RESUMO
Prediction of rat, dog, monkey, and human volume of distribution (VDss) by Rodgers-Lukacova model was evaluated using a data set of more than 100 compounds.The prediction accuracy was best for humans followed by monkeys and dogs with 59, 52, and 41% of compounds within 2-fold, respectively.The accuracy of predictions in preclinical species was indicative of the human situation. This was particularly true for monkeys, where 87% of the compounds that were predicted within 2-fold in monkeys were also predicted within 2-fold in humans.The model's tendency to underestimate VDss was higher in rats and dogs compared to humans and monkeys for all ion classes but zwitterions. Hence, correction of human predictions using prediction errors in rats and dogs resulted in overestimation of VDss.The model had a similar degree of underestimation in humans and monkeys. Correction using monkeys improved the accuracy of the human estimate, especially for basic and zwitterion compounds.A strategy is proposed based on the accuracy of prediction in monkey and monkey scalars for prediction and prospective assessment of the accuracy of human VDss.
Assuntos
Estudos Prospectivos , Humanos , Animais , Cães , Ratos , HaplorrinosRESUMO
PURPOSE: This study aims to expand our understanding of the mechanisms of drug absorption, distribution, metabolism and excretion in the Göttingen minipig to aid a knowledge-driven selection of the optimal species for preclinical pharmaceutical research. METHODS: The pharmacokinetics of seven reference compounds (antipyrine, atenolol, cimetidine, diazepam, hydrochlorothiazide, midazolam and theophylline) was investigated after intravenous and oral dosing in minipigs. Supportive in vitro data were generated on hepatocellularity, metabolic clearance in hepatocytes, blood cell and plasma protein binding and metabolism routes. RESULTS: Systemic plasma clearance for the seven drugs ranged from low (1.1 ml/min/kg, theophylline) to close to liver blood flow (37.4 ml/min/kg, cimetidine). Volume of distribution in minipigs ranged from 0.7 L/kg for antipyrine to 3.2 L/kg for hydrochlorothiazide. A gender-related difference of in vivo metabolic clearance was observed for antipyrine. The hepatocellularity for minipig was determined as 124 Mcells/g liver, similar to the values reported for human. Based on these data a preliminary in vitro to in vivo correlation (IVIVC) for metabolic clearance measured in hepatocytes was investigated. Metabolite profiles of diazepam and midazolam compared well between minipig and human. CONCLUSIONS: The results of the present study support the use of in vitro metabolism data for the evaluation of minipig in preclinical research and safety testing.
Assuntos
Hepatócitos/metabolismo , Modelos Animais , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Animais , Feminino , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Ligação Proteica/fisiologia , Especificidade da Espécie , Suínos , Porco MiniaturaRESUMO
The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a prime example of targeted therapy for treatment of cancer. The approval of the tyrosine kinase inhibitor imatinib has significantly improved patient survival, but emerging resistance under treatment and relapse is observed. Several additional KIT inhibitors have been approved; still, there is a high unmet need for KIT inhibitors with high selectivity and broad coverage of all clinically relevant KIT mutants. An imidazopyridine hit featuring excellent kinase selectivity was identified in a high-throughput screen (HTS) and optimized to the clinical candidate M4205 (IDRX-42). This molecule has a superior profile compared to approved drugs, suggesting a best-in-class potential for recurrent and metastatic GISTs driven by KIT mutations.