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1.
Int J Clin Pharmacol Ther ; 57(9): 464-473, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31319908

RESUMO

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This analysis characterized the pharmacokinetics (PK) of tofacitinib in adult patients with active PsA and evaluated the impact of covariates (baseline characteristics) on the disposition of tofacitinib. MATERIALS AND METHODS: Data were pooled from two phase 3 studies of tofacitinib of up to 12 months' duration in patients with active PsA (OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439)). This analysis included 650 tofacitinib-treated patients with 3,252 tofacitinib plasma concentration measurements. Tofacitinib PK was described using a one-compartment disposition model parameterized in terms of apparent oral clearance (CL/F) and apparent volume of distribution (V/F) with first-order absorption rate (Ka) and a lag time. Covariates evaluated were baseline age, baseline body weight, sex, race, ethnicity, baseline creatinine clearance (BCCL), and baseline C-reactive protein. RESULTS: The estimates (95% confidence interval) of PK model parameters of a reference patient were CL/F: 20.4 (18.6, 21.8) L/h; V/F: 110 (108, 113) L; and Ka: 13.8 (12.1, 16.6)/h. Among the covariates, only BCCL led to clinically relevant changes in exposure; however, this was consistent with the known contribution of renal excretion to the total clearance of tofacitinib (~ 30%). CONCLUSION: Tofacitinib did not require dose modification or restrictions for age, body weight, sex, race, ethnicity, or baseline disease severity in patients with active PsA based on the magnitude of exposure relative to a reference patient. Dosing adjustments for renal impairment were derived from a separate phase 1 study.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Piperidinas/farmacocinética , Pirimidinas/farmacocinética , Pirróis/farmacocinética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Biomater Sci ; 7(9): 3801-3811, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237275

RESUMO

Nanotechnology-based systems have been proposed for rectal drug delivery, often rendering promising outcomes concerning disease prophylaxis or therapeutics. However, nanocarriers often feature reduced colorectal retention when administered in liquid vehicles (enemas). Semi-solid platforms may be considered as alternative but usually result in limited local distribution. Thermosensitive enemas undergoing sol-gel transition just below body temperature have been used for abbreviating these issues, but the actual impact on the colorectal distribution and retention of incorporated nanosystems is not clear. We prepared and characterized a potential drug delivery platform by incorporating poly(lactic-co-glycolic acid)-based nanoparticles (170-180 nm mean hydrodynamic diameter) into a poloxamer 407-based thermosensitive enema (NPs-in-thermo). The system featured suitable functional properties for rectal administration such as sol-gel transition temperature of approximately 27-28 °C, sol-gel transition time of 1.6 min, and viscosity around 31 and 2100 mPa s at 20 °C and 37 °C, respectively. NPs-in-thermo presented osmolality and pH values deemed compatible with the colorectal compartment, as well as reduced toxicity to the Caco-2 colorectal cell line. The composite system was also used to incorporate the anti-HIV microbicide model drug dapivirine. In vitro studies showed that dapivirine-loaded NPs-in-thermo was able to provide overall faster drug release as compared to dapivirine directly dispersed into phosphate buffered saline or the thermosensitive enema base. Finally, NPs-in-thermo was tested for distribution and retention in a mouse model by in vivo and ex vivo near infrared imaging. Qualitative and semi-quantitative data indicated that NPs exhibited slower but overall wider distribution and enhanced retention in the distal colon of mice treated intrarectally with NPs-in-thermo, namely when compared to NPs dispersed in liquid phosphate buffered saline. Overall, our data support that thermosensitive enemas may provide suitable platforms for the rectal administration of polymeric NPs, namely in the context of drug delivery.


Assuntos
Colo/metabolismo , Enema/métodos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Reto/metabolismo , Administração Retal , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos , Humanos , Camundongos Endogâmicos ICR , Concentração Osmolar , Tamanho da Partícula , Transição de Fase , Poloxâmero/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Temperatura Ambiente , Distribuição Tecidual
3.
Oncology ; 97(2): 102-111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31230047

RESUMO

BACKGROUND: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. METHODS: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. RESULTS: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). CONCLUSIONS: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética
4.
Eur J Med Chem ; 177: 12-31, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129451

RESUMO

Synthesis of novel and potent hit molecules has an eternal demand. It is our continuous study to search novel bioactive hit molecules and as a part of this, a series of novel N'-isonicotinoyl-2-methyl-4-(pyridin-2-yl)-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3-carbohydrazide analogs (5a-5n) were synthesized with good yields by the conventional method. The various novel compounds have been characterized and identified by many analytical technique such as IR, 1H NMR, 13C NMR, mass spectral analysis, and elemental analysis. All the synthetic analogs (5a-5n) are evaluated for their in vitro antibacterial and anti-mycobacterial activities against different bacterial strains. Molecular docking and Molecular dynamics studies were helped in revealing the mode of action of these compounds through their interactions with the active site of the Mycobacterium tuberculosis enoyl reductase (InhA) enzyme. The calculated ADMET descriptors for the synthesized compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new Anti-mycobacterial agents.


Assuntos
Antituberculosos/farmacologia , Benzotiazóis/farmacologia , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Pirimidinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Coenzima A Ligases/química , Coenzima A Ligases/metabolismo , Isoniazida/metabolismo , Isoniazida/farmacocinética , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética
5.
Drug Des Devel Ther ; 13: 949-964, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962677

RESUMO

Background: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. Subjects and methods: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. Results: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ETB receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure-response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. Conclusion: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.


Assuntos
Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Receptores de Endotelina/metabolismo , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Tolerância a Medicamentos , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Adulto Jovem
6.
Int J Pharm ; 564: 207-213, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30999049

RESUMO

The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginally-administered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES is incorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Quimiocinas CC/administração & dosagem , Dispositivos Anticoncepcionais Femininos , Infecções por HIV/prevenção & controle , Pirimidinas/administração & dosagem , Animais , Fármacos Anti-HIV/farmacocinética , Quimiocinas CC/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Combinação de Medicamentos , Feminino , Pirimidinas/farmacocinética , Ovinos , Vagina/metabolismo
7.
Anticancer Res ; 39(3): 1309-1316, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842163

RESUMO

BACKGROUND/AIM: Pazopanib is approved for advanced soft tissue sarcoma (STS) patients. The aim of the study was to examine the usefulness of (18F)-Fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) imaging for early evaluation of the response of STS patients to pazopanib, as well as the association between pazopanib pharmacokinetics and early metabolic response. PATIENTS AND METHODS: Twenty STS patients underwent FDG-PET scans at baseline, two- and eight-weeks following treatment with pazopanib. The FDG-PET scans were evaluated by quantitative PERCIST analysis and visually by an independent nuclear medicine physician and related to RECIST1.1 outcome at eight weeks. RESULTS: After eight weeks of therapy, 14 out of 20 patients had discontinued pazopanib due to tumor progression identified radiologically ('non-responders' n=12) or toxicity (n=2). Quantitative FDG-PET scoring at two weeks, according to PERCIST guidelines, identified 25% (3 of 12) of the patients radiologically as non-responders versus 42% (5 of 12) identified by visual response analysis. CONCLUSION: In this heterogeneous STS patients' cohort, early FDG-PET/CT identified a substantial part of pazopanib non-responders.


Assuntos
Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Sarcoma , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Adulto , Idoso , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Sarcoma/diagnóstico por imagem , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Sarcoma/patologia , Resultado do Tratamento
8.
Cancer Sci ; 110(5): 1686-1694, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30815927

RESUMO

We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second-generation, enhanced-selectivity Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-cell NHL) and chronic lymphocytic leukemia (CLL). This was an open-label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose-limiting toxicity for 300 mg twice daily. Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1-4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B-cell NHL/CLL.


Assuntos
Imidazóis/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antígenos CD79/genética , Esquema de Medicação , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Japão , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Recidiva Local de Neoplasia/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
9.
Pharmacol Res Perspect ; 7(2): e00470, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30906562

RESUMO

Nilotinib is a broad-based tyrosine kinase inhibitor with the highest affinity to inhibit Abelson (c-Abl) and discoidin domain receptors (DDR1/2). Preclinical evidence indicates that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson's disease (PD). We previously showed that Nilotinib penetrates the blood-brain barrier (BBB) and potentially improves clinical outcomes in individuals with PD and dementia with Lewy bodies (DLB). We performed a physiologically based population pharmacokinetic/pharmacodynamic (popPK/PD) study to determine the effects of Nilotinib in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into five groups (n = 15) and received open-label random single dose (RSD) 150:200:300:400 mg Nilotinib vs placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3, and 4 hours after Nilotinib administration. The results show that Nilotinib enters the brain in a dose-independent manner and 200 mg Nilotinib increases the level of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), suggesting alteration to dopamine metabolism. Nilotinib significantly reduces plasma total alpha-synuclein and appears to reduce CSF oligomeric: total alpha-synuclein ratio. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect. Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha-synuclein.


Assuntos
Encéfalo/metabolismo , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Encéfalo/efeitos dos fármacos , Estudos de Coortes , Dopamina/sangue , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Drogas em Investigação/administração & dosagem , Drogas em Investigação/análise , Drogas em Investigação/farmacocinética , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Homovanílico/metabolismo , Humanos , Glicoproteínas de Membrana/líquido cefalorraquidiano , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Placebos/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/líquido cefalorraquidiano , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/sangue , Pirimidinas/líquido cefalorraquidiano , Pirimidinas/farmacocinética , Receptores Imunológicos , alfa-Sinucleína/sangue , alfa-Sinucleína/metabolismo
11.
Biomed Chromatogr ; 33(7): e4525, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30822365

RESUMO

A rapid, sensitive and selective liquid chromatography-tandem mass spectrometry method for the detection of tandospirone (TDS) and its active metabolite 1-[2-pyrimidyl]-piperazine (1-PP) in Sprague-Dawley rat plasma is described. It was employed in a pharmacokinetic study. These analytes and the internal standards were extracted from plasma using protein precipitation with acetonitrile, then separated on a CAPCELL PAK ADME C18 column using a mobile phase of acetonitrile and 5 mm ammonium formate acidified with formic acid (0.1%, v/v) at a total flow rate of 0.4 mL/min. The detection was performed with a tandem mass spectrometer equipped with an electrospray ionization source. The method was validated to quantify the concentration ranges of 1.000-500.0 ng/mL for TDS and 10.00-500.0 ng/mL for 1-PP. Total time for each chromatograph was 3.0 min. The intra-day precision was between 1.42 and 6.69% and the accuracy ranged from 95.74 to 110.18% for all analytes. Inter-day precision and accuracy ranged from 2.47 to 6.02% and from 98.37 to 105.62%, respectively. The lower limits of quantification were 1.000 ng/mL for TDS and 10.00 ng/mL for 1-PP. This method provided a fast, sensitive and selective analytical tool for quantification of tandospirone and its metabolite 1-PP in plasma necessary for the pharmacokinetic investigation.


Assuntos
Buspirona/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Isoindóis/sangue , Piperazinas/sangue , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Buspirona/sangue , Buspirona/química , Buspirona/farmacocinética , Estabilidade de Medicamentos , Feminino , Isoindóis/química , Isoindóis/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Piperazinas/química , Piperazinas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
12.
Pharm Res ; 36(4): 56, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30796596

RESUMO

PURPOSE: Lipid suspensions have been shown to be a suitable bio-enabling formulation approach for highly lipophilic or 'grease ball' drug molecules, but studies on 'brick dust' drugs are lacking. This study explored the utility of lipid suspensions for enhancing oral bioavailability of the rather hydrophobic drug nilotinib in vivo in rats. METHODS: Four lipid suspensions were developed containing long chain triglycerides, medium chain triglyceride, long chain monoglycerides and medium chain monoglycerides and in vivo bioavailability was compared to an aqueous suspension. Additionally, in vitro lipolysis and wettability tests were conducted. RESULTS: Nilotinib lipid suspensions did not show a bioavailability increase compared to an aqueous suspension. The bioavailability was lower for triglyceride suspensions, relative to both monoglyceride and an aqueous suspension. The long chain monoglyceride displayed a significantly higher bioavailability relative to triglycerides. In vitro lipolysis results suggested entrapment of nilotinib crystals within poorly dispersible triglycerides, leading to slower nilotinib release and absorption. This was further supported by higher wettability of nilotinib by lipids. CONCLUSION: Monoglycerides improved oral bioavailability of nilotinib in rats, relative to triglycerides. For 'brick dust' drugs formulated as lipid suspensions, poorly dispersible formulations may delay the release of drug crystals from the formulation leading to reduced absorption. Graphical Abstract An aqueous and four lipid suspensions have been evaluated in in vitro and in vivo to gain insights into the potential benefits and limitations of lipid suspensions.


Assuntos
Antineoplásicos/farmacocinética , Excipientes/química , Monoglicerídeos/química , Proteínas Tirosina Quinases/farmacocinética , Pirimidinas/farmacocinética , Triglicerídeos/química , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Disponibilidade Biológica , Química Farmacêutica/métodos , Composição de Medicamentos , Absorção Gastrointestinal , Interações Hidrofóbicas e Hidrofílicas , Lipólise , Masculino , Soluções Farmacêuticas , Proteínas Tirosina Quinases/administração & dosagem , Proteínas Tirosina Quinases/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos Sprague-Dawley , Suspensões , Molhabilidade
13.
Biomed Chromatogr ; 33(5): e4502, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30725476

RESUMO

Macitentan is an endothelin receptor antagonist commonly used in the treatment of pulmonary arterial hypertension (PAH). A novel, rapid, simple and sensitive UPLC-MS/MS method was developed and validated for pharmacokinetic study and the determination of macitentan in PAH patients. Macitentan and bosentan, which are used as internal standards, were detected using atmospheric pressure chemical ionization in positive ion and multiple reaction monitoring mode by monitoring the mass transitions m/z 589.1 → 203.3 and 552.6 → 311.5, respectively. Chromatographic separation was performed on a reverse-phase C18 column (5 µm, 4.6 × 150 mm) with an isocratic mobile phase, which consisted of water containing 0.2% acetic acid-acetonitrile (90:10, v/v) at a flow rate of 1 mL/min. Retention times were 1.97 and 1.72 min for macitentan and IS, respectively. The calibration curve with high correlation coefficient (0.9996) was linear in the range 1-500 ng/mL. The lower limit of quantitation and average recovery values were determined as 1 ng/mL and 89.8%, respectively. This method is the first UPLC-MS/MS method developed and validated for the determination of macitentan from human plasma. The developed analytical method was fully validated for linearity, selectivity, specificity, accuracy, precision, sensitivity, stability, matrix effect and recovery according to US Food and Drug Administration guidelines. The developed method was applied successfully for pharmacokinetic study and the determination of macitentan in PAH patients.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/sangue , Sulfonamidas/sangue , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico
14.
Biomed Chromatogr ; 33(5): e4507, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30754071

RESUMO

The aim of this study was to investigate the effect of naringenin on the pharmacokinetics of ibrutinib in rats. A simple and sensitive quantitation method based on ultra-high-performance liquid chromatography-Q-Exactive Orbitrap tandem mass spectrometry was developed and validated for the determination of ibrutinib in rat plasma. The samples were extracted using ethyl acetate containing 1% triethylamine and separated on a Waters Acquity UPLC BEH C18 column with acetonitrile and water containing 0.1% formic acid as mobile phase. The assay showed good linearity over the concentration range of 1-1000 ng/mL with coefficient of correlation >0.995. The LLOQ was 1 ng/mL. The assay showed acceptable precision (RSD < 8.65%), accuracy (RE within ±15%), extraction recovery (>78.25%) and negligible matrix effects. The validated method has been successfully applied to the pharmacokinetic study of ibrutinib in rats after oral administration of ibrutinib with or without coadministration of naringenin. Our results demonstrated that naringenin could significantly affect the pharmacokinetics of ibrutinib, including prolonging its half-life, increase the area under the concentration-time curve and reducing its clearance time. This study indicated that there is potential for drug-drug interactions between naringenin and ibrutinib, and coadministration of ibrutinib with naringenin or naringenin-containing herbal medicines should be avoided in the clinic.


Assuntos
Flavanonas/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão/métodos , Interações de Medicamentos , Estabilidade de Medicamentos , Flavanonas/sangue , Flavanonas/química , Limite de Detecção , Modelos Lineares , Masculino , Pirazóis/sangue , Pirazóis/química , Pirimidinas/sangue , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
15.
J Pharm Biomed Anal ; 168: 163-173, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30807921

RESUMO

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is critically involved in cell migration, spreading and proliferation at the early step of various cancers. Small molecule inhibitors of FAK are effective to inhibit its activation in the process of tumor formation in cell. To better understand biotransformation of FAK inhibitors, this work has investigated in vitro phase I metabolism of inhibitors (namely PF-573228, PF-562271 and PF-03814735) by rat liver microsomes model. Using liquid chromatography - quadrupole time of flight mass spectrometry and tandem mass spectrometry (LC/Q-TOF/MS and MS/MS), three metabolites of PF-573228 and PF-562271 were observed and characterized, respectively. These in vitro metabolites were reported for the first time. The structures and fragmentation patterns of these metabolites were elucidated, and phase I metabolic pathways for FAK inhibitors were proposed. The main metabolic pathways of PF-573228 were hydroxylation, dehydrogenation and N-dealkylation. For PF-562271, they were hydroxylation and dehydrogenation. Hydroxylation was observed as the primary metabolism for PF-0381473.


Assuntos
Cromatografia Líquida/métodos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Remoção de Radical Alquila , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Hidroxilação , Indóis/farmacocinética , Microssomos Hepáticos/metabolismo , Pirimidinas/farmacocinética , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacocinética , Sulfonas/farmacocinética
16.
Eur J Clin Pharmacol ; 75(6): 825-829, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30729257

RESUMO

PURPOSE: To obtain insight into the feasibility of, and the patients' perspective on, dried blood spot (DBS) self-sampling by patients with chronic myeloid leukemia (CML) using nilotinib. METHODS: Sixty-eight patients with CML using nilotinib participated in this multicenter observational study. Patients were asked to perform blood sampling by means of the DBS method at home just before drug intake (trough level) and to complete a questionnaire including demographics and five questions on their experience with DBS self-sampling. RESULTS: Sixty-one patients (57.5 ± 15.0 years, 49% female) provided 178 DBS samples of which 137 (77%) proved useful in clinical practice. Twenty percent of the samples were rejected because the spot size was too small for analysis. A further 3% were taken at the wrong time. Unsuitable DBS samples were provided by 23 patients. Their educational level was significantly lower than that of patients whose samples were all suitable (p = 0.041). Patients considered DBS self-sampling easy and not painful, and three quarters of the patients performed DBS sampling without additional assistance. Patients' belief in the reliability of DBS self-sampling was moderate to high. It was preferred over venous sampling by 37% of the patients, whereas 39% had no preference. CONCLUSION: DBS self-sampling by CML patients is feasible in clinical practice provided that patients, particularly those with a lower educational level, are adequately instructed about sample collection with emphasis on timing and volume of sample collection.


Assuntos
Antineoplásicos/sangue , Atitude Frente a Saúde , Teste em Amostras de Sangue Seco , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Participação do Paciente , Pirimidinas/sangue , Adulto , Idoso , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Autoadministração
17.
J Pharm Biomed Anal ; 166: 66-70, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30612075

RESUMO

Dacomitinib is a highly selective irreversible small-molecule inhibitor of the human epidermal growth factor receptor (HER) family of tyrosine kinases. A simple and quick bioanalytical method was completely developed and validated for the assay and pharmacokinetic investigation of dacomitinib in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Proteins in 0.1 mL plasma samples were prepared by precipitant acetonitrile containing ibrutinib as the internal standard (IS). Separation of the analyte from plasma samples was carried out on an Acquity UPLC BEH C18 column using acetonitrile and 0.1% formic acid in water as mobile phase for gradient elution. The total run time and the elution time of dacomitinib were 3.0 min and 1.07 min, respectively. Positive-ion electrospray ionization (ESI) and multiple reaction monitoring (MRM) on a triple quadrupole tandem mass spectrometer were used for detection at the transitions of m/z 470.1 → 124.1 for dacomitinib and m/z 441.2 → 84.3 for ibrutinib (IS), respectively. In the range of 1-150 ng/mL, the calibration curve of dacomitinib was linear with a lower limit of quantitation (LLOQ) of 1 ng/mL. Mean recovery of dacomitinib in plasma was in the range of 76.9-84.1%. The inter- and intra-day precision (RSD) was in the scope of 1.7-8.7% and the accuracy (RE) ranged from -6.1 to 8.5%. Stability studies under different conditions were indicated to be stable. A pharmacokinetic study after oral administration of 40 mg/kg dacomitinib in rats illustrated the applicability of the new presented determination of dacomitinib.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Quinazolinonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Confiabilidade dos Dados , Limite de Detecção , Masculino , Pirazóis/sangue , Pirazóis/farmacocinética , Pirimidinas/sangue , Pirimidinas/farmacocinética , Quinazolinonas/sangue , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray
18.
Biomed Chromatogr ; 33(4): e4460, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30536684

RESUMO

A sensitive, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of copanlisib in mouse plasma using enasidenib as an internal standard (IS) as per regulatory guideline. Copanlisib and the IS were extracted from mouse plasma using ethyl acetate as an extraction solvent and chromatographed using an isocratic mobile phase (0.2% formic acid-acetonitrile; 25:75, v/v) on a HyPURITY C18 column. Copanlisib and the IS eluted at ~0.95 and 2.00 min, respectively. The MS/MS ion transitions monitored were m/z 481.1 → 360.1 and m/z 474.0 → 456.0 for copanlisib and the IS, respectively. The calibration range was 3.59-3588 ng/mL. The intra- and inter-batch accuracy and precision (RE and RSD) across quality controls met the acceptance criteria. Stability studies showed that copanlisib was stable in mouse plasma for one month. This novel method has been applied to a pharmacokinetic study in mice.


Assuntos
Cromatografia Líquida/métodos , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Pirimidinas/sangue , Pirimidinas/farmacocinética , Quinazolinas/sangue , Quinazolinas/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/química , Quinazolinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
19.
Int J Clin Pharmacol Ther ; 57(2): 117-124, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30574864

RESUMO

BACKGROUND: Metformin and dipeptidyl peptidase-4 (DPP-IV) inhibitors are commonly combined to treat patients with diabetes mellitus (DM). A new fixed-dose combination (FDC) drug containing gemigliptin, a DPP-IV inhibitor, and sustained-release metformin has been developed. This study aimed to compare the PKs and tolerability of FDC versus loose combination of gemigliptin 50 mg and metformin 500 mg. MATERIALS AND METHODS: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was conducted in 28 healthy subjects, who received a single oral dose of an FDC tablet of gemigliptin (50 mg) and sustained-release metformin (500 mg) or were coadministered gemigliptin (50 mg) and extended-release metformin (500 mg) with a 1-week washout. Serial blood samples were collected up to 48 hours after study drug administration, and the plasma concentrations of gemigliptin, LC15-0636 (active metabolite of gemigliptin), and metformin were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using a noncompartmental method. Safety and tolerability were evaluated based on vital signs, adverse events, clinical laboratory tests, and electrocardiography. RESULTS: The concentration-time profiles of gemigliptin and metformin were similar when they were administered as FDC or were coadministered. The geometric mean ratio (GMR) and its 90% CIs of Cmax for gemigliptin, LC15-0636, and metformin were 0.93 (0.85 - 1.02), 1.00 (0.94 - 1.06), and 1.03 (0.98 - 1.09), respectively. The corresponding values of AUClast were 0.97 (0.93 - 1.01), 1.00 (0.97 - 1.04), and 1.00 (0.95 - 1.05), respectively. There were no clinically meaningful differences in safety and tolerability. CONCLUSION: When comparing the AUClast and Cmax of gemigliptin, LC15-0636, and metformin, the 90% CIs were all within the range of 0.8 - 1.25, which is the commonly accepted range for evaluating bioequivalence.


Assuntos
Metformina/farmacocinética , Piperidonas/farmacocinética , Pirimidinas/farmacocinética , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Combinação de Medicamentos , Quimioterapia Combinada , Voluntários Saudáveis , Humanos , Metformina/administração & dosagem , Piperidonas/administração & dosagem , Pirimidinas/administração & dosagem , Espectrometria de Massas em Tandem
20.
Med Chem ; 15(6): 602-623, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30569866

RESUMO

BACKGROUND: Aberrant expression of eukaryotic translation initiation factor 4E (eIF4E) is common in many types of cancer including acute myeloid leukaemia (AML). Phosphorylation of eIF4E by MAPK-interacting kinases (Mnks) is essential for the eIF4E-mediated oncogenic activity. As such, the pharmacological inhibition of Mnks can be an effective strategy for the treatment of cancer. METHODS: A series of N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine derivatives was designed and synthesised. The Mnk inhibitory activity of these derivatives as well as their anti-proliferative activity against MV4-11 AML cells was determined. RESULTS: These compounds were identified as potent Mnk2 inhibitors. Most of them demonstrated potent anti-proliferative activity against MV4-11 AML cells. The cellular mechanistic studies of the representative inhibitors revealed that they reduced the level of phosphorylated eIF4E and induced apoptosis by down-regulating the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and by cleaving poly(ADP-ribose)polymerase (PARP). The lead compound 7k possessed desirable pharmacokinetic properties and oral bioavailability. CONCLUSION: This work proposes that exploration of the structural diversity in the context of Nphenyl- 4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.


Assuntos
Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Desenho de Drogas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirróis/síntese química , Pirróis/metabolismo , Pirróis/farmacocinética , Relação Estrutura-Atividade
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