Journal of pharmacokinetics and pharmacodynamics2026; 53(6); 57; doi: 10.1007/s10928-026-10062-7

Prior-informed population pharmacokinetic-pharmacodynamic modeling of dexamethasone in horses.

Yu, R
·
Toutain, PL
·
Ekstrand, C
·
Jusko, WJ

Abstract: Dexamethasone (DEX) is widely used in equine practice with diverse studies having characterized its pharmacokinetics (PK) and pharmacodynamics (PD) including our published comprehensive meta-analysis. Individual DEX concentrations in plasma and urine and serum cortisol from five studies (n = 32 horses) were analyzed using a minimal physiologically-based PK (mPBPK) model and a circadian baseline-indirect response PD model. The previous meta-analysis provided complex structural models to assess sources of variability across an array of studies involving intravenous (IV), intramuscular (IM) and intra-articular (IA) dosing of various formulations. Here we compare three population estimation approaches: first-order conditional estimation with interaction (FOCEI), FOCEI with informative priors (FOCEI-Priors), and full Bayesian estimation. The primary covariate found was hepatic clearance of DEX being 17% higher in adult female horses (0.59 L/h/kg) than in geldings (0.49 L/h/kg). Between-subject variability was identified for some parameters. Standard FOCEI required extensive fixing of parameters to achieve convergence. FOCEI-Priors exhibited robust estimation performance, resulting in well-captured DEX PK and cortisol profiles, precise parameter estimates, and satisfactory model diagnostics. Bayesian estimation failed in the posterior exploration for cortisol PD, likely due to its greater sensitivity to prior specification and data variability. This work demonstrated effective population extensions of complex, prior-informed, mechanistic mPBPK/PD models to confirm determinants and assess variability of DEX disposition and adrenal effects in horses.

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Publication Date: 2026-09-26 PubMed ID: 42800839PubMed Central: 11185821DOI: 10.1007/s10928-026-10062-7Google Scholar: Lookup

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Summary
Cite This
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Affiliations
MeSH
Grants
Conflict of Interest
References
Citations

Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

This study developed and compared modeling approaches to understand how dexamethasone, a corticosteroid drug, is processed in horses’ bodies and how it affects their cortisol levels.
The research used prior knowledge from previous studies to improve population pharmacokinetic-pharmacodynamic (PK-PD) models, focusing on variability between individual horses and factors influencing drug clearance.

Background

Dexamethasone (DEX): A corticosteroid widely used in equine medicine for its anti-inflammatory and immunosuppressive properties.
Pharmacokinetics (PK): Study of how the drug moves through the body, including absorption, distribution, metabolism, and elimination.
Pharmacodynamics (PD): Study of the drug’s biological effects, here particularly its impact on serum cortisol levels, a hormone influenced by dexamethasone.
Previous extensive meta-analysis provided a rich data foundation and complex structural models describing DEX PK-PD in horses.

Study Data and Methods

Data pooled from five studies involving 32 horses, including plasma and urine DEX concentrations plus serum cortisol measurements.
Applied a minimal physiologically-based PK model (mPBPK) to describe drug kinetics, using physiological parameters for better mechanistic understanding.
Adopted a circadian baseline-indirect response PD model to capture how cortisol levels vary naturally over time and under drug influence.
Examined three population modeling strategies to estimate parameters and inter-individual variability:
- FOCEI (First-Order Conditional Estimation with Interaction): Traditional frequentist method.
- FOCEI-Priors: FOCEI enhanced by incorporating informative prior knowledge from previous studies.
- Full Bayesian Estimation: Incorporates prior distributions throughout the estimation process and explores parameter posteriors fully probabilistically.

Key Findings

Hepatic clearance differences: Adult female horses cleared DEX in the liver about 17% faster (0.59 L/h/kg) compared to geldings (0.49 L/h/kg), indicating sex-based differences in metabolism.
Between-subject variability: Significant individual differences in some parameters, emphasizing distinct pharmacokinetic and pharmacodynamic behavior among horses.
Modeling approach outcomes:
- Standard FOCEI: Needed many fixed parameters to converge, signaling difficulties in stable model fitting without prior knowledge integration.
- FOCEI-Priors: Demonstrated strong and robust performance, with good fits to the DEX concentration and cortisol data, accurate parameter estimates, and favorable diagnostic metrics.
- Bayesian Estimation: Encountered challenges during posterior exploration for the cortisol PD component, likely because cortisol’s PD modeling was highly sensitive to prior assumptions and data variability, leading to estimation failures.

Significance and Implications

This study highlights the advantages of incorporating informative prior knowledge into population PK-PD modeling in veterinary pharmacology to reliably characterize drug behavior and effects.
Findings about sex differences in DEX clearance can inform individualized dosing strategies for horses, potentially improving therapeutic outcomes and safety.
Results suggest that FOCEI with priors may be preferred for such complex, mechanistic models when frequentist estimation struggles, while full Bayesian approaches may require more careful tuning or richer data sets.
The combined use of mechanistic physiology-based models and population approaches strengthens understanding of adrenal effects of DEX, aiding better clinical decision-making in equine practice.

Cite This Article

APA

Yu R, Toutain PL, Ekstrand C, Jusko WJ. (2026). Prior-informed population pharmacokinetic-pharmacodynamic modeling of dexamethasone in horses. J Pharmacokinet Pharmacodyn, 53(6), 57. https://doi.org/10.1007/s10928-026-10062-7

Publication

Journal of pharmacokinetics and pharmacodynamics

ISSN: 1573-8744

NlmUniqueID: 101096520

Country: United States

Language: English

Volume: 53

Issue: 6

PII: 57

Researcher Affiliations

Yu, Ruihong

Division of Pharmacokinetics, Pharmacodynamics, and Systems Pharmacology, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 160 Hayes Road, 404 Pharmacy Building, Buffalo, NY, 14214-8033, USA.

Toutain, Pierre-Louis

Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK.

Ekstrand, Carl

Department of Animal Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

Jusko, William J

Division of Pharmacokinetics, Pharmacodynamics, and Systems Pharmacology, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 160 Hayes Road, 404 Pharmacy Building, Buffalo, NY, 14214-8033, USA. wjjusko@buffalo.edu.

MeSH Terms

Animals
Horses
Dexamethasone / pharmacokinetics
Dexamethasone / pharmacology
Dexamethasone / blood
Dexamethasone / administration & dosage
Female
Models, Biological
Bayes Theorem
Male
Hydrocortisone / blood

Grant Funding

R35 GM131800 / NIGMS NIH HHS
R35 GM131800 / NIGMS NIH HHS
No. 82204508 / National Natural Science Foundation of China

Conflict of Interest Statement

Declarations. Competing interests: The authors declare no competing interests.

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