RESUMEN
Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (Foral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foral was also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. Foral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.
Asunto(s)
Biofarmacia/métodos , Simulación por Computador , Modelos Biológicos , Preparaciones Farmacéuticas/clasificación , Preparaciones Farmacéuticas/metabolismo , Administración Oral , Evaluación Preclínica de Medicamentos/métodos , Predicción , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, Foral and relative AUC (Frel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.
Asunto(s)
Biofarmacia/métodos , Simulación por Computador , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Administración Oral , Evaluación Preclínica de Medicamentos/métodos , Predicción , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5'-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination.
Asunto(s)
Tracto Gastrointestinal/metabolismo , Absorción Intestinal/fisiología , Modelos Animales , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Animales , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Predicción , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Absorción Intestinal/efectos de los fármacos , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
A growing awareness of the risks associated with extensive intestinal metabolism has triggered an interest in developing robust methods for its quantitative assessment. This study explored the utility of intestinal S9 fractions, human liver microsomes, and recombinant cytochromes P450 to quantify CYP3A-mediated intestinal extraction in humans for a selection of marketed drugs that are predominantly metabolized by CYP3A4. A simple competing rates model is used to estimate the fraction of drug escaping gut wall metabolism (fg) from in vitro intrinsic clearance in humans. The fg values extrapolated from the three in vitro systems used in this study, together with literature-derived fg from human intestinal microsomes, were validated against fg extracted from human in vivo pharmacokinetic (PK) profiles using a generic whole-body physiologically-based pharmacokinetic (PBPK) model. The utility of the rat as a model for human CYP3A-mediated intestinal metabolism was also evaluated. Human fg from PBPK compares well with that from the grapefruit juice method, justifying its use for the evaluation of human in vitro systems. Predictive performance of all human in vitro systems was comparable [root mean square error (RMSE) = 0.22-0.27; n = 10]. Rat fg derived from in vivo PK profiles using PBPK has the lowest RMSE (0.19; n = 11) for the prediction of human fg for the selected compounds, most of which have a fraction absorbed close to 1. On the basis of these evaluations, the combined use of fg from human in vitro systems and rats is recommended for the estimation of CYP3A4-mediated intestinal metabolism in lead optimization and preclinical development phases.