Nonclinical Drug Administration: Formulations, Routes and Regimens for Solving Drug Delivery Problems in Animal Model Systems

421 Pages·2017·2.91 MB·English

by  Shayne C. Gad

Nonclinical Drug
Administration

Nonclinical Drug
Administration
Formulations, Routes and Regimens
for Solving Drug Delivery Problems
in Animal Model Systems
By
Shayne C. Gad
Principal
Gad Consulting Services
and
Charles B. Spainhour
Executive Vice President and Chief Scientific Officer
Calvert Holding & Calvert Laboratories
and
President and Chief Scientific Officer
Spainhour & Associates LLC
CRC Press
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Contents
Preface ......................................................................................................................xi
About the Author ................................................................................................xiii
1. Introduction .....................................................................................................1
Receptor Theory of Drug Efficacy and Drug Toxicity ................................4
References .........................................................................................................7
2. Pharmacotherapy, Toxicodynamics, and Regulatory Science:
Divergent Objectives .....................................................................................9
Introduction ......................................................................................................9
References .......................................................................................................12
3. Nonclinical Pharmacokinetics and Toxicokinetics: A Primer.............15
Introduction ....................................................................................................15
Regulations .....................................................................................................17
Principles .........................................................................................................18
Preliminary Work .....................................................................................18
Absorption .................................................................................................18
Absorption from the Pulmonary System .........................................25
Absorption across the Skin .................................................................26
Parameters Controlling Absorption ..................................................28
Distribution ................................................................................................28
Protein Binding .....................................................................................30
Water Solubility ....................................................................................31
Volume of Distribution ........................................................................31
Metabolism/Biotransformation ..............................................................32
Metabolic Activation ............................................................................38
Induction of P-450 Metabolism and Isoenzymes ............................38
Species Differences ..............................................................................40
Sex-Related Differences in Rodents ...................................................41
Excretion .....................................................................................................41
Urine .......................................................................................................41
Feces .......................................................................................................42
Expired Air ............................................................................................43
Pharmacokinetics ...........................................................................................43
Sampling Methods and Intervals ................................................................43
Blood ...........................................................................................................43
Excreta ........................................................................................................44
Bile ...............................................................................................................45
Expired Air ................................................................................................45
vii
viii Contents
Milk .............................................................................................................45
Analysis of Data .............................................................................................46
Use of Data from Metabolism and Pharmacokinetic Studies ............50
Physiologically Based Pharmacokinetic (PBPK) Modeling .....................50
Points to Consider ..........................................................................................53
Biologically Derived Materials .....................................................................54
Immunoassay Methods ............................................................................56
Metabolism and Elimination ..............................................................58
Points to Consider ..........................................................................................60
References .......................................................................................................62
4. Routes of Administration: With Considerations for Species
Specificity .......................................................................................................65
Bioavailability and Thresholds ....................................................................65
Dermal Route ..................................................................................................71
Parenteral Route .............................................................................................74
Intravenous Route (IV) .............................................................................75
Bolus versus Infusion ...............................................................................77
Intramuscular Route (IM) ........................................................................77
Subcutaneous Route (SC) .........................................................................78
Intraperitoneal Route (IP) ........................................................................79
Oral Route (PO) ..............................................................................................79
Mechanisms of Absorption .....................................................................80
Factors Affecting Oral Absorption .........................................................82
Techniques of Oral Administration .......................................................86
Buccal and Sublingual ..............................................................................88
Lesser Routes ..................................................................................................89
Perocular and Intraocular Routes ...........................................................89
Rectal Administration ..............................................................................90
Vaginal Administration ...........................................................................90
Nasal Administration ...............................................................................91
Implantation ...............................................................................................91
Route Comparisons and Contrasts ..............................................................92
Volume Limitations by Route ..................................................................92
References .......................................................................................................95
5. Delivery Systems ..........................................................................................99
Purposes ..........................................................................................................99
Examples .......................................................................................................103
Liquid Formulation......................................................................................104
Instillation and Rhinyle Catheter ..............................................................104
Drops .............................................................................................................104
Powder Dosage Forms .................................................................................105
Insufflators and Mono-Dose Powder Inhaler ..........................................105
Pressurized MDIs ........................................................................................105
Contents ix
Nasal Gels .....................................................................................................106
Patented Nasal Formulations .....................................................................106
References .....................................................................................................107
6. Dosing Regimens as a Means of Improving Drug Delivery and
Tolerance .......................................................................................................109
References .....................................................................................................110
7. The Utility of Circadian Oscillations in Formulation and Drug
Development ................................................................................................111
Charles B. Spainhour
Background and Introduction ...................................................................111
Circadian Clock ............................................................................................113
Reality of the Science of Timed Cyclical Rhythms .................................114
Timed Rhythms and the Hepatic System .................................................116
Biological Rhythms in Species Other Than Mammals ..........................117
Use of the Internal Clock in Pharmacokinetics, Formulation
Development, and Drug Delivery .............................................................117
Biological Oscillations in Pharmacokinetics ............................................118
Timed Rhythms in Absorption ..................................................................118
Timed Patterns in the Absorption of Drugs ............................................122
Biological Rhythms and Heavy Metal Absorption .................................125
Diurnal Rhythms and the Gastrointestinal Tract ...................................125
Internal Clock-Driven Rhythms and Distribution ..................................128
Diurnal Patterns and Excretion .................................................................129
Internal Clock and the Renal System ........................................................130
Biological Rhythms and Mixed-Function Oxidases ...............................136
Hepatic Conjugation Reactions and Diurnal Variations ........................141
Biological Rhythms and the Otic System .................................................144
Timed Oscillation Patterns Associated with Exposures to
Substances Other Than Drugs ...................................................................144
Patterns in Time and Other Physiologic Phenomena .............................145
Internal Clock and Mathematical Modeling ............................................147
Conclusion ....................................................................................................149
References .....................................................................................................150
8. Fundamentals of Nonclinical Formulation: Chemistry and
Biological Behavior ....................................................................................159
Mechanisms ..................................................................................................163
Preformulation ........................................................................................170
Dermal Formulations .............................................................................175
Interactions between Skin, Vehicle, and Test Chemical ....................179
Oral Formulations ...................................................................................181
Parenteral Formulations .........................................................................185