Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine.

Physiologically-based pharmacokinetics in drug development and regulatory science.

The aim of this tutorial is to introduce the concept of physiologically based pharmacokinetic (PBPK) modeling to individuals in the pharmaceutical industry who may be relatively new to this area and to demonstrate application of this approach in a preclinical and clinical setting. The tutorial provides some background on PBPK models and their data requirements, introduces strategies for PBPK modeling in drug development, and includes a discussion on regulatory considerations and potential resource issues.

https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1038/psp.2013.41

Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development.

Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted intestinal availability (F(G)) from in vitro metabolic clearance and permeability data of 25 drugs using the Q(Gut) model. The drug selection included a wide range of physicochemical properties and in vivo F(G) values (0.07-0.94). In vitro clearance data (CLu(int)) were determined in human intestinal (HIM) and three liver (HLM) microsomal pools (n = 105 donors) using the substrate depletion method. Apparent drug permeability (P(app)) was determined in Caco-2 and Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK-MDR1 cells) under isotonic conditions (pH = 7.4). In addition, effective permeability (P(eff)) data, estimated from regression analyses to P(app) or physicochemical properties were used in the F(G) predictions. Determined CLu(int) values ranged from 0.022 to 76.7 microl/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLu(int) values obtained in HIM and HLM were not significant after normalization for tissue-specific CYP3A abundance, supporting their interchangeable usability. The F(G) predictions were most successful when P(app) data from Caco-2/MDCK-MDR1 cells were used directly; in contrast, the use of physicochemical parameters resulted in significant F(G) underpredictions. Good agreement between predicted and in vivo F(G) was noted for drugs with low to medium intestinal extraction (e.g., midazolam predicted F(G) value 0.54 and in vivo value 0.51). In contrast, low prediction accuracy was observed for drugs with in vivo F(G) <0.5, resulting in considerable underprediction in some instances, as for saquinavir (predicted F(G) is 6% of the observed value). Implications of the findings are discussed.

https://dmd.aspetjournals.org/content/dmd/early/2010/04/05/dmd.110.032649.full.pdf

Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data

Oral bioavailability (F) is a product of fraction absorbed (Fa), fraction escaping gut-wall elimination (Fg), and fraction escaping hepatic elimination (Fh). In this study, using a database comprised of Fa, Fg, Fh, and F values for 309 drugs in humans, an analysis of the interrelation of physicochemical properties and the individual parameters was carried out in order to define the physicochemical space for optimum human oral bioavailability. Trend analysis clearly indicated molecular weight (MW), ionization state, lipophilicity, polar descriptors, and free rotatable bonds (RB) influence bioavailability. These trends were due to a combination of effects of the properties on Fa and first-pass elimination (Fg and Fh). Higher MW significantly impacted Fa, while Fg and Fh decreased with increasing lipophilicity. Parabolic trends were observed for bioavailability with polar descriptors. Interestingly, RB has a negative effect on all three parameters, leading to its pronounced effect on bioavailability. In conclusion, physicochemical properties influence bioavailability with typically opposing effects on Fa and first-pass elimination. This analysis may provide a rational judgment on the physicochemical space to optimize oral bioavailability.

Physicochemical Space for Optimum Oral Bioavailability: Contribution of Human Intestinal Absorption and First-Pass Elimination

This study aims to assess utility and limitations of grapefruit juice (GFJ) interaction studies as alternative in vivo approach to estimate intestinal availability (F(G)) in comparison to the predominantly used i.v./oral method. The F(G) estimates were obtained from the ratio of AUC in the control and the GFJ group reported previously. Due to large variability in the study design, the following inclusion criteria were applied for the selection of clinical studies: no change in elimination half-life in the presence of GFJ, administration of GFJ with or up to 4 h before drug intake, and a reported significant increase in AUC in the presence of GFJ. Weighted mean F(G) values were compared to estimates from i.v./oral data. Additionally, inter-study and inter-individual variation of GFJ F(G) estimates was assessed by meta-analysis for drugs with multiple studies reported. F(G) values ranged from 0.07 to 0.92 for lovastatin and quinidine, respectively. Overall, the inter-individual variation in GFJ F(G) estimates (16-54%) was higher than the inter-study (5.7-39%) with the exception of nisoldipine and simvastatin where inter-study variations of 53-88% were observed. Weighted average GFJ F(G) estimates were comparable to i.v./oral, supporting the application of this approach as an alternative to i.v./oral data for predominantly metabolised drugs (r(2) = 0.65; n=10). In contrast, this approach is of limited use for drugs whose disposition is co-dependent on efflux/uptake transporters and metabolic enzymes. An area of high intestinal extraction (F(G) < or = 0.25) is identified as problematic, as availability of conclusive data is limited in this area.

Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations.

A systematic analysis of the heteroactivation of CYP3A-mediated carbamazepine 10,11-epoxidation has been investigated in three different in vitro systems, namely recombinant CYP3A4 and CYP3A5, human liver microsomes (HLMs) and cryopreserved human hepatocytes. The effect of 10 endogenous steroids and flavonoids was studied over a range of substrate and effector concentrations. A novel heteroactivation model was used to obtain the parameters EC200 (concentration of effector required to produce 200% control) and heteroactivation ratio (the ratio of maximum observed reaction velocity to control). The EC200 values obtained in HLMs and human hepatocytes were corrected for nonspecific binding. Heteroactivation of CYP3A5 has been demonstrated with mean heteroactivation ratios in CYP3A5, HLMs and hepatocytes on average 2-fold greater than in recombinant CYP3A4 for most of the effectors investigated. In recombinant CYP3A4, heteroactivation was greatest at substrate concentrations below Km. Heteroactivation increased with effector concentration in a nonlinear manner and differed between effectors (mean heteroactivation ratios varied up to 12-fold). A greater extent of heteroactivation was observed in HLMs than in human hepatocytes for steroid effectors, but the opposite was true for flavonoid effectors. The observed heteroactivation of CYP3A in intact cells supports an in vivo relevance. From the in vitro heteroactivation data, a significant increase in clearance in vivo was predicted for substrates with a high dependence on CYP3A4 to the overall elimination, indicating that heteroactivation of CYP3A may be a potential source of interindividual variability.

https://dmd.aspetjournals.org/content/dmd/early/2008/04/17/dmd.108.021279.full.pdf

Comparative analysis of CYP3A heteroactivation by steroid hormones and flavonoids in different in vitro systems and potential in vivo implications.

vitro clearance and permeability data

Impact of permeability on in vitro predictions of intestinal availability in the QGut model

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Harrison A

Author Tools

Chat about Author