Optimal design of dose and drug pharmacokinetic characteristics to achieve the desired pharmacodynamic profile in repeated drug dosing
Martin Dodek, Zuzana Vitková, Anton Vitko, Eva Miklovičová
Abstract
Oral drug therapy requires achieving a delicate balance between therapeutic efficacy and patient safety, yet current dosing strategies often rely on empirical trial-and-error methods that overlook the complex nonlinear dynamic nature of drug behavior in the human body. Conventional pharmacokinetic/pharmacodynamic (PK–PD) approaches provide valuable insights but lack a systematic method for designing dose sequences and formulations that achieve an optimal therapeutic response.
Introduction
Executing effective oral drug therapy for various diseases lies at the heart of modern medicine, yet achieving the right balance between efficacy and safety remains a persistent challenge. Pharmacokinetics (PK)—the study of how a drug is absorbed, distributed, and eliminated by the body—traditionally provides a good quantitative framework to understand drug behavior over time.
Materials and method
Pharmacokinetic model
One of the central methodological pillars is the use of compartmental PK models, which provide a mathematically rigorous yet physiologically interpretable framework to describe the dynamics of drugs in the body [2,35]. This methodology provides a structured and systematic framework for modeling the dynamic distribution of substances within an organism, encompassing absorption, distribution, metabolism, and excretion processes (ADME) [35].
Results and discussion
Compartmental model
For validation of the proposed methodology, we will consider a particular four-compartment pharmacokinetic model describing the drug liberation, absorption, elimination, and the transport mechanisms via four state variables in terms of general linear state-space model given by Eq (1) such that
Conclusion
This paper presented a methodology for joint optimization of dosing and formulation-dependent release characteristics to achieve a desired therapeutic response in a combined PK–PD framework. The methodology integrated cybernetic principles, a linear state-space compartmental PK model, sensitivity theory, and nonlinear least-squares optimization, with the PD effect modeled by the Hill function.
Citation: Dodek M, Vitková Z, Vitko A, Miklovičová E (2026) Optimal design of dose and drug pharmacokinetic characteristics to achieve the desired pharmacodynamic profile in repeated drug dosing. PLoS One 21(7): e0354029. https://doi.org/10.1371/journal.pone.0354029
Editor: Pasquale Palumbo, University of Milano Bicocca, ITALY
Received: February 9, 2026; Accepted: July 2, 2026; Published: July 22, 2026
Copyright: © 2026 Dodek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant information is contained within the paper. While the paper does not include raw experimental data, all presented results can be fully reproduced using the provided numerical computations, parameters, and stated assumptions.
Funding: The research is supported by the grant VEGA 1/0229/24 Advanced methods of modeling, identification and control of biosystems, granted by the Ministry of education, science, development, and sport of the Slovak republic. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: No.
