scholarly journals Lost in modelling and simulation?

ADMET & DMPK ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 75-109
Author(s):  
Kiyohiko Sugano
Keyword(s):  
Scientific Literacy ◽  
Oral Absorption ◽  
Evaluation Studies ◽  
Modelling And Simulation ◽  
Systematic Evaluation ◽  
Pbpk Modelling ◽  
Feature Article ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic

Over the past few decades, physiologically-based pharmacokinetic modelling (PBPK) has been anticipated to be a powerful tool to improve the productivity of drug discovery and development. However, recently, multiple systematic evaluation studies independently suggested that the predictive power of current oral absorption (OA) PBPK models needs significant improvement. There is some disagreement between the industry and regulators about the credibility of OA PBPK modelling. Recently, the editorial board of AMDET&DMPK has announced the policy for the articles related to PBPK modelling (Modelling and simulation ethics). In this feature article, the background of this policy is explained: (1) Requirements for scientific writing of PBPK modelling, (2) Scientific literacy for PBPK modelling, and (3) Middle-out approaches. PBPK models are a useful tool if used correctly. This article will hopefully help advance the science of OA PBPK models.　

scholarly journals Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 672
Author(s):  
Lisa Cheng ◽  
Harvey Wong
Keyword(s):  
Oral Absorption ◽  
Current Knowledge ◽  
Pediatric Population ◽  
Physicochemical Characteristics ◽  
Oral Drug ◽  
Food Effects ◽  
Predictive Tool ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow. Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions, while integrating drug properties such as solubility and permeability. This review discusses the PBPK models published in the literature predicting the food effects, the models’ strengths and shortcomings, as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric population. Overall, the further development of PBPK models to predict food effects will provide a mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable the drug development process.

scholarly journals Current Approaches and Techniques in Physiologically Based Pharmacokinetic (PBPK) Modelling of Nanomaterials

Nanomaterials ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1267 ◽  
Author(s):  
Wells Utembe ◽  
Harvey Clewell ◽  
Natasha Sanabria ◽  
Philip Doganis ◽  
Mary Gulumian
Keyword(s):  
Circulatory System ◽  
Mononuclear Phagocyte ◽  
Pbpk Modelling ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Corona Formation ◽  
Physiologically Based ◽  
The Many ◽  
Species Specific ◽  
Air Liquid Interface

There have been efforts to develop physiologically based pharmacokinetic (PBPK) models for nanomaterials (NMs). Since NMs have quite different kinetic behaviors, the applicability of the approaches and techniques that are utilized in current PBPK models for NMs is warranted. Most PBPK models simulate a size-independent endocytosis from tissues or blood. In the lungs, dosimetry and the air-liquid interface (ALI) models have sometimes been used to estimate NM deposition and translocation into the circulatory system. In the gastrointestinal (GI) tract, kinetics data are needed for mechanistic understanding of NM behavior as well as their absorption through GI mucus and their subsequent hepatobiliary excretion into feces. Following absorption, permeability (Pt) and partition coefficients (PCs) are needed to simulate partitioning from the circulatory system into various organs. Furthermore, mechanistic modelling of organ- and species-specific NM corona formation is in its infancy. More recently, some PBPK models have included the mononuclear phagocyte system (MPS). Most notably, dissolution, a key elimination process for NMs, is only empirically added in some PBPK models. Nevertheless, despite the many challenges still present, there have been great advances in the development and application of PBPK models for hazard assessment and risk assessment of NMs.

scholarly journals Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhongxia Tan ◽  
Youxi Zhang ◽  
Chao Wang ◽  
Le Sun
Keyword(s):  
Plasma Concentration ◽  
Pbpk Model ◽  
Oral Absorption ◽  
Time Profile ◽  
Infected Tissue ◽  
Dose Selection ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

The aim of this study was to develop physiologically based pharmacokinetic (PBPK) models capable of simulating cefadroxil concentrations in plasma and tissues in mouse, rat, and human. PBPK models in this study consisted of 14 tissues and 2 blood compartments. They were established using measured tissue to plasma partition coefficient (Kp) in mouse and rat, absolute expression levels of hPEPT1 along the entire length of the human intestine, and the transporter kinetic parameters. The PBPK models also assumed that all the tissues were well-stirred compartments with perfusion rate limitations, and the ratio of the concentration in tissue to the unbound concentration in plasma is identical across species. These PBPK models were validated strictly by a series of observed plasma concentration–time profile data. The average fold error (AFE) and absolute average fold error (AAFE) values were all less than 2. The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of Vss and CL. The model suggests that hPEPT1 is the major transporter responsible for the oral absorption of cefadroxil in human, and the plasma concentration–time profiles of cefadroxil were not sensitive to dissolution rate faster than T85% = 2 h. The cefadroxil PBPK model in human is reliable and can be used to predict concentration–time profile at infected tissue. It may be useful for dose selection and informative decision-making during clinical trials and dosage form design of cefadroxil and provide a reference for the PBPK model establishment of hPEPT1 substrate.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

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