9780853699804

Basic Pharmacokinetics

by ;
  • ISBN13:

    9780853699804

  • ISBN10:

    0853699801

  • Edition: 2nd
  • Format: Paperback
  • Copyright: 2012-04-30
  • Publisher: Pharmaceutical Pr

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Summary

Basic Pharmacokinetics provides an understanding of the principles of pharmacokinetics and biopharmaceutics and of how these principles can be applied to achieve successful drug therapy.

Author Biography

Sunil S Jambhekar is Professor and Associate Dean, LECOM-Bradenton School of Pharmacy, Florida, USA. Phillip J Breen is Associate Professor of Pharmaceutics, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, USA.

Table of Contents

Prefacep. xi
About the authorsp. xiii
Introduction and overviewp. 1
Use of drugs in disease statesp. 1
Important definitions and descriptionsp. 2
Sites of drug administrationp. 4
Review of ADME processesp. 5
Pharmacokinetic modelsp. 7
Rate processesp. 12
Mathematical reviewp. 17
Introductionp. 17
A brief history of pharmacokineticsp. 18
Hierarchy of algebraic operationsp. 18
Exponents and logarithmsp. 18
Variables, constants, and parametersp. 19
Significant figuresp. 20
Units and their manipulationp. 21
Slopes, rates, and derivativesp. 21
Time expressionsp. 24
Construction of pharmacokinetic sketches (profiles)p. 25
Intravenous bolus administration (one-compartment model)p. 29
Introductionp. 29
Useful pharmacokinetic parametersp. 30
The apparent volume of distribution (V)p. 32
The elimination half life (t1/2)p. 36
The elimination rate constant (K or Kel)p. 38
Plotting drug concentration versus timep. 40
Intravenous bolus administration of drugs: summaryp. 41
Intravenous bolus administration: monitoring drug in urinep. 42
Use of urinary excretion datap. 43
Clearance conceptsp. 55
Introductionp. 55
Clearance definitionsp. 56
Clearance: rate and concentrationp. 58
Clearance: tank and faucet analogyp. 58
Organ clearancep. 60
Physiological approach to clearancep. 61
Estimation of systemic clearancep. 65
Calculating renal clearance (Clr) and metabolic clearance (clm)p. 66
Determination of the area under the plasma concentration versus time curve: application of the trapezoidal rulep. 67
Elimination mechanismp. 69
Use of creatinine clearance to determine renal functionp. 69
Recently developed equations for estimating creatinine clearance and glomerular filtration ratep. 76
Problem set 1p. 79
Drug absorption from the gastrointestinal tractp. 95
Gastrointestinal tractp. 95
Mechanism of drug absorptionp. 98
Factors affecting passive drug absorptionp. 100
pH-partition theory of drug absorptionp. 101
Extravascular routes of drug administrationp. 105
Introductionp. 106
Drug remaining to be absorbed, or drug remaining at the site of administrationp. 106
Determination of elimination half life (t1/2) and elimination rate constant (K or Kel)p. 109
Absorption rate constant (Ka)p. 110
Wagner-Nelson method (one-compartment model) and Loo-Riegelman method (two-compartment model)p. 111
Lag time (t0)p. 115
Some important comments on the absorption rate constantp. 116
The apparent volume of distribution (V)p. 116
Time of maximum drug concentration, peak time (tmax)p. 117
Maximum (peak) plasma concentration (Cp)maxp. 118
Some general commentsp. 120
Example for extravascular route of drug administrationp. 121
Flip-flop kineticsp. 126
Problem set 2p. 127
Bioavailability/bioequivalencep. 137
Introductionp. 138
Important definitionsp. 138
Types of bioavailabilityp. 139
Bioequivalencep. 141
Factors affecting bioavailabilityp. 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 urinep. 143
Methods and criteria for bioavailability testingp. 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 formsp. 155
Equivalency termsp. 157
Food and Drug Administration codesp. 157
Fallacies on bioequivalencep. 158
Evidence of generic bioinequivalence or of therapeutic inequivalence for certain formulations approved by the FDAp. 159
Problem set 3p. 161
Factors affecting drug absorption: Physicochemical factorsp. 175
Dissolution ratep. 175
Dissolution processp. 175
Noyes-Whitney equation and drug dissolutionp. 176
Factors affecting the dissolution ratep. 177
Gastrointestinal absorption: Role of the dosage formp. 187
Introductionp. 187
Solution (elixir, syrup, and solution) as a dosage formp. 188
Suspension as a dosage formp. 188
Capsule as a dosage formp. 189
Tablet as a dosage formp. 189
Dissolution methodsp. 191
Formulation and processing factorsp. 191
Correlation of in vivo data with in vitro dissolution datap. 194
Continuous intravenous infusion (one-compartment model)p. 203
Introductionp. 203
Monitoring drug in the body or blood (plasma/serum)p. 205
Sampling drug in body or blood during infusionp. 205
Sampling blood following cessation of infusionp. 220
Use of post-infusion plasma concentration data to obtain half life, elimination rate constant and the apparent volume of distributionp. 222
Rowland and Tozer methodp. 225
Problem set 4p. 227
Multiple dosing: Intravenous bolus administrationp. 237
Introductionp. 237
Useful pharmacokinetic parameters in multiple dosingp. 241
Designing or establishing the dosage regimen for a drugp. 248
Concept of drug accumulation in the body (R)p. 249
Determination of fluctuation (): intravenous bolus administrationp. 251
Number of doses required to reach a fraction of the steady-state conditionp. 254
Calculation of loading and maintenance dosesp. 254
Maximum and minimum drug concentration at steady statep. 255
Multiple dosing: extravascular routes of drug administrationp. 257
Introductionp. 257
The peak time in multiple dosing to steady state (t′max)p. 259
Maximum plasma concentration at steady statep. 260
Minimum plasma concentration at steady statep. 261
"Average" plasma concentration at steady state: extravascular routep. 262
Determination of drug accumulation: extravascular routep. 263
Calculation of fluctuation factor () for multiple extravascular dosingp. 264
Number of doses required to reach a fraction of steady state: extravascular routep. 264
Determination of loading and maintenance dose: extravascular routep. 265
Interconversion between loading, maintenance, oral, and intravenous bolus dosesp. 266
Problem set 5p. 271
Two-compartment modelp. 285
Introductionp. 285
Intravenous bolus administration: two-compartment modelp. 287
Determination of the post-distribution rate constant () and the coefficient Bp. 292
Determination of the distribution rate constant () and the coefficient Ap. 292
Determination of micro rate constants: the inter-compartmental rate constants (K21 and K12) and the pure elimination rate constant (K10)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 commentsp. 299
Examplep. 300
Further calculations to perform and determine the answersp. 302
Extravascular dosing of a two-compartment model drugp. 303
Problem set 6p. 305
Multiple intermittent infusionsp. 309
Introductionp. 309
Drug concentration guidelinesp. 311
Example: determination of a multiple intermittent infusion dosing regimen for an aminoglycoside antibioticp. 311
Does to the patient from a multiple intermittent infusionp. 313
Multiple intermittent infusion of a two-compartment drug: vancomycin "peak" at 1 hour post infustionp. 313
Vancomycin dosing regimen problemp. 314
Adjustment for early or late drug concentrationsp. 315
Problem set 7p. 319
Nonlinear pharmacokineticsp. 323
Introductionp. 323
Capacity-limited metabolismp. 325
Estimation of Michaelis-Menten parameters (Vmax and Km)p. 327
Relationship between the area under the plasma concentration versus time curve and the administered dosep. 330
Time to reach a given fraction of steady statep. 332
Example: calculation of parameters for phenytoinp. 333
Problem set 8p. 337
Drug interactionsp. 341
Introductionp. 341
The effect of protein-binding interactionsp. 342
The effect of tissue-binding interactionsp. 348
Cytochrome P450-based drug interactionsp. 349
Drug interactions linked to transportersp. 355
Problem set 9p. 357
Pharmacokinetic and pharmacodynamic relationshipsp. 359
Introductionp. 359
Generation of a pharmacokinetic- pharmacodynamic (PKPD) equationp. 361
Pharmacokinetic and pharmacodynamic drug interactionsp. 364
Problem set 10p. 367
Metabolite pharmacokineticsp. 369
Introductionp. 369
General modelp. 370
Single intravenous bolus of drug conforming to a one-compartment modelp. 370
Single oral dose of drug conforming to a one-compartment modelp. 382
Intravenous infusion of a one-compartment model parent drugp. 384
Chronic dosing to steady statep. 385
Study design required to obtain various metabolite pharmacokinetic parametersp. 388
Computer-aided simulation and fitting of metabolite pharmacokinetic datap. 388
Case in point: meperidine and normeperidinep. 388
Active metabolites in renal dysfunctionp. 388
Sample metabolite pharmacokinetics calculationsp. 393
Pharmacokinetic data fittingp. 395
Introductionp. 395
Pharmacokinetic parameter determinationp. 395
Nonlinear regressionp. 397
Goodness of fit indicesp. 398
Ways to improve fitp. 401
Evaluation of program outputp. 401
How are the values of the parameters determined?p. 404
Problems that may occur during a nonlinear regression runp. 407
Weighting of data pointsp. 408
Simulationp. 409
Initial estimatesp. 411
Conclusionp. 412
Pharmacokinetics and pharmacodynamics of biotechnology drugsp. 413
Introductionp. 413
Proteins and peptidesp. 413
Monoclonal antibodiesp. 419
Oligonucleotidesp. 423
Vaccines (immunotherapy)p. 424
Gene therapiesp. 425
p. 427
Introductionp. 427
Statistical moment theoryp. 428
Applicationsp. 439
Glossaryp. 443
Referencesp. 453
Indexp. 461
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