Basic Pharmacokinetics

Cover......Page 1
Table of Contents......Page 6
Preface......Page 14
About the authors......Page 16
1.1 Use of drugs in disease states......Page 18
1.2 Important definitions and descriptions......Page 19
1.3 Sites of drug administration......Page 21
1.4 Review of ADME processes......Page 23
1.5 Pharmacokinetic models......Page 24
1.6 Rate processes......Page 29
2.2 A brief history of pharmacokinetics......Page 34
2.4 Exponents and logarithms......Page 35
2.5 Variables, constants and parameters......Page 36
2.8 Slopes, rates and derivatives......Page 38
2.10 Construction of pharmacokinetic sketches (profiles)......Page 40
3.1 Introduction......Page 46
3.2 Useful pharmacokinetic parameters......Page 47
3.3 The apparent volume of distribution (V)......Page 49
3.4 The elimination half life (t1/2)......Page 53
3.5 The elimination rate constant (K or Kel)......Page 55
3.6 Plotting drug concentration versus time......Page 57
3.8 Intravenous bolus administration: monitoring drug in urine......Page 59
3.9 Use of urinary excretion data......Page 61
4.1 Introduction......Page 70
4.2 Clearance definitions......Page 72
4.4 Clearance: tank and faucet analogy......Page 73
4.5 Organ clearance......Page 75
4.6 Physiological approach to clearance......Page 76
4.8 Calculating renal clearance (Clr) and metabolic clearance (Clm)......Page 81
4.9 Determination of the area under the plasma concentration versus time curve: application of the trapezoidal rule......Page 82
4.10 Elimination mechanism......Page 84
4.11 Use of creatinine clearance to determine renal function......Page 85
Problem set 1......Page 94
5.1 Gastrointestinal tract......Page 104
5.2 Mechanism of drug absorption......Page 106
5.3 Factors affecting passive drug absorption......Page 109
5.4 pH--partition theory of drug absorption......Page 110
6.1 Introduction......Page 114
6.2 Drug remaining to be absorbed, or drug remaining at the site of administration......Page 116
6.3 Determination of elimination half life (t1/2) and elimination rate constant (K or Kel)......Page 118
6.4 Absorption rate constant (Ka)......Page 119
6.5 Lag time (t0)......Page 120
6.6 Some important comments on the absorption rate constant......Page 121
6.8 Time of maximum drug concentration, peak time (tmax)......Page 122
6.9 Maximum (peak) plasma concentration (Cp)max......Page 124
6.10 Some general comments......Page 126
6.11 Example for extravascular route of drug administration......Page 127
6.12 Flip-flop kinetics......Page 131
Problem set 2......Page 134
7.1 Introduction......Page 142
7.3 Types of bioavailability......Page 143
7.4 Bioequivalence......Page 146
7.6 The first-pass effect (presystemic clearance)......Page 147
7.7 Determination of the area under the plasma concentration--time curve and the cumulative amount of drug eliminated in urine......Page 148
7.8 Methods and criteria for bioavailability testing......Page 152
7.9 Characterizing drug absorption from plasma concentration versus time and urinary data following the administration of a drug via different extravascular routes and/or dosage forms......Page 160
7.11 Food and Drug Administration codes......Page 162
7.12 Fallacies on bioequivalence......Page 164
7.13 Evidence of generic bioinequivalence or of therapeutic inequivalence for certain formulations approved by the Food and Drug Administration......Page 165
Problem set 3......Page 166
8.2 Dissolution process......Page 176
8.3 Noyes--Whitney equation and drug dissolution......Page 177
8.4 Factors affecting the dissolution rate......Page 178
9.1 Introduction......Page 188
9.3 Suspension as a dosage form......Page 189
9.5 Tablet as a dosage form......Page 190
9.7 Formulation and processing factors......Page 192
9.8 Correlation of in vivo data with in vitro dissolution data......Page 195
10.1 Introduction......Page 202
10.2 Monitoring drug in the body or blood (plasma/serum)......Page 205
10.3 Sampling drug in body or blood during infusion......Page 206
10.4 Sampling blood following cessation of infusion......Page 220
10.5 Use of post-infusion plasma concentration data to obtain half life, elimination rate constant and the apparent volume of distribution......Page 221
10.6 Rowland and Tozer method......Page 225
Problem set 4......Page 228
11.1 Introduction......Page 238
11.2 Useful pharmacokinetic parameters in multiple dosing......Page 242
11.4 Concept of drug accumulation in the body (R)......Page 250
11.5 Determination of fluctuation (F): intravenous bolus administration......Page 253
11.7 Calculation of loading and maintenance doses......Page 256
11.8 Maximum and minimum drug concentration at steady state......Page 257
12.1 Introduction......Page 260
12.2 The peak time in multiple dosing to steady state (t0max)......Page 262
12.3 Maximum plasma concentration at steady state......Page 263
12.4 Minimum plasma concentration at steady state......Page 264
12.5 ‘‘Average’’ plasma concentration at steady state: extravascular route......Page 265
12.6 Determination of drug accumulation: extravascular route......Page 266
12.7 Calculation of fluctuation factor (F) for multiple extravascular dosing......Page 267
12.8 Number of doses required reaching a fraction of steady state: extravascular route......Page 268
12.9 Determination of loading and maintenance dose: extravascular route......Page 269
12.10 Interconversion between loading, maintenance, oral and intravenous bolus doses......Page 270
Problem set 5......Page 274
13.1 Introduction......Page 286
13.2 Intravenous bolus administration: two-compartment model......Page 289
13.3 Determination of the postdistribution rate constant (β) and the coefficient (B)......Page 293
13.4 Determination of the distribution rate constant (α) and the coefficient (A)......Page 294
13.5 Determination of micro rate constants: the inter-compartmental rate constants (K21 and K12) and the pure elimination rate constant (K10)......Page 295
13.6 Determination of volumes of distribution (V)......Page 297
13.8 General comments......Page 299
13.9 Example......Page 300
13.10 Futher calculations to perform and determine the answers......Page 303
Problem set 6......Page 304
14.1 Introduction......Page 306
14.2 Drug concentration guidelines......Page 308
14.3 Example: determination of a multiple intermittent infusion dosing regimen for an aminoglycoside antibiotic......Page 309
14.4 Dose to the patient from a multiple intermittent infusion......Page 310
14.5 Multiple intermittent infusion of a two-compartment drug: vancomycin ‘‘peak’’ at 1 h post-infusion......Page 311
14.6 Vancomycin dosing regimen problem......Page 312
14.7 Adjustment for early or late drug concentrations......Page 313
Problem set 7......Page 316
15.1 Introduction......Page 318
15.2 Capacity-limited metabolism......Page 321
15.3 Estimation of Michaelis-- Menten parameters (Vmax and Km)......Page 322
15.4 Relationship between the area under the plasma concentration versus time curve and the administered dose......Page 326
15.5 Time to reach a given fraction of steady state......Page 328
15.6 Example: calculation of parameters for phenytoin......Page 330
Problem set 8......Page 334
16.1 Introduction......Page 336
16.2 The effect of protein-binding interactions......Page 337
16.3 The effect of tissue-binding interactions......Page 344
16.4 Cytochrome P450-based drug interactions......Page 345
17.1 Introduction......Page 354
17.2 Generation of a pharmacokinetic-- pharmacodynamic (PKPD) equation......Page 355
17.3 Pharmacokinetic and pharmacodynamic drug interactions......Page 359
18.2 Proteins and peptides......Page 362
18.3 Monoclonal antibodies......Page 368
18.4 Oligonucleotides......Page 372
18.5 Vaccines (immunotherapy)......Page 373
18.6 Gene therapies......Page 374
A.1 Introduction......Page 378
A.2 Statistical moment theory......Page 379
A.3 Applications......Page 391
Glossary......Page 394
References......Page 400
Index......Page 408