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1.
Clin Pharmacol Ther ; 106(1): 139-147, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30993668

RESUMO

Liver plays a major role in drug metabolism and is one of the main sites of drug adverse effects. Microphysiological systems (MPS), also known as organs-on-a-chip, are a class of microfluidic platforms that recreate properties of tissue microenvironments. Among different properties, the liver microenvironment is three-dimensional, fluid flows around its cells, and different cell types regulate its function. Liver MPS aim to recreate these properties and enable drug testing and measurement of functional endpoints. Tests with these systems have demonstrated their potential for predicting clinical drug effects. Properties of liver MPS that improve the physiology of cell culture are reviewed, specifically focusing on the importance of recreating a physiological microenvironment to evaluate and model drug effects. Advances in modeling hepatic function by leveraging MPS are addressed, noting the need for standardization in the use, quality control, and interpretation of data from these systems.


Assuntos
Avaliação Pré-Clínica de Medicamentos/instrumentação , Dispositivos Lab-On-A-Chip , Fígado/metabolismo , Técnicas Analíticas Microfluídicas/métodos , Modelos Biológicos , Humanos
2.
Clin J Am Soc Nephrol ; 10(1): 159-64, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25189923

RESUMO

The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed.


Assuntos
Injúria Renal Aguda/terapia , Cálculos da Dosagem de Medicamento , Nefrologia/normas , Preparações Farmacêuticas/metabolismo , Farmacocinética , Terapia de Substituição Renal , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/metabolismo , Estado Terminal , Humanos , Nefrologia/métodos , Preparações Farmacêuticas/administração & dosagem , Terapia de Substituição Renal/efeitos adversos
3.
J Clin Pharmacol ; 54(8): 865-73, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24710841

RESUMO

Carriers of two copies of the loss-of-function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19 * 2 variant, we enrolled 18 healthy participants in a genotype-stratified, multi-dose, three-period, fixed-sequence crossover study. Six participants with the *1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 poor metabolizer genotypes each received 75 mg, 150 mg, and 300 mg each for 8 days. In each period, maximal platelet aggregation 4 hours post-dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P < .05 for all). At day 8, PMs needed 300 mg daily and IMs needed 150 mg daily to attain a similar MPA4 as EMs on the 75 mg dose (32.6%, 33.2%, 31.3%, respectively). Similarly, PMs needed 300 mg daily to achieve active metabolite concentrations that were similar to EMs on 75 mg (AUC 37.7 and 33.5 ng h/mL, respectively). These results suggest that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism.


Assuntos
Citocromo P-450 CYP2C19/metabolismo , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/análogos & derivados , Adulto , Idoso , Amish/genética , Área Sob a Curva , Clopidogrel , Estudos Cross-Over , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/sangue , Ticlopidina/administração & dosagem , Ticlopidina/sangue , Ticlopidina/farmacocinética , Adulto Jovem
4.
Clin Pharmacokinet ; 50(10): 627-35, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21895036

RESUMO

Pharmacometric analyses have become an increasingly important component of New Drug Application (NDA) and Biological License Application (BLA) submissions to the US FDA to support drug approval, labelling and trial design decisions. Pharmacometrics is defined as a science that quantifies drug, disease and trial information to aid drug development, therapeutic decisions and/or regulatory decisions. In this report, we present the results of a survey evaluating the impact of pharmacometric analyses on regulatory decisions for 198 submissions during the period from 2000 to 2008. Pharmacometric review of NDAs included independent, quantitative analyses by FDA pharmacometricians, even when such analysis was not conducted by the sponsor, as well as evaluation of the sponsor's report. During 2000-2008, the number of reviews with pharmacometric analyses increased dramatically and the number of reviews with an impact on approval and labelling also increased in a similar fashion. We also present the impact of pharmacometric analyses on selection of paediatric dosing regimens, approval of regimens that had not been directly studied in clinical trials and provision of evidence of effectiveness to support a single pivotal trial. Case studies are presented to better illustrate the role of pharmacometric analyses in regulatory decision making.


Assuntos
Técnicas de Apoio para a Decisão , Rotulagem de Medicamentos/estatística & dados numéricos , Rotulagem de Medicamentos/normas , Aplicação de Novas Drogas em Teste/estatística & dados numéricos , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Rotulagem de Medicamentos/legislação & jurisprudência , Rotulagem de Medicamentos/métodos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacocinética , Humanos , Aplicação de Novas Drogas em Teste/legislação & jurisprudência , Aplicação de Novas Drogas em Teste/métodos , Modelos Biológicos , Estados Unidos , United States Food and Drug Administration
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