TY - BOOK AU - Huang,Shiew Mei AU - Lertora,Juan J.L AU - Vicini,Paolo AU - Atkinson,Jr,Arthur J TI - Atkinson's principles of clinical pharmacology SN - 9780128198698 AV - RM 105 .A85 2022 PY - 2022/// CY - London, United Kingdom: PB - Academic Press N1 - Includes bibliographical references and indexes.; Intro Atkinson's Principles of Clinical Pharmacology Copyright Contents Contributors Preface to the first edition Preface to the fourth edition Chapter 1: Introduction to clinical pharmacology Background Optimizing use of existing medicines Evaluation and development of medicines Pharmacokinetics The concept of clearance Clinical estimation of renal function Dose-related toxicity often occurs when impaired renal function is unrecognized References Additional sources of information Chapter 2: Clinical pharmacokinetics The target concentration strategy Monitoring serum concentrations of digoxin as an example General indications for drug concentration monitoring Concepts underlying clinical pharmacokinetics Initiation of drug therapy (concept of apparent distribution volume) Continuation of drug therapy (concepts of elimination half-life and clearance) Elimination half-life Elimination clearance Drugs not eliminated by first-order kinetics Mathematical basis of clinical pharmacokinetics First-order elimination kinetics Concept of elimination half-life Relationship of k to elimination clearance Cumulation factor The plateau principle Application of Laplace transforms to pharmacokinetics References Study problems Chapter 3: Compartmental analysis of drug distribution Fit-for-purpose modeling of drug distribution Physiological significance of drug distribution volumes Physiological basis of multicompartmental models of drug distribution Formulation of multicompartmental models Basis of multicompartmental structure Mechanisms of transcapillary exchange Clinical consequences of different drug distribution patterns Drugs with faster elimination than distribution Estimating model parameters from experimental data. Derivation of equations for a two-compartment model Calculation of rate constants and compartment volumes from data Different estimates of apparent volume of distribution References Study problems Chapter 4: Drug absorption and bioavailability Drug absorption Metabolism by intestinal bacteria Presystemic elimination Drug-drug and food-drug interactions Bioavailability Absolute bioavailability Relative bioavailability In vitro prediction of bioavailability Kinetics of drug absorption after oral administration Time to peak level Value of peak level Use of convolution/deconvolution to assess in vitro-in vivo correlations References Study problems Chapter 5: Effect of kidney disease on pharmacokinetics Drug dosing in patients with impaired kidney function Effects of kidney disease on renal drug elimination mechanisms Excretion mechanisms: Filtration and secretion Reabsorption mechanisms Renal metabolism Analysis and interpretation of renal excretion data Effects of impaired kidney function on nonrenal clearance pathways Nonrenal metabolism Nonrenal transport Potential mechanisms of altered nonrenal clearance Effects of kidney disease on drug distribution Plasma protein binding of acidic drugs Plasma protein binding of basic and neutral drugs Tissue binding of drugs Effects of kidney disease on drug absorption Study problem References Chapter 6: Pharmacokinetics in patients requiring renal replacement therapy Kinetics of intermittent hemodialysis Solute transfer across dialyzing membranes Calculation of dialysis clearance Patient factors affecting hemodialysis of drugs Hemodynamic changes during Dialysis Kinetics of CRRT and sustained renal replacement therapy Clearance by continuous hemofiltration. Clearance by continuous hemodialysis and SLED Extracorporeal clearance during continuous renal replacement therapy Clinical considerations Drug dosing guidelines for patients requiring renal replacement therapy Extracorporeal therapy of patients with drug toxicity References Chapter 7: Effect of liver disease on pharmacokinetics Physiologic determinants of hepatic drug clearance Hepatic elimination of drugs Restrictively metabolized drugs (ER0.3) Effect of changes in protein binding on hepatic clearance Effect of changes in intrinsic clearance on hepatic drug clearance Drugs with an intermediate extraction ratio (0.3ER0.7) Nonrestrictively metabolized drugs (ER0.70) Biliary excretion of drugs Enterohepatic circulation Effects of liver disease on pharmacokinetics Acute hepatitis Chronic liver disease and cirrhosis Pharmacokinetic consequences of liver cirrhosis Influence of portosystemic shunting on nonrestrictively metabolized drugs Consequences of decreased protein binding Consequences of hepatocellular changes Use of therapeutic drugs in patients with liver disease Classification schemes for liver function FDA guidance for industry on pharmacokinetic studies in patients with impaired hepatic function Other tools for the assessment of liver function Effects of liver disease on the hepatic elimination of drugs Correlation of laboratory tests with drug metabolic clearance Use of probe drugs to characterize hepatic drug clearance Effects of liver disease on the renal elimination of drugs Effects of liver disease on patient response Modification of drug therapy in patients with liver disease References Chapter 8: Noncompartmental and compartmental approaches to pharmacokinetic data analysis Introduction. Kinetics, pharmacokinetics, and pharmacokinetic parameters Kinetics and the link to mathematics The pharmacokinetic parameters Accessible pool parameters System parameters Moments Noncompartmental analysis Noncompartmental model Kinetic parameters of the noncompartmental model The single accessible pool model The two accessible pool model Estimating the kinetic parameters of the noncompartmental model Estimating AUC and AUMC using sums of exponentials Estimating AUC and AUMC using other functions Estimating t1tnC(t)dt and t1tntC(t)dt Extrapolating from tn to infinity Estimating AUC and AUMC from 0 to infinity Compartmental analysis Definitions and assumptions Linear, constant coefficient compartmental models Parameters estimated from compartmental models Experimenting on compartmental models: Input and measurements Nonlinearities in compartmental models Calculating pharmacokinetic parameters from a compartmental model Model parameters Residence time calculations Noncompartmental versus compartmental models Models of data vs. models of system The equivalent sink and source constraints Linearity and time invariance Recovering pharmacokinetic parameters from compartmental models Conclusion References Chapter 9: Population pharmacokinetics Introduction Analysis of pharmacokinetic data Structure of pharmacokinetic models Fitting individual data Population pharmacokinetics Population analysis methods The naïve pooled data method The two-stage method Nonlinear mixed effects modeling method Model comparison Model evaluation Model applications Mirogabalin case study Milademetan case study Conclusions References Chapter 10: Pathways of drug metabolism Introduction. The chemistry and enzymology of drug metabolism Oxidations and nonconjugation reactions Cytochrome P450 monooxygenases Cytochrome P450 families The CYP3A family The CYP2C family The CYP2D6 family The CYP 1A family Non-CYP oxidations Flavin-containing monooxygenases Monoamine oxidases Molybdenum-containing oxidases Esterases Epoxide hydrolases Conjugation reactions Glucuronosyl transferases Sulfotransferases Acetyl transferases Methyltransferases Glutathione transferases References Chapter 11: Bioanalytical methods: Technological platforms and method validation Technological platforms of bioassays High performance/pressure liquid chromatography Chromatographic column Mobile phase Detectors Alternative chromatographic approaches Gas chromatography LC-MS/MS and high resolution mass spectrometry (HRMS) Internal standards Accelerator mass spectrometry Immunoassays Polymerase chain reaction assays Method validation Sample analysis Cross-validation Case examples Interference Establishing assay range Impact of sample handling or instability Assessing results from two assays: Cross-validation Conclusion References Chapter 12: Clinical pharmacogenetics Introduction General principles Pharmacogenetics and pharmacogenomics Human genetics Indications for performing pharmacogenetic studies Genetic analysis techniques and informatics Examples of clinically relevant genetic polymorphisms Genetic variation in Phase I metabolic pharmacogenes CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4 and CYP3A5 Genetic variation in Phase II metabolic pharmacogenes Thiopurine S-methyltransferase (TPMT) N-Acetyltransferase 2 (NAT2) Target/efficacy pharmacogenetics N2 - "Atkinson's Principles of Clinical Pharmacology, Fourth Edition is the essential reference on the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development. This well-regarded survey continues to focus on the basics of clinical pharmacology for the development, evaluation and clinical use of pharmaceutical products while also addressing the most recent advances in the field. Written by leading experts in academia, industry, clinical and regulatory settings, the fourth edition has been thoroughly updated to provide readers with an ideal reference on the wide range of important topics impacting clinical pharmacology"-- ER -