Basic Pharmacokinetics

by Jambhekar, Sunil S., Ph.D.; Breen, Philip J., Ph.D.

• ISBN13: 9780853699804
• ISBN10: 0853699801
• Edition: 2nd
• Format: Paperback
• Copyright: 2012-04-30
• Publisher: Pharmaceutical Pr

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

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 (t1/2)	p. 36
The elimination rate constant (K or Kel)	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 (Clr) and metabolic clearance (clm)	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 (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 constant	p. 116
The apparent volume of distribution (V)	p. 116
Time of maximum drug concentration, peak time (tmax)	p. 117
Maximum (peak) plasma concentration (Cp)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 (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 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 (Vmax and Km)	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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