RESUMO
Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 µM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose.
Assuntos
Antineoplásicos/farmacocinética , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacocinética , Cálculos da Dosagem de Medicamento , Avaliação Pré-Clínica de Medicamentos , Modelos Biológicos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Aurora Quinase A/metabolismo , Azepinas/administração & dosagem , Azepinas/sangue , Células CACO-2 , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Cães , Feminino , Células HCT116 , Meia-Vida , Humanos , Infusões Subcutâneas , Fígado/metabolismo , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Camundongos Nus , Modelos Animais , Pan troglodytes , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Ratos Sprague-Dawley , Especificidade da Espécie , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Drug-drug interactions comprise a significant cause of morbidity and mortality worldwide as they may lead to adverse clinical events, result in decrease/inactivation of the therapeutic effect of a drug, may enhance drug toxicity and indirectly compromise treatment outcomes and adherence. Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism, and elimination (ADME). Inhibition or induction of transporter and drug metabolism enzymes can alter the ADME of a co-administered drug, which may lead to drug-induced toxicity or lack of efficacy. This review assesses our current understanding of the in vitro methods of evaluating CYPs and transporter-mediated DDI. The DDI prediction models based on in vitro assays are also discussed in this review. The applications, advantages and limitations of each method are also addressed in this review.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/metabolismo , Farmacocinética , Animais , Transporte Biológico , Interações Medicamentosas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Inativação MetabólicaRESUMO
Drug transporters, including efflux transporters (the ATP binding cassette (ABC) proteins) and uptake transporters (the solute carrier proteins (SLC)), have an important impact on drug disposition, efficacy, drug-drug interactions and toxicity. Identification of the interactions of chemical scaffolds with transporters at the early stages of drug development can assist in the optimization and selection of new drug candidates. In this review, we discuss current in vitro and in vivo models used to investigate the interactions between drugs and transporters such as P-gp, MRP, BCRP, BSEP, OAT, OATP, OCT, NTCP, PEPT1/2 and NT. In vitro models including cell-based, cell-free, and yeast systems as well as in vivo models such as genetic knockout, gene deficient and chemical knockout animals are discussed and compared. The applications, throughput, advantages and limitations of each model are also addressed in this review.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Autorradiografia , Ligação Competitiva , Bioensaio , Transporte Biológico , Células Cultivadas , Corantes Fluorescentes/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Microscopia Confocal , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Tomografia por Emissão de Pósitrons , Frações Subcelulares , Simportadores/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , TransfecçãoRESUMO
Apparent intrinsic clearance (CL(int,app)) of 7-ethoxycoumarin, phenacetin, propranolol, and midazolam was measured using rat and human liver microsomes and freshly isolated and cryopreserved hepatocytes to determine factors responsible for differences in rates of metabolism in these systems. The cryopreserved and freshly isolated hepatocytes generally provided similar results, although there was greater variability using the latter system. The CL(int,app) values in hepatocytes are observed to be lower than that in microsomes, and this difference becomes greater for compounds with high CL(int,app). This could partly be attributed to the differences in the free fraction (fu). The fu in hepatocyte incubations (fu,hep-inc) was influenced not only by the free fraction of compounds in the incubation buffer (fu,buffer) but also by the rate constants of uptake (k(up)) and metabolism (k(met)). This report provides a new derivation for fu,hep-inc, which can be expressed as fu,hep-inc = [k(up)/(k(met) + k(up))]/[1 + (C(hep)/C(buffer)) x (V(hep)/V(buffer))], where the C(hep), C(buffer), V(hep), and V(buffer) represent the concentrations of a compound in hepatocytes and buffer and volumes of hepatocytes and buffer, respectively. For midazolam, the fu,hep-inc was calculated, and the maximum metabolism rate in hepatocytes was shown to be limited by the uptake rate.