data, especially in fitting the plasma point at low drug concentrations. Covariate analysis indicated that weight affected CL/F, V1/F, and V3/F and that eGFR only affected CL/F in the power function model, while gender affected V3/F in the linear model by forward selection and backward deletion. IMPLICATIONS: The population PK parameters of nemonoxacin were evaluated in patients with hepatic impairment. The hepatic function did not have a significant impact on the PK parameters of nemonxacin, but renal function was a meaningful covariate that is consistent with its PK characteristics. In this study, nemonoxacin was well tolerated in the patients with moderate hepatic impairment as well as in the healthy subjects. Based on these data, it is not necessary to consider dose adjustment of nemonoxacin in patients with mild or moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02604498.


Assuntos
Antibacterianos/farmacocinética , Hepatopatias/metabolismo , Modelos Biológicos , Quinolonas/farmacocinética , Adulto , Idoso , Antibacterianos/sangue , Antibacterianos/urina , Área Sob a Curva , Povo Asiático , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Quinolonas/sangue , Quinolonas/urina
15.
Rapid Commun Mass Spectrom ; 33(11): 1024-1035, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30889624

RESUMO

RATIONALE: Brexpiprazole is a novel serotonin-dopamine activity modulator approved by the USFDA in July 2015 for the treatment of schizophrenia and as an adjunctive therapy with other antidepressants for major depressive disorder in adults. However, limited numbers of metabolites are reported in the literature for brexpiprazole. Our prime intent behind this study is to revisit metabolite profiling of brexpiprazole and to identify and characterize all possible in vitro and in vivo metabolites. METHODS: Firstly, the site of metabolism for brexpiprazole was predicted by a Xenosite web predictor model. Secondly, in vitro metabolite profiling was performed by incubating the drug individually with rat liver microsomes, human liver microsomes and rat S9 fraction at 37°C for 1 h in incubator shaker. Finally, for in vivo metabolite identification, a 50 mg kg-1 dose of brexpiprazole was administered to male Sprague-Dawley rats and the presence of various metabolites was confirmed in rat plasma, urine and feces. RESULTS: The predicted atomic site of metabolism was obtained as a color gradient by the Xenosite web predictor tool and, from this study, probable metabolites were listed. In total, 14 phase I and 2 phase II metabolites were identified and characterized in the in vitro and in vivo matrices using ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC/QTOF-MS/MS). The majority of metabolites were found in the sample incubated with human liver microsomes and in rat urine, while in the other matrices only a few metabolites were detected. CONCLUSIONS: All the 16 metabolites were identified and characterized using UHPLC/QTOF-MS/MS. The study revealed that brexpiprazole is metabolized via hydroxylation, glucuronidation, S-oxidation, N-oxidation, dioxidation, oxidative deamination, N-dealkylation, etc.


Assuntos
Antipsicóticos/química , Antipsicóticos/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Tiofenos/química , Tiofenos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Quinolonas/sangue , Quinolonas/urina , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tiofenos/sangue , Tiofenos/urina
17.
Clin Transl Sci ; 12(3): 267-275, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30694595

RESUMO

Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4-fold and ivacaftor 15.6-fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P-gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.


Assuntos
Aminofenóis/farmacocinética , Benzodioxóis/farmacocinética , Indóis/farmacocinética , Quinolonas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Aminofenóis/sangue , Benzodioxóis/sangue , Ciprofloxacina/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Quimioterapia Combinada , Etinilestradiol , Feminino , Humanos , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Quinolonas/sangue , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-30572204

RESUMO

Dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine are antiretroviral drugs used as part of combined antiretroviral treatment for HIV-infection. For quantification of these drugs in human K2EDTA plasma samples an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) bioanalytical method was developed and validated. Stable isotope labeled internal standards were used for each analyte. Simple protein precipitation with methanol was implemented to prepare plasma samples of at least 50 µL. The method was validated for dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine over the ranges 9.7-9700, 52-10,470, 9.7-9730, 73-14,680 and 15-3010 ng/mL, respectively. Within-run and between-run accuracy and precision were within ±15% of the nominal concentration for quality controls at high, medium and low concentrations, and within ±20% at the lower limit of quantification for all analytes. Recovery was ≥76% and reproducible. Long-term stability of patient plasma samples was demonstrated for at least 12 months at -40 °C (4 months for etravirine). Currently, this robust method with a run time of 10 min is used in clinical research and for therapeutic drug monitoring of these frequently used antiretroviral drugs.


Assuntos
Antirretrovirais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 3 Anéis/sangue , Quinolonas/sangue , Antirretrovirais/química , Antirretrovirais/farmacocinética , Estabilidade de Medicamentos , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Limite de Detecção , Modelos Lineares , Oxazinas , Piperazinas , Piridonas , Quinolonas/química , Quinolonas/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
19.
Mol Imaging Biol ; 21(4): 705-712, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30357568

RESUMO

PURPOSE: Lymphokine-activated killer T cell-originated protein kinase (TOPK) is a fairly new cancer biomarker with great potential for clinical applications. The labeling of a TOPK inhibitor with F-18 can be exploited for positron emission tomography (PET) imaging allowing more accurate patient identification, stratification, and disease monitoring. PROCEDURES: [18F]FE-OTS964 was produced starting from OTS964, a preclinical drug which specifically binds to TOPK, and using a two-step procedure with [18F]fluoroethyl p-toluenesulfonate as a prosthetic group. Tumors were generated in NSG mice by subcutaneous injection of U87 glioblastoma cells. Animals were injected with [18F]FE-OTS964 and PET imaging and ex vivo biodistribution analysis was carried out. RESULTS: [18F]FE-OTS964 was successfully synthesized and validated in vivo as a PET imaging agent. The labeling reaction led to 15.1 ± 7.5 % radiochemical yield, 99 % radiochemical purity, and high specific activity. Chemical identity of the radiotracer was confirmed by co-elution on an analytical HPLC with a cold-labeled standard. In vivo PET imaging and biodistribution analysis showed tumor uptake of 3.06 ± 0.30 %ID/cc, which was reduced in animals co-injected with excess blocking dose of OTS541 to 1.40 ± 0.42 %ID/cc. CONCLUSIONS: [18F]FE-OTS964 is the first TOPK inhibitor for imaging purposes and may prove useful in the continued investigation of the pharmacology of TOPK inhibitors and the biology of TOPK in cancer patients.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Tomografia por Emissão de Pósitrons , Quinolonas/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/diagnóstico por imagem , Linhagem Celular Tumoral , Glioblastoma/sangue , Meia-Vida , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinolonas/sangue , Quinolonas/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Bibliotecas de Moléculas Pequenas/farmacologia
20.
Am J Respir Crit Care Med ; 199(3): 342-351, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130412

RESUMO

RATIONALE: Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. OBJECTIVES: To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion. METHODS: Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests. MEASUREMENTS AND MAIN RESULTS: Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on ß-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04). CONCLUSIONS: Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.


Assuntos
Aminofenóis/uso terapêutico , Glicemia/efeitos dos fármacos , Fibrose Cística/sangue , Fibrose Cística/tratamento farmacológico , Incretinas/sangue , Quinolonas/uso terapêutico , Adolescente , Adulto , Aminofenóis/sangue , Peptídeo C/sangue , Peptídeo C/efeitos dos fármacos , Criança , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Masculino , Quinolonas/sangue , Adulto Jovem
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