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1.
J Am Chem Soc ; 142(2): 867-873, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31833768

RESUMO

Platinum(II) complexes bearing terpyridyl (tpy) and thiolate ligands were used to test the design of a "dual layer" self-sorting system in the presence of Cucurbit[8]uril (CB[8]). Pt(II) thiolates and CB[8] form 2:1 assemblies, with both metallic centers sitting on top of one another at one of the macrocycle portals. We showed that any pair of these CB[8]-secured Pt(II) complex dimers bearing different tpy "heads" and thiolate "tails" scrambles to afford up to 10 ternary assemblies via two processes: (1) supramolecular exchanges (i.e., the egression and ingression of Pt complexes from and into CB[8]) and (2) ligand exchanges between the Pt thiolates. The mixtures of 10 assemblies were fully characterized by nuclear magnetic resonance spectroscopy. While the thiolate tails do not significantly affect the rate of the supramolecular exchanges, they were found to control (1) the kinetics of ligand exchange, with bulkier thiolates causing dramatic rate retardations, as well as (2) the thermodynamics of the self-sorting process, i.e., the distribution of assemblies at equilibrium, via intra-CB[8] assembly interactions between pairs of thiolates. Ligand exchanges are consistently slower than supramolecular exchanges. An associative pathway that involves the formation of dimers of CB[8]-secured Pt dimers (a total of 4 Pt complexes) during the ligand exchange process was invoked to rationalize the observed kinetics.

2.
Clin Transl Sci ; 13(1): 41-46, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31498564

RESUMO

A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer and disease progression post-EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3-32. At baseline, both patients had abnormal liver function tests (LFTs; Child-Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10-fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax )) and LFTs, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.

3.
Chem Commun (Camb) ; 55(81): 12160-12163, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31552935

RESUMO

The trans- and cis conformations of 5,5'-substituted 2,2'-dithiophenes can be stabilized when those are secured with two Cucurbit[8]uril macrocycles (CB[8]) on top of rigid 2,6- and 2,7-substituted naphthalenes, which respectively mimic the trans and cis conformations of the dithiophene. The substituents are Pt(ii) terpyridyl groups bearing CB[8]-binding sites at their 4'-position, as those form dimers in the presence of the macrocycle through Pt-Pt and dispersive interactions between the terpyridyl ligands.

4.
Biomed Chromatogr ; 33(11): e4665, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31339581

RESUMO

This study aimed to investigate the effect of the maturation process of sweet marjoram (Origanum majorana L.) on essential oil composition, the phenolic profile of ethanolic extract and their antioxidant capacities. The essential oil composition was studied at three stages of maturity by GC-MS. Thirty compounds were detected representing 100% of the total essential oil. p-Menth-1-en-4-ol was the major compound (37.15-76.94%) followed by cyclohexanol-3,3,5 trimethyl (5.41-15.99%) and α-terpineol (0.94-11.34%). During the maturation process, an accumulation of oxygenated monoterpenes was observed. The phenolic composition was studied using matrix-assisted laser desorption/ionization time of flight. The analysis showed the presence of short flavonoid monomers at all stages of maturation. The antioxidant capacity of ethanolic extracts and essential oils was evaluated using the DPPH assay, iron chelating power and reducing power assay. The highest phenolic content and antioxidant capacity were found at flowering stage. These findings on essential oil composition, phenolic profile and antioxidant capacity of O. majorana at three different stages of development provide more information on how these secondary metabolites are accumulated.


Assuntos
Antioxidantes/análise , Óleos Voláteis/química , Origanum , Fenóis/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Origanum/química , Origanum/crescimento & desenvolvimento , Origanum/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
5.
J Clin Pharmacol ; 59(4): 463-471, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30536979

RESUMO

Evaluation of the effect of food on the pharmacokinetics of oral oncology drugs is critical to drug development, as food can mitigate or exacerbate toxicities and alter systemic exposure. Our aim is to expand on current US Food and Drug Administration (FDA) guidance and provide data-driven food-effect study design recommendations specific to the oncology therapeutic area. Data for recently approved small-molecule oncology drugs was extracted from the clinical pharmacology review in the sponsor's FDA submission package. Information on subject selection, meal types, timing of the study relative to the pivotal trial, and study outcomes was analyzed. The number of subjects enrolled ranged from 12 to 60, and the majority of studies (19 of 29) were conducted in healthy volunteers. Using AstraZeneca cost data, healthy volunteer studies were estimated to cost 10-fold less than cancer patient studies. Nine of 29 (31%) studies included meals with multiple levels of fat content. Analysis of a subset of 16 drugs revealed that final results for the food-effect study were available before the start of the pivotal trial for only 2 drugs. Conducting small food-effect studies powered to estimate effect, rather than confirm no effect, with only a standardized high-fat meal according to FDA guidance may eliminate unnecessary studies, reduce cost, and improve efficiency in oncology drug development. Starting food-effect studies as early as possible is key to inform dosing in pivotal trials.

6.
J Cancer Res Clin Oncol ; 144(11): 2245-2261, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30132118

RESUMO

PURPOSE: Classical clinical endpoints [e.g., objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)] may not be appropriate for immune checkpoint blockers (ICBs). We evaluated correlations between these endpoints and overall survival (OS) for surrogacy. METHODS: Randomized controlled trials (RCTs) of solid tumors patients treated with ICBs published between 01/2005 and 03/2017, and congress proceedings (2014-2016) were included. Arm-level analyses measured 6-month PFS rate to predict 18-month OS rate. Comparison-level analyses measured ORR odds ratio (OR), DCR OR, and 6-month PFS hazard ratio (HR) to predict OS HR. A pooled analysis for single-agent ICBs and ICBs plus chemotherapy vs chemotherapy was conducted. Studies of single-agent ICBs vs chemotherapy were separately analyzed. RESULTS: 27 RCTs involving 61 treatment arms and 10,300 patients were included. Arm-level analysis showed higher 6- or 9-month PFS rates predicted better 18-month OS rates for ICB arms and/or chemotherapy arms. ICB arms had a higher average OS rate vs chemotherapy for all PFS rates. Comparison-level analysis showed a nonsignificant/weak correlation between ORR OR (adjusted R2 = - 0.069; P = 0.866) or DCR OR (adjusted R2 = 0.271; P = 0.107) and OS HR. PFS HR correlated weakly with OS HR in the pooled (adjusted R2 = 0.366; P = 0.005) and single-agent (adjusted R2 = 0.452; P = 0.005) ICB studies. Six-month PFS HR was highly predictive of OS HR for single-agent ICBs (adjusted R2 = 0.907; P < 0.001), but weakly predictive in the pooled analysis (adjusted R2 = 0.333; P = 0.023). CONCLUSIONS: PFS was an imperfect surrogate for OS. Predictive value of 6-month PFS HR for OS HR in the single-agent ICB analysis requires further exploration.


Assuntos
Antineoplásicos/uso terapêutico , Determinação de Ponto Final/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida
7.
Chemistry ; 24(34): 8670-8678, 2018 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-29601113

RESUMO

To maximize Coulombic interactions, cucurbit[8]uril (CB[8]) typically forms ternary complexes that distribute the positive charges of the pair of guests (if any) over both carbonylated portals of the macrocycle. We present here the first exception to this recognition pattern. Platinum(II) acetylides flanked by 4'-substituted terpyridyl ligands (tpy) form 2:1 complexes with CB[8] in an exclusively stacked head-to-head orientation in a water/acetonitrile mixture. The host encapsulates the pair of tpy substituents, and both positive Pt centers sit on top of each other at the same CB[8] rim, leaving the other rim free of any interaction with the guests. This dramatic charge imbalance between the CB[8] rims would be electrostatically penalizing, were it not for allosteric π-π interactions between the stacked tpy ligands, and possible metal-metal interactions between both Pt centers. When both tpy and acetylides are substituted with aryl units, the metal-ligand complexes form 2:2 assemblies with CB[8] in aqueous medium, and the directionality of the assembly (head-to-head or head-to-tail) can be controlled, both kinetically and thermodynamically.

8.
J Am Chem Soc ; 140(9): 3371-3377, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29444409

RESUMO

The self-assembly into dynamic oligomers of Cucurbit[8]uril (CB[8]), a positive ditopic Ir(III) bis-terpyridine complex, and a negative ditopic Fe(II) bis-terpyridine complex flanked by four butyrate side chains was assessed to answer a seemingly straightforward question: does CB[8] adopt a social self-sorting pattern by encapsulating both positive and negative units into a heteroternary complex? We showed that this is indeed the case, with CB[8] linking a positive Ir unit to a neighboring negative Fe unit whenever possible. Furthermore, the solubility of the dynamic oligomers was significantly affected by their sequence; upon addition of 0.6-1.2 equiv of positive Ir oligomer to its negative Fe counterpart, the predominant assembly present in solution was a mixed oligomer with a (Fe-Ir-Ir-) n sequence. Weak interactions between the negative butyrate side chains and the partially positive outer wall of CB[7] were also identified by two-dimensional nuclear magnetic resonance techniques, and resulted in a negative p Ka shift (0.10 p Ka unit) for the terminal carboxylic groups.

9.
Clin Pharmacol Ther ; 103(2): 271-280, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29063606

RESUMO

Certain oncology compounds exhibit fundamental pharmacokinetic (PK) disparities between healthy and malignant conditions. Given the effects of tumor-associated inflammation on enzyme and transporter expression, we performed a meta-analysis of CYP- and transporter-sensitive substrate clinical PK to quantitatively compare enzyme and transporter abundances between healthy volunteers (HV) and cancer patients (CP). Hepatic and intestinal CYP1A2, CYP2C19, and CYP3A4 abundance were subsequently adjusted via Simcyp's sensitivity analysis tool. Of the 11 substrates we investigated, seven displayed marked exposure differences >1.25-fold between CP and HV. Although CP studies are limited, meta-analysis-based reduction in CYP1A2, CYP2C19, and CYP3A4 enzyme abundances in a virtual oncology population effectively captures CP-PK for caffeine, theophylline, midazolam, simvastatin, omeprazole, and a subset of oncology compounds. These changes allow extrapolation from HV to CP, enhancing predictive capability; therefore, conducting simulations in this CYP-modified oncology (MOD-CP) population provides a more relevant characterization of CP-PK.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Modelos Biológicos , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Transporte Biológico , Biotransformação , Sistema Enzimático do Citocromo P-450/metabolismo , Mineração de Dados , Bases de Dados Factuais , Medicina Baseada em Evidências/métodos , Humanos , Intestinos/enzimologia , Fígado/enzimologia , Proteínas de Membrana Transportadoras/metabolismo , Neoplasias/enzimologia , Neoplasias/patologia , Segurança do Paciente , Medição de Risco , Pesquisa Médica Translacional/métodos , Resultado do Tratamento
10.
Chemistry ; 24(9): 2144-2150, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29131927

RESUMO

Gold-catalyzed alkyne hydration was studied by using in situ reacting mass spectrometry (MS) technology. By monitoring the reaction process in solution under different conditions (regular and very diluted catalyst concentrations, different pH values) and examining the reaction occurrence in the early reaction stage (1-2 ms after mixing) with MS, we collected a series of experimental evidence to support that the bis-gold complex is a potential key reaction intermediate. Furthermore, both experimental and computational studies confirmed that the σ,π-bis-gold complexes are not active intermediates toward nucleophilic addition. Instead, formation of geminally diaurated complex C is crucial for this catalytic process.

11.
Environ Sci Pollut Res Int ; 25(2): 1497-1507, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29090449

RESUMO

The main purpose of this study was to understand the effect of time and temperature during the hydrothermal carbonisation (HTC) of olive stones (OS). For that purpose, the severity factor was introduced, by which the effect of the HTC conditions on the resultant products could be described. HTC was carried out at various temperatures (160, 180, 200, 220 and 240 °C) and times (3, 6, 12, 24 and 48 h) for producing 25 hydrochars. The yield to hydrochar varied from 70 to 50%. Hydrochars were all submitted to thermogravimetric and elemental analysis. The liquid fractions were also recovered and analysed in order to valorise OS as completely as possible. Thus, highly added-value products such as furfural and 5-hydroxymethylfurfural were detected. At the highest temperature and time, the hydrochar elemental composition was similar to that of lignite coals. Hydrochars were further carbonised at 900 °C, leading to materials with surface areas as high as 1200 m2 g-1 and with narrow pore size distributions centred on 0.5 nm. The severity factor allowed finding clear tendencies in the production of hydrochars and derived carbons in terms of yield, composition, and surface area, which would have been hardly analysed if the effects of temperature and time had to be considered separately. We proved that the severity factor, which use is quite uncommon in studies dealing with materials production, is a valuable tool for studying the effects of HTC experimental conditions.


Assuntos
Carbono/química , Carvão Vegetal/química , Conservação dos Recursos Naturais/métodos , Olea , Carvão Mineral/análise , Furaldeído/análogos & derivados , Temperatura , Termogravimetria , Fatores de Tempo
12.
J Clin Pharmacol ; 58(4): 485-493, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29193123

RESUMO

Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is used for the treatment of non-small-cell lung cancer (NSCLC) with activating EGFR mutations. Gefitinib is metabolized by CYP2D6 and CYP3A4. This analysis compared the systemic exposure of gefitinib after oral administration in CYP2D6 ultrarapid metabolizers (UM) vs extensive metabolizers (EM). Physiologically based pharmacokinetic (PBPK) modeling was conducted using a population-based simulator. The model was calibrated using itraconazole-gefitinib clinical drug-drug interaction data and validated with gefitinib data in CYP2D6 EM vs poor metabolizers (PM). System components of the PBPK model were evaluated using published clinical metoprolol pharmacokinetic data in CYP2D6 UM, EM, and PM. Our PBPK model predicted a gefitinib geometric least-squares mean area under the plasma concentration-time curve (AUC) from time 0 to 264 hours (AUC(0-264) ) ratio in the presence vs absence of itraconazole of 1.85, similar to the ratio of 1.78 from clinical study data. Predicted and observed metoprolol geometric least-squares mean AUC(0-24) ratios in UM vs EM were also similar (0.46 and 0.55, respectively), suggesting that system components related to CYP2D6 in the PBPK model were properly established. In addition, the PBPK model also captured gefitinib pharmacokinetic profiles in CYP2D6 polymorphic populations. The final PBPK model predicted a decrease in gefitinib AUC of ∼39% in CYP2D6 UM vs EM. Such changes in exposure will have limited impact as the reduced exposure is still above gefitinib's in vitro IC90 for EGFR activating mutations in NSCLC patients.


Assuntos
Antineoplásicos/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Gefitinibe/farmacocinética , Modelos Biológicos , Inibidores de Proteínas Quinases/farmacocinética , Adolescente , Adulto , Idoso , Antineoplásicos/sangue , Estudos Cross-Over , Citocromo P-450 CYP2D6/genética , Interações Medicamentosas , Feminino , Gefitinibe/sangue , Genótipo , Humanos , Itraconazol/farmacologia , Masculino , Metoprolol/farmacologia , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/sangue , Adulto Jovem
13.
Br J Clin Pharmacol ; 84(4): 726-737, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29274100

RESUMO

AIMS: A multistudy analysis of cediranib, a potent, selective inhibitor of all three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), was conducted to establish population exposure-safety models for the relationship of cediranib exposure to the safety endpoints, diastolic and systolic blood pressure (DBP and SBP) and diarrhoea in cancer patients. These models were applied to predict safety outcomes for different cediranib dose regimens. METHODS: Models for hypertension and diarrhoea were constructed based on data from 10 Phase I and three Phase II studies comprising 631 cancer patients following cediranib once-daily oral dosing. Daily DBP and SBP were simultaneously characterized using indirect response models for predicted cediranib concentration-time courses, while daily diarrhoea events were modelled as ordered categorical variables with a proportional odds model with a Markov element for predicted average cediranib concentrations. RESULTS: For 20 mg cediranib once-daily oral administration, the mean increase in DBP and SBP was predicted to be 7 (95% CI 3-13) and 8 mmHg (95% CI 3-16), respectively, while the probability of mild diarrhoea, but not the severity, was predicted to increase over time. Severe diarrhoea was predicted to be resolved rapidly upon discontinuation of cediranib treatment. CONCLUSIONS: Maximum blood pressure increase was observed within the first few days of cediranib treatment, consistent with the pharmacokinetic profile of cediranib reaching steady state in about 5 days. The probability of diarrhoea increased with cediranib concentration but was far more dependent on the status of diarrhoea predicted on the previous day.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase III como Assunto , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Feminino , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Probabilidade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Fatores de Tempo , Adulto Jovem
14.
Angew Chem Int Ed Engl ; 56(49): 15688-15692, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-29048713

RESUMO

The ability to mimic the activity of natural enzymes using supramolecular constructs (artificial enzymes) is a vibrant scientific research field. Herein, we demonstrate that cucurbit[7]uril (CB[7]) can catalyse Diels-Alder reactions for a number of substituted and unreactive N-allyl-2-furfurylamines under biomimetic conditions, without the need for protecting groups, yielding powerful synthons in previously unreported mild conditions. CB[7] rearranges the substrate in a highly reactive conformation and shields it from the aqueous environment, thereby mimicking the mode of action of a natural Diels-Alderase. These findings can be directly applied to the phenomenon of product inhibition observed in natural Diels-Alderase enzymes, and pave the way toward the development of novel, supramolecular-based green catalysts.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Catálise , Reação de Cicloadição , Substâncias Macromoleculares/química , Estrutura Molecular , Termodinâmica
15.
Org Lett ; 19(16): 4303-4306, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28795816

RESUMO

The affinities of 20 hydrocarbons for the cavity formed by the inner wall of cucurbit[8]uril and a tolyl unit linked to an auxiliary guest were measured in aqueous solution. Cucurbit[8]uril and the auxiliary guest, a substituted ruthenium tris(2,2'-bipyridyl) complex bearing a trifluoromethyl 19F NMR probe, displayed perfect selectivity toward cyclic hydrocarbons, and cis- and trans-decalin, in particular. Unlike π-π interactions, CH-π interactions, as well as differences in hydrocarbon solvation, contribute significantly to the recognition process.

16.
Eur J Pharm Sci ; 109S: S39-S46, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28506868

RESUMO

Modeling & simulation (M&S) methodologies are established quantitative tools, which have proven to be useful in supporting the research, development (R&D), regulatory approval, and marketing of novel therapeutics. Applications of M&S help design efficient studies and interpret their results in context of all available data and knowledge to enable effective decision-making during the R&D process. In this mini-review, we focus on two sets of modeling approaches: population-based models, which are well-established within the pharmaceutical industry today, and fall under the discipline of clinical pharmacometrics (PMX); and systems dynamics models, which encompass a range of models of (patho-)physiology amenable to pharmacological intervention, of signaling pathways in biology, and of substance distribution in the body (today known as physiologically-based pharmacokinetic models) - which today may be collectively referred to as quantitative systems pharmacology models (QSP). We next describe the convergence - or rather selected integration - of PMX and QSP approaches into 'middle-out' drug-disease models, which retain selected mechanistic aspects, while remaining parsimonious, fit-for-purpose, and able to address variability and the testing of covariates. We further propose development opportunities for drug-disease systems models, to increase their utility and applicability throughout the preclinical and clinical spectrum of pharmaceutical R&D.


Assuntos
Indústria Farmacêutica/estatística & dados numéricos , Liberação Controlada de Fármacos/fisiologia , Animais , Desenho de Fármacos , Descoberta de Drogas/estatística & dados numéricos , Humanos , Modelos Biológicos , Pesquisa/estatística & dados numéricos
17.
Biopharm Drug Dispos ; 38(6): 389-393, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28255999

RESUMO

Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CLint of 9 µl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69 l/h, which was comparable to those observed (55 to 88 l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary.


Assuntos
Benzamidas/farmacocinética , Compostos de Benzil/farmacocinética , Modelos Biológicos , Oxigenases/genética , Oxigenases/metabolismo , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Benzamidas/sangue , Compostos de Benzil/sangue , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
18.
Clin Pharmacol Drug Dev ; 6(5): 517-523, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28176470

RESUMO

This open-label, randomized, phase 1 crossover study investigated the effect of elevated gastric pH level (>5) on the relative bioavailability and pharmacokinetic profile of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Healthy male volunteers (n = 26) were randomized to gefitinib 250 mg (fasted), either alone on day 1 (unmodified gastric pH) or 1 hour following the second of 2 oral doses of the H2 -receptor antagonist ranitidine 450 mg (elevated gastric pH). After a 3-week washout period, volunteers crossed to the other treatment. The geometric least-squares (GLS) mean AUC0-∞ and Cmax for gefitinib were reduced by 47% and 71%, respectively, under conditions of sustained elevated gastric pH; for both parameters, the 90%CI for the ratio of the GLS means lay below the prespecified lower limit. Median tmax was delayed from 5 to 6 hours. Mean t1/2 was similar under both gastric pH conditions. No serious adverse events were reported. The bioavailability of a single oral gefitinib 250-mg dose was reduced by approximately 50% when gefitinib was administered under conditions of sustained elevated gastric pH.


Assuntos
Antagonistas dos Receptores Histamínicos H2/administração & dosagem , Quinazolinas/farmacocinética , Ranitidina/administração & dosagem , Estômago/química , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Gefitinibe , Voluntários Saudáveis , Antagonistas dos Receptores Histamínicos H2/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Análise dos Mínimos Quadrados , Masculino , Quinazolinas/administração & dosagem , Distribuição Aleatória , Ranitidina/farmacocinética
19.
Br J Clin Pharmacol ; 83(8): 1723-1733, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28213941

RESUMO

AIMS: A population pharmacokinetic (PK) model was developed for cediranib to simulate cediranib exposure for different doses, including comedication with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin, in cancer patients. METHODS: Plasma concentrations and covariates from 625 cancer patients after single or multiple oral cediranib administrations ranging from 0.5 to 90 mg in 19 Phase I and II studies were included in the analysis. Stepwise covariate modelling was used to develop the population PK model. The final model was used to simulate cediranib exposure in cancer patients to evaluate cediranib target coverage and the need for dose adjustment for covariates or coadministration with rifampicin. RESULTS: A two-compartment model with sequential zero- and first-order absorption and first-order elimination adequately described the cediranib concentration-time courses. Body weight and age were identified as having statistically significant impact on cediranib PK, but only <21% impact on AUC and maximum concentrations. Simulated lower bounds of 90% prediction interval or median of unbound cediranib concentrations after cediranib 15 or 20 mg exceeded the IC50 for vascular endothelial growth factor receptors-1, -2 and -3. Exposures of cediranib 20 or 30 mg with coadministration of rifampicin were comparable to those of 15 or 20 mg, respectively, without coadministration. CONCLUSIONS: No covariate was identified to require dose adjustment for cediranib. Cediranib exposure following 15 or 20 mg daily dose administration is adequate overall for inhibition of in vitro estimated vascular endothelial growth factor receptor-1, -2 and -3 activities. An increase in cediranib dose may be needed for cediranib coadministered with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Administração Oral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Peso Corporal , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Esquema de Medicação , Feminino , Glucuronosiltransferase/biossíntese , Glucuronosiltransferase/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/sangue , Polimedicação , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Rifampina/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto Jovem
20.
Br J Clin Pharmacol ; 83(2): 370-380, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27552251

RESUMO

AIM: This open-label study investigated the effect of belatacept on cytokine levels and on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam, as CYP probe substrates after oral administration of the Inje cocktail in healthy volunteers. METHODS: Twenty-two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4. RESULTS: Since belatacept caused no major alterations to cytokine levels, there were no major effects on CYP-substrate pharmacokinetics, except for a slight (16-30%) increase in omeprazole exposure, which was probably due to omeprazole-mediated, time-dependent CYP inhibition. Belatacept did not cause major alterations in the pharmacokinetics, as measured by the geometric mean ratios and associated 90% confidence interval for area under the plasma concentration -time curve from time zero to infinity on Day 7 comparing administration with and without belatacept for caffeine (1.002 [0.914, 1.098]), dextromethorphan (1.031 [0.885, 1.200]), losartan (1.016 [0.938, 1.101)], midazolam (0.968 [0.892, 1.049]) or their respective metabolites. CONCLUSIONS: Therefore, no dose adjustments of CYP substrates are indicated with belatacept coadministration.


Assuntos
Abatacepte/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Citocinas/metabolismo , Imunossupressores/farmacologia , Adulto , Área Sob a Curva , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Interações Medicamentosas , Feminino , Humanos , Masculino , Farmacocinética , Fatores de Tempo , Adulto Jovem
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