ReviewClinical pharmacology and therapeutics2022
Can In Vitro-In Vivo Extrapolation Be Successful? Recognizing the Incorrect Clearance Assumptions.
Review in Clinical pharmacology and therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 17 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
17 citing papers in PubMed.
- Application of New Approach Methodologies to Improve Oral Biopharmaceutic Assessments.Pharmaceutics · 2026Review
- Phytochemical profiling and pharmacological evaluation ofFrontiers in pharmacology · 2026Article
- Rethinking the seven-day treatment-free interval in T-cell engager therapy using agent-based modeling.bioRxiv : the preprint server for biology · 2025Article
- Selection of an Optimal Metabolic Model for Accurately Predicting the Hepatic Clearance of Albumin-Binding-Sensitive Drugs.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Application of Kirchhoff's Laws to pharmacologic and pharmacokinetic analyses.Pharmacological reviews · 2025Review
- DeepCt: Predicting Pharmacokinetic Concentration-Time Curves and Compartmental Models from Chemical Structure Using Deep Learning.Molecular pharmaceutics · 2024Article
- Commentary: Pharmacokinetic Theory Must Consider Published Experimental Data.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- Are all measures of liver KpEuropean journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2024Article
- Uridine 5'-Diphospho-glucuronosyltransferase 1A3 (UGT1A3) Prediction of Hepatic Clearance of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) Substrate Telmisartan by Glucuronidation Using In Vitro-In Vivo Extrapolation (IVIVE).European journal of drug metabolism and pharmacokinetics · 2024Article
- An insight into pharmacokinetics and dose optimization of antimicrobials agents in elderly patients.Frontiers in pharmacology · 2024Review
- The Uses and Advantages of Kirchhoff's Laws vs. Differential Equations in Pharmacology, Pharmacokinetics, and (Even) Chemistry.The AAPS journal · 2023Article
- Process and System Clearances in Pharmacokinetic Models: Our Basic Clearance Concepts Are Correct.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Simplifying the Extended Clearance Concept Classification System (EC3S) to Guide Clearance Prediction in Drug Discovery.Pharmaceutical research · 2023Article
- Fast Methods for Drug Approval: Research Perspectives for Pandemic Preparedness.International journal of environmental research and public health · 2023Article
- Large-scale perfused tissues via synthetic 3D soft microfluidics.Nature communications · 2023Article
- Review of the application of Kirchhoff's Laws of series and parallel flows to pharmacology: Defining organ clearance.Pharmacology & therapeutics · 2022Review
- Does Addition of Protein to Hepatocyte or Microsomal In Vitro Incubations Provide a Useful Improvement in In Vitro-In Vivo Extrapolation Predictability?Drug metabolism and disposition: the biological fate of chemicals · 2022Article
Corrections and comments
- Commented on by
- Erratum issuedErratum.2022
Authors and funding
2 authors.
Funding
Abstract
For a number of years, our laboratory has been investigating the underlying reasons for the published poor in vitro-in vivo extrapolation (IVIVE) predictability of human clearance both from a theoretical and from an experimental perspective. Here, we critically examine clearance concepts and commonly employed IVIVE approaches, concluding that there is no theoretical reason that IVIVE should work, just as it does not. Our analysis, however, has identified 10 misconceptions and/or poorly understood aspects of clearance that are listed in the Conclusion section of this manuscript. Chief among these are that all published human drug clearance values are arterial clearances-clearance calculated as organ blood flow multiplied by the extraction ratio is the arterial clearance of the organ of elimination (and not the published drug clearance value)-and that the well-stirred model equation taught in all pharmacokinetic courses that relates organ blood flow, fraction unbound in blood, and intrinsic clearance has no validity. We further list 10 conclusions relating to the IVIVE process. The primary IVIVE-related conclusions are that the intrinsic clearance value determined from an in vitro incubation is an arterial intrinsic clearance, there is no theoretical basis upon which an arterial intrinsic clearance can be related to a whole-body arterial clearance to accomplish IVIVE, there are no published data demonstrating that in vitro intrinsic metabolic clearance can predict in vivo organ clearance as IVIVE assumes, and the scientific basis for the hypothesized albumin-mediated hepatic uptake phenomenon is invalid. We further propose three IVIVE process recommendations.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.