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Chapter one: Introduction to biopharmaceutics and pharmacokinetics 1. Introduction 2. Application of the biopharmaceutic and pharmacokinetic principles in the biomedical fields 2.1. Drug formulation design: 2.2. Drug dosage form design: 2.3. Pharmacological testing: 2.4. Toxicological testing: 2.5. Evaluation of organ function: 2.6. Dosage regimen design: 3. The drug concentration-time profile 4. Linear and nonlinear pharmacokinetics 4.1. Linear pharmacokinetics 4.2. Nonlinear pharmacokinetics 5. Pharmacokinetic modeling 5.1. Compartmental modeling 5.2. Physiological modeling: 5.3. Noncompartmental approach: 6. Pharmacokinetic simulation 7. Questions Chapter Two: Drug pharmacokinetics following single intravenous administration 1. Introduction 2. The elimination rate constant 2.1. Rate of drug elimination 2.1.1. The rate constant for drug elimination 2.2. The order of drug elimination 2.2.1. Zero-order elimination 2.2.2. First-order elimination 2.3. Determination of the first-order elimination rate constant (k) 2.4. The mathematical expressions that describe the amount of the drug in the body when the elimination process follow first-order elimination 2.5. Clinical importance of the elimination rate constant 2.6. In summary 3. The volume of distribution 3.1. The relationship between the drug amount in the body and the blood drug concentration 3.2. Drug protein binding and the volume of distribution 3.3. Determination of the volume of distribution 3.4. Clinical importance of the volume of distribution 3.5. In summary 43. The half life 4.1. The half life during zero-order and first-order elimination 4.1.1. Zero-order elimination 4.1.2. First-order elimination 4.2. Graphical determination of the half life 4.3. Clinical importance of the half life 4.4. In summary 5. The total body clearance 5.1. The relationship between the total body clearance, volume of distribution and elimination rate constant 5.2. Determination of the total body clearance 5.3. The total body clearance and volume of distribution are the independent pharmacokinetic parameters 5.4. Clinical importance of the total body clearance 5.5. In summary 6. The area under the curve 6.1. Factors affecting the area under the curve after a single IV bolus dose 6.2. Calculation of AUC after a single IV bolus dose 6.3. Clinical importance of the area under the curve 7. Factors affecting the blood concentration-time profile after a single IV bolus dose: 7.1. Dose 7.2. Volume of distribution: 7.3. Total body clearance: 8. Practice problems: Chapter three: Drug absorption following oral administration: Biopharmaceutical considerations 1. Introduction 2. Physiological factors affecting oral drug absorption 2.1. The nature of the GIT membrane 2.1.1. Passive diffusion 2.1.2. Carrier-mediated transport 2.1.3. Paracellular 2.1.4. Others: 2.2. Gastrointestinal physiology 2.2.1. The buccal cavity: 2.2.2. Esophagus: 2.2.3. Stomach: 2.2.4. Small intestine: 2.2.5. Large intestine: 2.2.6. Rectum: 2.3. Effect of food on drug absorption 2.4. Pathological conditions affecting drug absorption 3. Physical factors affecting oral drug absorption 3.1. The drug physicochemical properties 3.1.1. The drug lipid solubility 3.1.2. The pH-partition theory 3.2. The dissolution of the drug 3.2.1. Surface area 3.2.2. Diffusion coefficient 3.2.3. Thickness of the unstirred layer 3.2.4. Drug solubility 4. The dosage form characteristics 4.1. Types of oral dosage forms 4.1.1. Solutions 4.1.2. Suspensions 4.1.3. Capsules 4.1.4. Tablets 4.1.5. Coated tablets: 4.1.6. Sustained release tablets: 4.2. In vitro disintegration test 4.3. In vitro dissolution test 4.3.1. The rotating basket 4.3.2. The paddle method 4.3.3. Others 4.3.4. Dissolution requirements 4.3.5. Correlation of in vitro drug dissolution with in vivo drug absorption 5. Questions Chapter four: Drug pharmacokinetics following single oral drug administration: a- The rate of drug absorption 1. Introduction 2. Drug absorption after oral administration 3. The plasma concentration-time profile after a single oral dose 4. Determination of the absorption rate constant 4.1. The method of residuals 4.1.1. Lag time 4.1.2. Flip flop of ka and k 4.2. Wagner-Nelson method 5. Clinical importance of the absorption rate constant 6. In summary: 7. Practice problems Chapter five: Drug pharmacokinetics following single oral drug administration: B- The extent of drug absorption 1. Introduction 1.1. General definitions 2. The purpose of the bioavailability and bioequivalence studies 3. Causes for variation in drug bioavailability 3.1. Factors related to the drug formulation and route of administration 3.1.1. Route of administration: 3.1.2. Dosage form: 3.1.3. Excipient: 3.2. Factors related to the drug 3.2.1. Drug solubility: 3.2.2. Drug partition coefficient: 3.2.3. Stability and drug interaction: 3.3. Factors related to the patient 3.3.1. Individual variability: 3.3.2. Site of administration: 3.3.3. Diseases: 3.4. The first-pass effect 4. Pharmacokinetic basis of drug bioavailability and bioequivalence 5. Determination of the drug bioavailability 5.1. Expected values for the drug bioavailability 5.2. Clinical importance of bioavailability and bioequivalence 6. Calculation of the AUC (The linear trapezoidal rule) 7. Regulatory requirements for bioavailability and bioequivalence 7.1. Design and evaluation of bioequivalence studies 7.2. Criteria for waiver of bioavailability requirements 8. The factors affecting the blood concentration-time profile after a single oral dose 8.1. Dose: 8.2. Bioavailability: 8.3. Total body clearance: 8.4. Volume of distribution: 8.5. Absorption rate constant: 9. Practice problems Chapter six: The steady state principle and drug pharmacokinetics during constant rate IV infusion. 1. Introduction 2. The plasma concentration during continuous constant rate IV drug administration 3. The time required to reach steady state 4. Loading dose 5. Determination of the pharmacokinetic parameters 5.1. Total body clearance 5.2. Elimination rate constant 5.3. Volume of distribution 6. Effect of changing the pharmacokinetic parameters on the steady state plasma concentration during constant rate IV infusion 6.1. Infusion rate 6.2. Volume of distribution 6.3. Total body clearance 7. Practice problems Chapter seven: Steady state during multiple drug administration 1. Introduction 2. The drug plasma concentration-time profile during multiple drug administration 3. Average plasma concentration at steady state 4. The time required to reach steady state 5. Loading dose 5.1. For IV drug administration: 5.2. For extravascular drug administration: 6. Drug accumulation 7. Controlled release formulations 8. The effect of changing the pharmacokinetic parameters on the steady state plasma concentration during repeated drug administration. 8.1- Dosing rate 8.2. Total body clearance 8.3. Volume of distribution 8.4. The absorption rate constant 9. Dosage Regimen Design 9.1. Factors to be considered 9.1.1. Therapeutic effect of the drug 9.1.2. Required onset of effect 9.1.3. Drug product 9.1.4. Patient disease state 9.2. Estimation of the patient pharmacokinetic parameters 9.2.1. When no information is known about the patient¿s medical history 9.2.2. When information is available about the patient¿s medical history 9.2.3. When the patient has history of using the drug under consideration 9.3. Selection of dose and dosing interval 9.3.1. Controlled release oral formulation 9.3.2. Fast release oral formulations and IV administration 9.3.2.1. Selection of the dosing interval 9.3.2.2. Selection of dose 9.4. Selection of the loading dose 10. Practice problems Chapter eight: Renal drug elimination 1. Introduction 2. Mechanisms of renal excretion of drugs 2.1. Glomerular filtration 2.2. Tubular secretion 2.3. Tubular reabsorption 3. Determination of the renal excretion rate 3.1. Experimental determination of the renal excretion rate 3.2. The renal excretion rate-time profile 4. The renal clearance 4.1. Creatinine clearance as a measure of kidney function 5. The cumulative amount of the drug excreted in urine 5.1 Determination of the renal clearance from the cumulative amount excreted in urine 6. Determination of the pharmacokinetic parameters from the renal excretion rate data 6.1. Elimination rate constant and half life (k and t1/2) 6.2. Renal excretion rate constant (ke) 6.3. Volume of distribution (Vd) 6.4. Renal clearance (CLR) 6.5. Fraction of dose excreted unchanged in urine 6.6. Bioavailability 7. The effect of changing the pharmacokinetic parameters on the urinary excretion of drugs. 7.1. Dose 7.2. The total body clearance 7.3. Renal clearance 8. Practice problems Chapter nine: Metabolite pharmacokinetics. 1. Introduction 2. Simple model for metabolite kinetics 2.1. Elimination rate limitation 2.2. Formation rate limitation 2.3. Mathematical description of the elimination rate and formation rate limited metabolites 2.4. The time to achieve the maximum metabolite concentration 4. Estimation of the metabolite pharmacokinetic parameters 4.1. Metabolite elimination rate constant 4.2. Fraction of the parent drug converted to a specific metabolite (or amount of metabolite formed) 4.3. Metabolite clearance 4.5. Metabolite volume of distribution 4.6. Metabolite formation clearance 5. The effect of changing the pharmacokinetic parameters on the drug and metabolite concentration-time profiles after a single IV drug administration. 5.1. Drug dose 5.2. Drug total body clearance, CLT 5.3. Drug volume of distribution, Vd 5.4. Fraction of the drug dose converted to the metabolite, fm 5.5. Metabolite CLT(m) 5.6. Metabolite volume of distribution, Vd(m) 6. Steady state metabolite concentration during repeated administration of the parent drug 7. The effect of changing the pharmacokinetic parameters on the steady state drug and metabolite concentrations during repeated drug administration. 7.1. Drug dose 7.2. Drug total body clearance CLT 7.3. Drug volume of distribution, Vd 7.4. Fraction of the drug dose converted to the metabolite, fm 7.5. Metabolite total body clearance, CLT(m) 7.6. Metabolite volume of distribution, Vd(m) 8. Metabolite kinetics after extravascular administration of the parent drug 9. Kinetics of sequential metabolism 10. Practice problems: Chapter ten: Disease state and drug pharmacokinetics. 1. Introduction 2. Patients with kidney dysfunction 2.1. Factors affecting the change in pharmacokinetics in patients with kidney dysfunction 2.1.1. The fraction of dose excreted unchanged in urine. 2.1.2. The degree of kidney dysfunction 2.2. Dosage adjustment in patients with renal dysfunction 2.2.1. Determination of kidney function: 2.2.2. Determination of the fraction of dose excreted unchanged in urine: 2.2.3. Determination of the dosage requirements in patients with reduced kidney function: 3. Patients with Liver diseases 3.1. The Child-Pugh Score: 4. Practice problems Chapter eleven: Nonlinear pharmacokinetics 1. Introduction 1.1. Causes of nonlinear pharmacokinetics 1.1.1. Saturable drug absorption 1.1.2. Saturable protein binding 1.1.3. Saturable renal elimination 1.1.4. Saturable drug metabolism 1.1.5. Others 1.2. Evidences of nonlinear pharmacokinetics 2. Michaelis-Menten enzyme kinetics 2.1. The pharmacokinetic parameters 2.2. Plasma concentration-time profile after a single IV dose of a drug which is eliminated by a metabolic pathway that follows Michaelis-Menten kinetics 2.2.1. After a single drug administration 2.2.2. After multiple drug administration 3. Determination of the pharmacokinetic parameters 3.1. The total body clearance: 3.2. Half life: 4. The effect of changing the pharmacokinetic parameters on the plasma concentration-time profile 4.1. Dose 4.2. Vmax 4.3. Km 5. Oral administration of drugs that are eliminated by Michaelis-Menten process 6. Pharmacokinetic parameter determination and dosage recommendation 6.1. Mathematical method 6.2. The direct linear plot 6.3. The linear transformation method 7. Multiple elimination pathways 8. Practice problems Chapter twelve: Multi-compartment pharmacokinetic models 1. Introduction 2. The two-compartment pharmacokinetic model 3. The parameters of the two-compartments pharmacokinetic model 3.1. Definition of the pharmacokinetic parameters 3.2. The mathematical equation that describes the plasma concentration-time profile 4. Determination of the two-compartment pharmacokinetic model parameters 4.1. The method of residuals 4.2. Determination of the model parameters 4.2.1. Volume of the central compartment ( Vc ) 4.2.2. The area under the curve ( AUC ) 4.2.3. The total body clearance ( CLT ) 4.2.4. The first-order elimination rate constant from the central compartment (k3) 4.2.5. The first-order transfer rate constant from the peripheral compartment to the central compartment (k2) 4.2.6. The first-order transfer rate constant from the central compartment to the peripheral compartment ( k1 ) 4.2.7. The volume of distribution at steady state ( Vdss ) 4.2.8. The volume of distribution in the elimination phase ( Vd? ) 5. Effect of changing the pharmacokinetic parameters on the drug concentration-time profile after a single IV dose 5.1. Dose 5.2. Volume of Distribution 5.3. The hybrid distribution rate constant, ? 5.4. The hybrid elimination rate constant, ? 6. Oral administration of drugs that follow the two-compartment pharmacokinetic model 7. Constant rate IV administration of drugs that follow the two-compartment pharmacokinetic model 8. Multiple drug administration 9. Renal excretion of drugs that follow two-compartment pharmacokinetic model 10. The effect of changing the pharmacokinetic parameters on the drug distribution between the central and peripheral compartments 10.1. Dose 10.2. The first-order transfer rate constant from the central to the peripheral compartment, k1 10.3. The first-order transfer rate constant from the peripheral to the central compartment, k2 10.4. The first-order elimination rate constant from the central compartment, k3 11. The three-compartment pharmacokinetic model 12. Practice Problems Chapter thirteen: Drug pharmacokinetics following administration by intermittent intravenous infusion. 1. Introduction 2. The drug concentration-time profile during intermittent IV infusion 2.1. After the first dose 2.2. After repeated administration before reaching steady state 2.3. At steady state 3. The effect of changing the pharmacokinetic parameters on the steady state plasma concentration during repeated intermittent IV infusion. 3.1. Dose 3.2. Infusion time 3.3. Total body clearance 3.4. Volume of distribution 4. Application of the pharmacokinetic principles for intermittent IV infusion to the therapeutic use of aminoglycoside 4.1. Pharmacokinetic characteristics 4.2. Guidelines for aminoglycoside plasma concentration 4.3. The extended- interval aminoglycoside dosing regimen 5. Individualization of aminoglycoside therapy 5.1. Determination of the initial dosing regimen based on the population parameters 5.2. Determination of the patient-specific pharmacokinetic parameters 5.2.1. If the patient is to receive the first aminoglycoside dose 5.2.2. If the patient received aminoglycosides before but the steady state was not achieved 5.2.3. If the patient received aminoglycosides and steady state has been achieved 5.3. Determination of the dosing regimen based on the patient¿s specific parameters 5.3.1. Selection of the dosing interval (?) 5.3.2. Selection of dose 5.3.3. Selection of the loading dose 6. Practice problems: Chapter fourteen: Noncompartmental approach pharmacokinetic data analysis 1. Introduction 2. The noncompartmental approach in data analysis 3. The mean residence time (MRT) 3.1. Calculation of the AUC and AUMC 3.1.1. Area under the plasma concentration-time curve 3.1.2. Area under the first moment-time curve 3.2. The Mean residence time after different routes of administration 3.2.1. The MRT after extravascular administration 3.2.2. The MRT after constant rate IV infusion 4. Other pharmacokinetic parameters that can be determined using the noncompartmental approach. 5. Determination of the MRT for compartmental models 6. Practice problems Chapter fifteen: Physiological approach to hepatic clearance 1. Introduction 2. The organ Clearance 3. Hepatic extraction ratio 4. Intrinsic Clearance (CLint) 5. Systemic bioavailability 6. The effect of the change in intrinsic clearance and hepatic blood flow on the hepatic clearance, systemic availability and drug concentration-time profile 6.1. Low extraction ratio drugs 6.2. High extraction ratio drugs: 7. Protein binding and hepatic extraction 8. Practice problems: Chapter sixteen: Pharmacokinetic-pharmacodynamic relationship 1. Introduction 2. Pharmacodynamic models 2.1. The fixed effect model 2.2. The linear model 2.3. The log-linear model 2.4. The Emax model 2.5. The sigmoid Emax model 3. The link between the pharmacokinetic and the pharmacodynamic models 4. Application of pharmacodynamic models 4.1. Duration of drug effect: 4.2. The dosing regimen: 5. Practice problems Chapter seventeen: Therapeutic drug monitoring 1. Introduction 2. General principles of initiation and management of drug therapy 3. Drug blood concentration versus drug dose 4. The therapeutic range 5. The variability in the drug pharmacokinetics and response 5.1. Body weight 5.2. Age 5.3. Drug-drug interactions 5.4. Genetic factors 5.5. Pregnancy 5.6. Diseases 5.7. Other factors 6. Advantage of therapeutic drug monitoring 6.1. Facilitate the rapid achievement of an appropriate dosing regimen 6.2. Evaluate existing dosing regimen 6.3. A prophylactic mean against toxicity: 6.4. Distinguish between pharmacokinetic and pharmacodynamic causes of therapeutic failure: 6.5. Cost-effectiveness: 7. Candidate drugs for therapeutic drug monitoring 7.1. Drugs with low therapeutic index 7.2. Drugs with great variability in their pharmacokinetic properties 7.3. Drugs used in patients who are at high risk of toxicity 8. Methods for measuring drug blood concentrations 9. Establishing a therapeutic drug monitoring service 9.1. Major requirements 9.2. Procedures 9.2.1. Determination of the initial dosing regimen: 9.2.2. Determination of the patient¿s specific pharmacokinetic parameters 9.2.3. Calculation of the dosage requirements based on the patient¿s specific pharmacokinetic parameters of the drug. 10. Questions

Library of Congress Subject Headings for this publication:

Pharmacokinetics.

Pharmacokinetics.