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Preface | p. xi |
About the authors | p. xiii |
Introduction and overview | p. 1 |
Use of drugs in disease states | p. 1 |
Important definitions and descriptions | p. 2 |
Sites of drug administration | p. 4 |
Review of ADME processes | p. 5 |
Pharmacokinetic models | p. 7 |
Rate processes | p. 12 |
Mathematical review | p. 17 |
Introduction | p. 17 |
A brief history of pharmacokinetics | p. 18 |
Hierarchy of algebraic operations | p. 18 |
Exponents and logarithms | p. 18 |
Variables, constants, and parameters | p. 19 |
Significant figures | p. 20 |
Units and their manipulation | p. 21 |
Slopes, rates, and derivatives | p. 21 |
Time expressions | p. 24 |
Construction of pharmacokinetic sketches (profiles) | p. 25 |
Intravenous bolus administration (one-compartment model) | p. 29 |
Introduction | p. 29 |
Useful pharmacokinetic parameters | p. 30 |
The apparent volume of distribution (V) | p. 32 |
The elimination half life (t_{1/2}) | p. 36 |
The elimination rate constant (K or K_{el}) | p. 38 |
Plotting drug concentration versus time | p. 40 |
Intravenous bolus administration of drugs: summary | p. 41 |
Intravenous bolus administration: monitoring drug in urine | p. 42 |
Use of urinary excretion data | p. 43 |
Clearance concepts | p. 55 |
Introduction | p. 55 |
Clearance definitions | p. 56 |
Clearance: rate and concentration | p. 58 |
Clearance: tank and faucet analogy | p. 58 |
Organ clearance | p. 60 |
Physiological approach to clearance | p. 61 |
Estimation of systemic clearance | p. 65 |
Calculating renal clearance (Cl_{r}) and metabolic clearance (cl_{m}) | p. 66 |
Determination of the area under the plasma concentration versus time curve: application of the trapezoidal rule | p. 67 |
Elimination mechanism | p. 69 |
Use of creatinine clearance to determine renal function | p. 69 |
Recently developed equations for estimating creatinine clearance and glomerular filtration rate | p. 76 |
Problem set 1 | p. 79 |
Drug absorption from the gastrointestinal tract | p. 95 |
Gastrointestinal tract | p. 95 |
Mechanism of drug absorption | p. 98 |
Factors affecting passive drug absorption | p. 100 |
pH-partition theory of drug absorption | p. 101 |
Extravascular routes of drug administration | p. 105 |
Introduction | p. 106 |
Drug remaining to be absorbed, or drug remaining at the site of administration | p. 106 |
Determination of elimination half life (t_{1/2}) and elimination rate constant (K or K_{el}) | p. 109 |
Absorption rate constant (K_{a}) | p. 110 |
Wagner-Nelson method (one-compartment model) and Loo-Riegelman method (two-compartment model) | p. 111 |
Lag time (t_{0}) | p. 115 |
Some important comments on the absorption rate constant | p. 116 |
The apparent volume of distribution (V) | p. 116 |
Time of maximum drug concentration, peak time (t_{max}) | p. 117 |
Maximum (peak) plasma concentration (C_{p})_{max} | p. 118 |
Some general comments | p. 120 |
Example for extravascular route of drug administration | p. 121 |
Flip-flop kinetics | p. 126 |
Problem set 2 | p. 127 |
Bioavailability/bioequivalence | p. 137 |
Introduction | p. 138 |
Important definitions | p. 138 |
Types of bioavailability | p. 139 |
Bioequivalence | p. 141 |
Factors affecting bioavailability | p. 141 |
The first-pass effect (presystemic clearance) | p. 142 |
Determination of the area under the plasma concentration-time curve and the cumulative amount of drug eliminated in urine | p. 143 |
Methods and criteria for bioavailability testing | p. 145 |
Characterizing drug absorption from plasma concentration versus time and from urinary data following the administration of a drug via different extravascular routes and/or dosage forms | p. 155 |
Equivalency terms | p. 157 |
Food and Drug Administration codes | p. 157 |
Fallacies on bioequivalence | p. 158 |
Evidence of generic bioinequivalence or of therapeutic inequivalence for certain formulations approved by the FDA | p. 159 |
Problem set 3 | p. 161 |
Factors affecting drug absorption: Physicochemical factors | p. 175 |
Dissolution rate | p. 175 |
Dissolution process | p. 175 |
Noyes-Whitney equation and drug dissolution | p. 176 |
Factors affecting the dissolution rate | p. 177 |
Gastrointestinal absorption: Role of the dosage form | p. 187 |
Introduction | p. 187 |
Solution (elixir, syrup, and solution) as a dosage form | p. 188 |
Suspension as a dosage form | p. 188 |
Capsule as a dosage form | p. 189 |
Tablet as a dosage form | p. 189 |
Dissolution methods | p. 191 |
Formulation and processing factors | p. 191 |
Correlation of in vivo data with in vitro dissolution data | p. 194 |
Continuous intravenous infusion (one-compartment model) | p. 203 |
Introduction | p. 203 |
Monitoring drug in the body or blood (plasma/serum) | p. 205 |
Sampling drug in body or blood during infusion | p. 205 |
Sampling blood following cessation of infusion | p. 220 |
Use of post-infusion plasma concentration data to obtain half life, elimination rate constant and the apparent volume of distribution | p. 222 |
Rowland and Tozer method | p. 225 |
Problem set 4 | p. 227 |
Multiple dosing: Intravenous bolus administration | p. 237 |
Introduction | p. 237 |
Useful pharmacokinetic parameters in multiple dosing | p. 241 |
Designing or establishing the dosage regimen for a drug | p. 248 |
Concept of drug accumulation in the body (R) | p. 249 |
Determination of fluctuation (¿): intravenous bolus administration | p. 251 |
Number of doses required to reach a fraction of the steady-state condition | p. 254 |
Calculation of loading and maintenance doses | p. 254 |
Maximum and minimum drug concentration at steady state | p. 255 |
Multiple dosing: extravascular routes of drug administration | p. 257 |
Introduction | p. 257 |
The peak time in multiple dosing to steady state (t′_{max}) | p. 259 |
Maximum plasma concentration at steady state | p. 260 |
Minimum plasma concentration at steady state | p. 261 |
"Average" plasma concentration at steady state: extravascular route | p. 262 |
Determination of drug accumulation: extravascular route | p. 263 |
Calculation of fluctuation factor (¿) for multiple extravascular dosing | p. 264 |
Number of doses required to reach a fraction of steady state: extravascular route | p. 264 |
Determination of loading and maintenance dose: extravascular route | p. 265 |
Interconversion between loading, maintenance, oral, and intravenous bolus doses | p. 266 |
Problem set 5 | p. 271 |
Two-compartment model | p. 285 |
Introduction | p. 285 |
Intravenous bolus administration: two-compartment model | p. 287 |
Determination of the post-distribution rate constant (ß) and the coefficient B | p. 292 |
Determination of the distribution rate constant (¿) and the coefficient A | p. 292 |
Determination of micro rate constants: the inter-compartmental rate constants (K_{21} and K_{12}) and the pure elimination rate constant (K_{10}) | p. 295 |
Determination of volumes of distribution (V) | p. 296 |
How to obtain the area under the plasma concentration-time curve from time zero to time t and time ∞ | p. 298 |
General comments | p. 299 |
Example | p. 300 |
Further calculations to perform and determine the answers | p. 302 |
Extravascular dosing of a two-compartment model drug | p. 303 |
Problem set 6 | p. 305 |
Multiple intermittent infusions | p. 309 |
Introduction | p. 309 |
Drug concentration guidelines | p. 311 |
Example: determination of a multiple intermittent infusion dosing regimen for an aminoglycoside antibiotic | p. 311 |
Does to the patient from a multiple intermittent infusion | p. 313 |
Multiple intermittent infusion of a two-compartment drug: vancomycin "peak" at 1 hour post infustion | p. 313 |
Vancomycin dosing regimen problem | p. 314 |
Adjustment for early or late drug concentrations | p. 315 |
Problem set 7 | p. 319 |
Nonlinear pharmacokinetics | p. 323 |
Introduction | p. 323 |
Capacity-limited metabolism | p. 325 |
Estimation of Michaelis-Menten parameters (V_{max} and K_{m}) | p. 327 |
Relationship between the area under the plasma concentration versus time curve and the administered dose | p. 330 |
Time to reach a given fraction of steady state | p. 332 |
Example: calculation of parameters for phenytoin | p. 333 |
Problem set 8 | p. 337 |
Drug interactions | p. 341 |
Introduction | p. 341 |
The effect of protein-binding interactions | p. 342 |
The effect of tissue-binding interactions | p. 348 |
Cytochrome P450-based drug interactions | p. 349 |
Drug interactions linked to transporters | p. 355 |
Problem set 9 | p. 357 |
Pharmacokinetic and pharmacodynamic relationships | p. 359 |
Introduction | p. 359 |
Generation of a pharmacokinetic- pharmacodynamic (PKPD) equation | p. 361 |
Pharmacokinetic and pharmacodynamic drug interactions | p. 364 |
Problem set 10 | p. 367 |
Metabolite pharmacokinetics | p. 369 |
Introduction | p. 369 |
General model | p. 370 |
Single intravenous bolus of drug conforming to a one-compartment model | p. 370 |
Single oral dose of drug conforming to a one-compartment model | p. 382 |
Intravenous infusion of a one-compartment model parent drug | p. 384 |
Chronic dosing to steady state | p. 385 |
Study design required to obtain various metabolite pharmacokinetic parameters | p. 388 |
Computer-aided simulation and fitting of metabolite pharmacokinetic data | p. 388 |
Case in point: meperidine and normeperidine | p. 388 |
Active metabolites in renal dysfunction | p. 388 |
Sample metabolite pharmacokinetics calculations | p. 393 |
Pharmacokinetic data fitting | p. 395 |
Introduction | p. 395 |
Pharmacokinetic parameter determination | p. 395 |
Nonlinear regression | p. 397 |
Goodness of fit indices | p. 398 |
Ways to improve fit | p. 401 |
Evaluation of program output | p. 401 |
How are the values of the parameters determined? | p. 404 |
Problems that may occur during a nonlinear regression run | p. 407 |
Weighting of data points | p. 408 |
Simulation | p. 409 |
Initial estimates | p. 411 |
Conclusion | p. 412 |
Pharmacokinetics and pharmacodynamics of biotechnology drugs | p. 413 |
Introduction | p. 413 |
Proteins and peptides | p. 413 |
Monoclonal antibodies | p. 419 |
Oligonucleotides | p. 423 |
Vaccines (immunotherapy) | p. 424 |
Gene therapies | p. 425 |
p. 427 | |
Introduction | p. 427 |
Statistical moment theory | p. 428 |
Applications | p. 439 |
Glossary | p. 443 |
References | p. 453 |
Index | p. 461 |
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