Viera Lukacova

Predicting pharmacokinetics of drugs using physiologically based modeling--application to food effects.

Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in development have distinctly sub-optimal biopharmaceutical properties, making the quantitative prediction of food effect for different formulations from in vitro data very challenging. If such drugs reach clinical development and show undesirable variability when dosed with food, improved formulation can help to reduce the food effect and carefully designed in vivo studies in dogs can be a useful guide to clinical formulation development. Even so, such in vivo studies provide limited throughput for screening, and food effects seen in dog cannot always be directly translated to human. This paper describes how physiologically based absorption modeling can play a role in the prediction of food effect by integrating the data generated during pre-clinical and clinical research and development. Such data include physicochemical and in vitro drug properties, biorelevant solubility and dissolution, and in vivo pre-clinical and clinical pharmacokinetic data. Some background to current physiological absorption models of human and dog is given, and refinements to models of in vivo drug solubility and dissolution are described. These are illustrated with examples using GastroPlus™ to simulate the food effect in dog and human for different formulations of two marketed drugs.

In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects.

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in todays knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.

Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine

The purpose of this study was to develop simulation and modeling methods for the evaluation of pharmacokinetics when intestinal influx and efflux transporters are involved in gastrointestinal absorption. The advanced compartmental absorption and transit (ACAT) model as part of the computer program GastroPlus™ was used to simulate the absorption and pharmacokinetics of valacyclovir, gabapentin, and talinolol. Each of these drugs is a substrate for an influx or efflux transporter and all show nonlinear dose dependence within the normal therapeutic range. These simulations incorporated the experimentally derived gastrointestinal distributions of transporter expression levels for oligopeptide transporters PepT1 and HPT1 (valacyclovir); System L-amino acid transporter LAT2 and organic cation transporter OCTN1 (gabapentin); and organic anion transporter (OATP1A2) and P-glycoprotein (talinolol). By assuming a uniform distribution of oligopeptide transporter and by application of the in vitro Km value for valacyclovir, the simulations accurately reproduced the experimental nonlinear dose dependence. For gabapentin, LAT2 distribution produced simulation results that were much more accurate than OCTN1 distributions. For talinolol, an influx transporter distribution for OATP1A2 and the efflux transporter P-glycoprotein distributed with increasing expression in the distal small intestine produced the best results. The physiological characteristics of the small and large intestines used in the ACAT model were able to accurately account for the positional and temporal changes in concentration and carrier-mediated transport of the three drugs included in this study. The ACAT model reproduced the nonlinear dose dependence for each of these drugs.

Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group

The critical importance of membrane‐bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.

Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

The aim of this study was to demonstrate the value of mechanistic simulations in gaining insight into the behaviors of modified release (MR) formulations in vivo and to use the properly calibrated models for prediction of pharmacokinetics (PK) and pharmacodynamics (PD). GastroPlusTM (Simulations Plus, Inc.) was used to fit mechanistic models for adinazolam and metoprolol that describe the absorption, PK, and PD after intravenous (i.v.) and immediate release (IR) oral (p.o.) administration. The fitted model for adinazolam was then used to predict the PD profile for a MR formulation and to design a new formulation with desired onset and duration of action. The fitted metoprolol model was used to gain insight and to explain the in vivo behaviors of MR formulations. For each drug, a single absorption/PK model was fitted that provided simulated plasma concentration–time profiles closely matching observed in vivo profiles across several different i.v. and p.o doses. Sedation score profiles of adinazolam were fitted with an indirect PD model. For metoprolol, the fitted absorption/PK model for IR p.o. doses was used to select in vitro dissolution conditions that best matched the in vivo release of MR doses. This model also explained differences in exposure after administration of MR formulations with different release rates. Mechanistic absorption/PK models allow for detailed descriptions of all processes affecting the two drugs’ bioavailability, including release/dissolution, absorption, and intestinal and hepatic first pass extraction. The insights gained can be used to design formulations that more effectively overcome identified problems.

Summary of the National Institute of Child Health and Human Development-Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System Working Group

BACKGROUND The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community to be an enabling guide for the rational selection of compounds, formulation for clinical advancement, and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) Working Group was convened to consider the possibility of developing an analogous pediatric-based classification system. Because there are distinct developmental differences that can alter intestinal contents, volumes, permeability, and potentially biorelevant solubilities at different ages, the PBCS Working Group focused on identifying age-specific issues that need to be considered in establishing a flexible, yet rigorous PBCS. OBJECTIVE We summarized the findings of the PBCS Working Group and provided insights into considerations required for the development of a PBCS. METHODS Through several meetings conducted both at The Eunice Kennedy Shriver National Institute of Child Health, Human Development-US Pediatric Formulation Initiative Workshop (November 2011) and via teleconferences, the PBCS Working Group considered several high-level questions that were raised to frame the classification system. In addition, the PBCS Working Group identified a number of knowledge gaps that need to be addressed to develop a rigorous PBCS. RESULTS It was determined that for a PBCS to be truly meaningful, it needs to be broken down into several different age groups that account for developmental changes in intestinal permeability, luminal contents, and gastrointestinal (GI) transit. Several critical knowledge gaps were identified, including (1) a lack of fully understanding the ontogeny of drug metabolizing enzymes and transporters along the GI tract, in the liver, and in the kidney; (2) an incomplete understanding of age-based changes in the GI, liver, and kidney physiology; (3) a clear need to better understand age-based intestinal permeability and fraction absorbed required to develop the PBCS; (4) a clear need for the development and organization of pediatric tissue biobanks to serve as a source for ontogenic research; and (5) a lack of literature published in age-based pediatric pharmacokinetics to build physiologically- and population-based pharmacokinetic (PBPK) databases. CONCLUSIONS To begin the process of establishing a PBPK model, 10 pediatric therapeutic agents were selected (based on their adult BCS classifications). These agents should be targeted for additional research in the future. The PBCS Working Group also identified several areas where greater emphasis on research was needed to enable the development of a PBCS.

Quantitative clinical pharmacology for size and age scaling in pediatric drug development: A systematic review

The establishment of drug dosing in children is often hindered by the lack of actual pediatric efficacy and safety data. To overcome this limitation, scaling approaches are frequently employed to leverage adult clinical information for informing pediatric dosing. The objective of this review is to provide a comprehensive overview of the different scaling approaches used in pediatric pharmacotherapy as well as their proper implementation in drug development and clinical use. We will start out with a brief overview of the current regulatory requirements in pediatric drug development, followed by a review of the most commonly employed scaling approaches in increasing order of complexity ranging from simple body weight‐based dosing to physiologically‐based pharmacokinetic (PBPK) modeling approaches. Each of the presented approaches has advantages and limitations, which will be highlighted throughout the course of the review by the use of clinically‐relevant examples. The choice of the approach employed consequently depends on the clinical question at hand and the availability of sufficient clinical data. The main effort while establishing and qualifying these scaling approaches should be directed towards the development of safe and effective dosing regimens in children rather than identifying the best model, ie models should be fit for purpose.

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes

&NA; 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. Graphical Abstract Figure. No caption available.

IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2 : An introduction to the simulation exercise and overview of results

&NA; 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. Graphical abstract Figure. No caption available.

A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children

A physiologically based pharmacokinetic (PBPK) model has been developed for ganciclovir and its prodrug valganciclovir. Initial bottom-up modeling based on physicochemical drug properties and measured in vitro inputs was verified in preclinical animal species, and then, a clinical model was verified in a stepwise fashion with pharmacokinetic data in adult, children, and neonatal patients. The final model incorporated conversion of valganciclovir to ganciclovir through esterases and permeability-limited tissue distribution of both drugs with active transport processes added in gut, liver, and kidney. A PBPK model which accounted for known age-related tissue volumes, composition and blood flows, and renal filtration clearance was able to simulate well the measured plasma exposures in adults and pediatric patients. Overall, this work illustrates the stepwise development of PBPK models which could be used to predict pharmacokinetics in infants and neonates, thereby assisting drug development in a vulnerable patient population where clinical data are challenging to obtain.