1st Edition

Pharmacokinetics and Toxicokinetics

By Mehdi Boroujerdi Copyright 2015
    550 Pages 182 B/W Illustrations
    by CRC Press

    Pharmacokinetics and Toxicokinetics provides an overview of pharmacokinetics and toxicokinetics in a comprehensible, interrelated, and applied manner. It integrates the principles held in common by both fields through a logical and systematic approach.

    The book presents mathematical descriptions of physiological processes employed in different approaches to PK/TK modeling. It focuses on emphasizing general principles and concepts, rather than isolated observations. Above all, the book is an effort to blend the pharmaceutical and toxicological aspects of both fields.

    The systematic compilation of mathematical concepts and methodologies allows readers to decide on relevant concepts and approaches for their research, scientific or regulatory decisions, or for offering advance courses and seminars. This is an invaluable resource for scientists in the pharmaceutical sciences, clinical sciences, and environmental health sciences, as well as those involved in drug discovery and development.

    The Influence of Routes of Administration on ADME
    Pharmacokinetics (PK) and Pharmacodynamics (PD)
    Toxicokinetics (TK) and Toxicodynamics (TD)
    Concepts Basic to PK and TK
    Influence of Routes of Exposure/Administration on PK/TK analysis

    Mechanisms of Absorption and Permeation of Xenobiotics
    Passive Diffusion
    Carrier-Mediated Transcellular Diffusion
    Transcellular Diffusion Subject to P-Glycoprotein EffluxActive Transport
    Endocytosis and Pinocytosis
    Solvent Drag, Osmosis, and Two-Pore Theory
    Ion-Pair Absorption

    In Vivo Distribution of Xenobiotics
    Factors Influencing the Distribution of Xenobiotics in the BodyReferences

    Elimination Rate, Clearance and the Theoretical Models
    Rate of Elimination and Extraction Ratio

    Renal Excretion of Xenobiotics and Estimation of Related PK/TK Parameters and Constants
    Glomerular Filtration
    Tubular Reabsorption and Secretion
    Estimation of Glomerular Filtration Rate (GFR)
    Analysis of Urinary Data
    Renal Metabolism
    Estimation of PK/TK Parameters and Constants of Elimination When Using Dialysis

    Biotransformation of Xenobiotics
    Biotransformation (Metabolism)
    In Vitro Systems for Xenobiotics Metabolism Study
    In Vivo Samples for Drug Metabolism Study

    Kinetics of In Vitro Metabolism Assimilation of Intrinsic Clearance in Hepatic Clearance
    Michaelis-Menten Kinetics
    Assimilation of Intrinsic Clearance in Hepatic Clearance Using Liver Models
    Inhibition of Xenobiotic Metabolism
    Induction of Xenobiotic Metabolism

    Pharmaceutical, Biopharmaceutical, and Physiological Factors Influencing Oral Absorption of Xenobiotics-Mechanistic Absorption Models
    Classification of Factors Influencing GI Tract Absorption
    Mechanistic Absorption Models

    Mathematical Modeling in Pharmacokinetics and Toxicokinetics
    Physiologically Based Pharmacokinetics Models (PBPK Models)
    Compartmental Analysis—Linear Pharmacokinetics
    Non-Compartmental Analysis Based on Statistical Moment Theory
    PK/PD and TK/TD Modeling
    Physiologically Based PK/PD or TK/TD Modeling
    Hysteresis Curve

    PK/TK Analysis of Instantaneous Exposure to Xenobiotics (Single Bolus Injection)
    Linear One-Compartment Open Model
    Linear Two-Compartment Open Model with Elimination from the Central Compartment
    Linear Two-Compartment Open Model with Bolus Injection in the Central Compartment and Elimination from Peripheral Compartment
    Linear Three-Compartment Open Model with Bolus Injection and Elimination from Central Compartment
    Linear Three-Compartment Open Model with Elimination from Peripheral Compartment
    Comparing Models

    PK/TK Analysis of Continuous Zero-Order Exposure to Xenobiotics (Intravenous Infusion)
    Compartmental Analysis

    PK/TK Analysis of Xenobiotics Absorbed via an Extravascular Route of Administration (Oral Administration)
    Compartmental Analysis

    PK/TK of Xenobiotics Absorbed through the Skin (Transdermal Absorption)
    Factors Influencing the Transdermal Absorption of Xenobiotics
    Mathematical Model for Prediction of Skin Concentration
    PK/TK of Percutaneous Absorption

    PK/TK Analysis of Multiple Dosing
    Kinetics of Multiple Intravenous Bolus Injections—One-Compartment Model
    Kinetics of Multiple Oral Administration
    Effect of Changing Dose, Dosing Interval, and Half-Life on Accumulation in the Body and Fluctuation of Plasma Concentration
    Effect of Irregular Dosing Interval on the Plasma Concentration of Multiple-Dosing Regimen
    Multiple Dosing Kinetics—Two-Compartment Model
    Multiple Intravenous Infusions

    Bioavailability, Bioequivalence, and Biosimilar Evaluations
    Peak Exposure, Total Exposure, and Early Exposure
    Bioavailability and First-Pass Metabolism
    Confirmation of Linearity of Relative and Absolute Bioavailability during Multiple Dosing Regimen
    Bioequivalence Study
    Biosimilars (Biosimilarity and Interchangeability)

    Preclinical PK/TK and Clinical Trials
    Preclinical PK/TK
    PK/TK and Clinical Trials
    Dose and Dosing Regimen Adjustment for Patients with Variable Renal Impairments in Clinical Trials

    Population Pharmacokinetics/Toxicokinetics
    Fixed Effect and Random Effect Parameters
    Linear and Nonlinear Mixed-Effects Models
    PLME Model
    Naïve-Pooled Data Approach (NPD)
    Two-Stage Approach
    Bayesian Approach
    Tools of Computational Statistics for PPK

    Quantitative Extrapolation Interspecies Scaling/Low Dose Extrapolation
    Interspecies Scaling in Mammals
    Low Dose Extrapolation

    Appendix A: Relevant Mathematical Concepts


    Mehdi Boroujerdi is a professor of pharmaceutical sciences and the founding dean of the School of Pharmacy at the University of Massachusetts Lowell. He previously served as a professor, dean and provost of the Albany College of Pharmacy and Health Sciences in New York. He earned his PhD in pharmaceutics and pharmacokinetics from the University of North Carolina at Chapel Hill and conducted postdoctoral research at the National Institutes of Health – National Institute of Environmental Health Sciences (NIH-NIEHS) in chemical carcinogenesis and low-dose extrapolation. Dr. Boroujerdi has a broad background and experience in pharmacokinetics/toxicokinetics and the role of influx and efflux proteins. His current research explores the chemoresistance of pancreatic cancer cells to chemotherapeutic agents both in cell culture and in vivo. He has published more than 110 peer-reviewed articles as well as a textbook on pharmacokinetics, principles, and applications.