Preface xiii
About the authors xv
Introduction and overview 1 (16)
Use of drugs in disease states 1 (1)
Important definitions and descriptions 2 (2)
Sites of drug administration 4 (2)
Review of ADME processes 6 (1)
Pharmacokinetic models 7 (5)
Rate processes 12 (5)
Mathematical review 17 (12)
Introduction 17 (1)
A brief history of pharmacokinetics 17 (1)
Hierarchy of algebraic operations 18 (1)
Exponents and logarithms 18 (1)
Variables, constants and parameters 19 (2)
Significant figures 21 (1)
Units and their manipulation 21 (1)
Slopes, rates and derivatives 21 (2)
Time expressions 23 (1)
Construction of pharmacokinetic sketches 23 (6)
(profiles)
Intravenous bolus administration 29 (24)
(one-compartment model)
Introduction 29 (1)
Useful pharmacokinetic parameters 30 (2)
The apparent volume of distribution (V) 32 (4)
The elimination half life (t1/2) 36 (2)
The elimination rate constant (K or Kel) 38 (2)
Plotting drug concentration versus time 40 (2)
Intravenous bolus administration of 42 (1)
drugs: summary
Intravenous bolus administration: 42 (2)
monitoring drug in urine
Use of urinary excretion data 44 (9)
Clearance concepts 53 (34)
Introduction 53 (2)
Clearance definitions 55 (1)
Clearance: rate and concentration 56 (1)
Clearance: tank and faucet analogy 56 (2)
Organ clearance 58 (1)
Physiological approach to clearance 59 (5)
Estimation of systemic clearance 64 (1)
Calculating renal clearance (Clr) and 64 (1)
metabolic clearance (Clm)
Determination of the area under the 65 (2)
plasma concentration versus time curve:
application of the trapezoidal rule
Elimination mechanism 67 (1)
Use of creatinine clearance to determine 68 (19)
renal function
Problem set 1 77 (10)
Drug absorption from the gastrointestinal 87 (10)
tract
Gastrointestinal tract 87 (2)
Mechanism of drug absorption 89 (3)
Factors affecting passive drug absorption 92 (1)
pH-partition theory of drug absorption 93 (4)
Extravascular routes of drug administration 97 (28)
Introduction 97 (2)
Drug remaining to be absorbed, or drug 99 (2)
remaining at the site of administration
Determination of elimination half life 101 (1)
(t1/2) and elimination rate constant (K
or Kel)
Absorption rate constant (Ka) 102 (1)
Lag time (T0) 103 (1)
Some important comments on the absorption 104 (1)
rate constant
The apparent volume of distribution (V) 105 (1)
Time of maximum drug concentration, peak 105 (2)
time (tmax)
Maximum (peak) plasma concentration 107 (2)
(Cp)max
Some general comments 109 (1)
Example for extravascular route of drug 110 (4)
administration
Flip-flop kinetics 114 (11)
Problem set 2 117 (8)
Bioavailability/bioequivalence 125 (34)
Introduction 125 (1)
Important definitions 126 (1)
Types of bioavailability 126 (3)
Bioequivalence 129 (1)
Factors affecting bioavailability 130 (1)
The first-pass effect (presystemic 130 (1)
clearance)
Determination of the area under the 131 (4)
plasma concentration-time curve and the
cumulative amount of drug eliminated in
urine
Methods and criteria for bioavailability 135 (8)
testing
Characterizing drug absorption from 143 (2)
plasma concentration versus time and
urinary data following the administration
of a drug via different extravascular
routes and/or dosage forms
Equivalency terms 145 (1)
Food and Drug Administration codes 145 (2)
Fallacies on bioequivalence 147 (1)
Evidence of generic bioinequivalence or 148 (11)
of therapeutic inequivalence for certain
formulations approved by the Food and
Drug Administration
Problem set 3 149 (10)
Factors affecting drug absorption: 159 (12)
physicochemical factors
Dissolution rate 159 (1)
Dissolution process 159 (1)
Noyes-Whitney equation and drug 160 (1)
dissolution
Factors affecting the dissolution rate 161 (10)
Gastrointestinal absorption: role of the 171 (14)
dosage form
Introduction 171 (1)
Solution (elixir, syrup and solution) as 172 (1)
a dosage form
Suspension as a dosage form 172 (1)
Capsule as a dosage form 173 (1)
Tablet as a dosage form 173 (2)
Dissolution methods 175 (1)
Formulation and processing factors 175 (3)
Correlation of in vivo data with in vitro 178 (7)
dissolution data
Continuous intravenous infusion 185 (36)
(one-compartment model)
Introduction 185 (3)
Monitoring drug in the body or blood 188 (1)
(plasma/serum)
Sampling drug in body or blood during 189 (14)
infusion
Sampling blood following cessation of 203 (1)
infusion
Use of post-infusion plasma concentration 204 (4)
data to obtain half life, elimination
rate constant and the apparent volume of
distribution
Rowland and Tozer method 208 (13)
Problem set 4 211 (10)
Multiple dosing: intravenous bolus 221 (22)
administration
Introduction 221 (4)
Useful pharmacokinetic parameters in 225 (8)
multiple dosing
Designing or establishing the dosage 233 (1)
regimen for a drug
Concept of drug accumulation in the body 233 (3)
(R)
Determination of fluctuation (Φ): 236 (3)
intravenous bolus administration
Number of doses required to reach a 239 (1)
fraction of the steady-state condition
Calculation of loading and maintenance 239 (1)
doses
Maximum and minimum drug concentration at 240 (3)
steady state
Multiple dosing: extravascular routes of 243 (26)
drug administration
Introduction 243 (2)
The peak time in multiple dosing to 245 (1)
steady state (t'max)
Maximum plasma concentration at steady 246 (1)
state
Minimum plasma concentration at steady 247 (1)
state
``Average'' plasma concentration at 248 (1)
steady state: extravascular route
Determination of drug accumulation: 249 (1)
extravascular route
Calculation of fluctuation factor (Φ) 250 (1)
for multiple extravascular dosing
Number of doses required reaching a 251 (1)
fraction of steady state: extravascular
route
Determination of loading and maintenance 252 (1)
dose: extravascular route
Interconversion between loading, 253 (16)
maintenance, oral and intravenous bolus
doses
Problem set 5 257 (12)
Two-compartment model 269 (20)
Introduction 269 (3)
Intravenous bolus administration: 272 (4)
two-compartment model
Determination of the post-distribution 276 (1)
rate constant (β) and the
coefficient (B)
Determination of the distribution rate 277 (1)
constant (α) and the coefficient (A)
Determination of micro rate constants: 278 (2)
the inter-compartmental rate constants
(k21 and K12) and the pure elimination
rate constant (K10)
Determination of volumes of distribution 280 (2)
(V)
How to obtain the area under the plasma 282 (1)
concentration-time curve from time zero
to time t and time
General comments 282 (1)
Example 283 (3)
Futher calculations to perform and 286 (3)
determine the answers
Problem set 6 287 (2)
Multiple intermittent infusions 289 (12)
Introduction 289 (2)
Drug concentration guidelines 291 (1)
Example: determination of a multiple 292 (1)
intermittent infusion dosing regimen for
an aminoglycoside antibiotic
Dose to the patient from a multiple 293 (1)
intermittent infusion
Multiple intermittent infusion of a 294 (1)
two-compartment drug: vancomycin ``peak''
at 1 h post-infusion
Vancomycin dosing regimen problem 295 (1)
Adjustment for early or late drug 296 (5)
concentrations
Problem set 7 299 (2)
Non-linear pharmacokinetics 301 (18)
Introduction 301 (3)
Capacity-limited metabolism 304 (1)
Estimation of Michaelis-Menten parameters 305 (4)
(Vmax and Km)
Relationship between the area under the 309 (2)
plasma concentration versus time curve
and the administered dose
Time to reach a given fraction of steady 311 (2)
state
Example: calculation of parameters for 313 (6)
phenytoin
Problem set 8 317 (2)
Drug interactions 319 (18)
Introduction 319 (1)
The effect of protein-binding interactions 320 (7)
The effect of tissue-binding interactions 327 (1)
Cytochrome P450-based drug interactions 328 (8)
Drug interactions linked to transporters 336 (1)
Pharmacokinetic and pharmacodynamic 337 (8)
relationships
Introduction 337 (1)
Generation of a 338 (4)
pharmacokinetic-pharmacodynamic (PKPD)
equation
Pharmacokinetic and pharmacodynamic drug 342 (3)
interactions
Pharmacokinetics and pharmacodynamics of 345 (16)
biotechnology drugs
Introduction 345 (1)
Proteins and peptides 345 (6)
Monoclonal antibodies 351 (4)
Oligonucleotides 355 (1)
Vaccines (immunotherapy) 356 (1)
Gene therapies 357 (4)
Appendix: Statistical moment theory in 361 (16)
pharmacokinetics
A.1 Introduction 361 (1)
A.2 Statistical moment theory 362 (12)
A.3 Applications 374 (3)
Glossary 377 (6)
References 383 (8)
Index 391
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