Dataset Information

Determinants of Biological Half-Lives and Terminal Slopes in Physiologically Based Pharmacokinetic Systems: Assessment of Limiting Conditions.

ABSTRACT: In pharmacokinetic (PK) analyses, the biological half-life T_1/2 is usually determined in the terminal phase after drug administration, which is readily calculated from the relationship T_1/2 = ln2/λ_z where λ_z is the terminal-phase slope obtainable from non-compartmental analysis (NCA). Since kinetic understanding of λ_z has been limited to the theory of a one-compartment model, this study seeks kinetic determinants of λ_z in more complex plasma concentration-time profiles. We utilized physiologically based pharmacokinetic (PBPK) systems that are consistent with the assumptions of NCA (e.g., linear PK and elimination occurring from plasma) to interrelate λ_z and disposition kinetic parameters of PBPK models. In a mammillary form of PBPK models, the two boundary conditions of λ_z are the inverses of the mean residence time in the body (1/MRT_B = CL/V_SS) and the mean transit time through the kinetically largest tissue (1/MTT_max = Q_Tf_dR_b/V_TK_p). Importantly, the limiting conditions of λ_z between 1/MRT_B and 1/MTT_max are dependent on a simple product MRT_Bλ_z (P_det) and a simple ratio MTT_max/MRT_B (K_det), leading to introduction of the unitless product-ratio plot for determination of the limiting condition of λ_z in linear PK. We found that the MRT_Bλ_z value of 0.5 serves as a practical threshold determining whether λ_z is more closely associated with 1/MRT_B or 1/MTT_max. The current theory was applied for assessment of the terminal slope λ_z for observed PK data of various compounds in man and rat.

SUBMITTER: Jeong YS

PROVIDER: S-EPMC9589903 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Determinants of Biological Half-Lives and Terminal Slopes in Physiologically Based Pharmacokinetic Systems: Assessment of Limiting Conditions.

Jeong Yoo-Seong YS Jusko William J WJ

The AAPS journal 20220830 5

In pharmacokinetic (PK) analyses, the biological half-life T1/2 is usually determined in the terminal phase after drug administration, which is readily calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable from non-compartmental analysis (NCA). Since kinetic understanding of λz has been limited to the theory of a one-compartment model, this study seeks kinetic determinants of λz in more com ...[more]

PMID: 36042121

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Project description:We developed a detailed, whole-body physiologically based pharmacokinetic (PBPK) modeling tool for calculating the distribution of pharmaceutical agents in the various tissues and organs of a human or animal as a function of time. Ordinary differential equations (ODEs) represent the circulation of body fluids through organs and tissues at the macroscopic level, and the biological transport mechanisms and biotransformations within cells and their organelles at the molecular scale. Each major organ in the body is modeled as composed of one or more tissues. Tissues are made up of cells and fluid spaces. The model accounts for the circulation of arterial and venous blood as well as lymph. Since its development was fueled by the need to accurately predict the pharmacokinetic properties of imaging agents, BioDMET is more complex than most PBPK models. The anatomical details of the model are important for the imaging simulation endpoints. Model complexity has also been crucial for quickly adapting the tool to different problems without the need to generate a new model for every problem. When simpler models are preferred, the non-critical compartments can be dynamically collapsed to reduce unnecessary complexity. BioDMET has been used for imaging feasibility calculations in oncology, neurology, cardiology, and diabetes. For this purpose, the time concentration data generated by the model is inputted into a physics-based image simulator to establish imageability criteria. These are then used to define agent and physiology property ranges required for successful imaging. BioDMET has lately been adapted to aid the development of antimicrobial therapeutics. Given a range of built-in features and its inherent flexibility to customization, the model can be used to study a variety of pharmacokinetic and pharmacodynamic problems such as the effects of inter-individual differences and disease-states on drug pharmacokinetics and pharmacodynamics, dosing optimization, and inter-species scaling. While developing a tool to aid imaging agent and drug development, we aimed at accelerating the acceptance and broad use of PBPK modeling by providing a free mechanistic PBPK software that is user friendly, easy to adapt to a wide range of problems even by non-programmers, provided with ready-to-use parameterized models and benchmarking data collected from the peer-reviewed literature.

Dataset Information

Determinants of Biological Half-Lives and Terminal Slopes in Physiologically Based Pharmacokinetic Systems: Assessment of Limiting Conditions.

Publications

Determinants of Biological Half-Lives and Terminal Slopes in Physiologically Based Pharmacokinetic Systems: Assessment of Limiting Conditions.

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