Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Experiment Videos

Estimating bioavailability when clearance varies with time

M O Karlsson1, L B Sheiner

  • 1Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0626.

Clinical Pharmacology and Therapeutics
|June 1, 1994
PubMed
Summary
This summary is machine-generated.

Related Concept Videos

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria.

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases·2020
Same author

Handling underlying discrete variables with bivariate mixed hidden Markov models in NONMEM.

Journal of pharmacokinetics and pharmacodynamics·2019
Same author

CORRIGENDUM: Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium.

Clinical pharmacology and therapeutics·2018
Same author

Reduced and optimized trial designs for drugs described by a target mediated drug disposition model.

Journal of pharmacokinetics and pharmacodynamics·2018
Same author

Pharmacometric Analysis of the Relationship Between Absolute Lymphocyte Count and Expanded Disability Status Scale and Relapse Rate, Efficacy End Points, in Multiple Sclerosis Trials.

Journal of clinical pharmacology·2018
Same author

Model averaging for robust assessment of QT prolongation by concentration-response analysis.

Statistics in medicine·2017
Same journal

Epcoritamab Step-Up Dosing Regimen Selection and Optimization Using Repeated Time-to-Event Modeling for Cytokine Release Syndrome Risk Mitigation.

Clinical pharmacology and therapeutics·2026
Same journal

From Executor to Orchestrator: The Pharmacology Scientist in the Age of Agentic AI.

Clinical pharmacology and therapeutics·2026
Same journal

The Future of Clinical Pharmacology: The Right Medicine at the Right Dose for Each Patient.

Clinical pharmacology and therapeutics·2026
Same journal

Effects of Trimethoprim on Three Previously Proposed Putative Biomarkers for OCT2/MATE-Mediated Renal Drug-Drug Interactions in Healthy Volunteers.

Clinical pharmacology and therapeutics·2026
Same journal

Clinical Characterization of Enzyme and Transporter Precipitants to Evaluate Drug-Drug Interactions for Orforglipron, a Small Molecule Glucagon-Like Peptide-1 Receptor Agonist.

Clinical pharmacology and therapeutics·2026
Same journal

Symposium Report: Stakeholders' Perspectives on Phase 1 Trials in Japanese Prior to Multi-Regional Clinical Trials and Future Pathways.

Clinical pharmacology and therapeutics·2026
See all related articles

Interoccasion variability in clearance biases bioavailability estimates in standard crossover analysis. A pharmacokinetic nonlinear mixed-effects model provides unbiased estimates of bioavailability parameters, offering a reliable analytical approach.

Area of Science:

  • Pharmacokinetics
  • Biopharmaceutics
  • Statistical analysis in drug development

Background:

  • Accurate bioavailability estimation is crucial for drug development.
  • Traditional crossover designs can be affected by interoccasion variability in drug clearance.
  • Existing analytical methods may yield biased bioavailability parameters.

Purpose of the Study:

  • To evaluate the impact of interoccasion variability in clearance on bioavailability estimates.
  • To compare the performance of five different analytical methods in crossover studies.
  • To identify a robust method for unbiased estimation of bioavailability parameters.

Main Methods:

  • Simulation of pharmacokinetic data with varying interoccasion variability and correlation between clearance and bioavailability.

Related Experiment Videos

  • Analysis using standard crossover, groupwise parallel, two correction procedures, and a pharmacokinetic nonlinear mixed-effects model.
  • Assessment of bias in population mean bioavailability (F), interindividual variance of bioavailability (omega 2F), and correlation of bioavailability with clearance (cor(CL,F)).

    • Main Results:

    • Standard crossover analysis produced biased estimates of F, omega 2F, and cor(CL,F) when interoccasion variability was present.
    • Parallel-group analysis yielded unreliable estimates due to the assumption of zero cor(CL,F).
    • Correction procedures were sensitive to random error in terminal half-life estimates.
    • The pharmacokinetic nonlinear mixed-effects model provided unbiased estimates for all three bioavailability parameters.

    Conclusions:

    • Interoccasion variability in clearance significantly impacts bioavailability estimates in traditional crossover designs.
    • Pharmacokinetic nonlinear mixed-effects modeling is a superior analytical approach for accurate bioavailability assessment.
    • This method offers unbiased estimation of key bioavailability parameters, crucial for reliable drug development decisions.