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Advanced Biopharmaceutics & Pharmacokinetics (Pharmaceutics First Edition) M.Pharm Second Semester

Name: Advanced Biopharmaceutics & Pharmacokinetics (Pharmaceutics First Edition) M.Pharm Second Semester
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Syllabus

MPH 202T

Advanced Biopharmaceutics & Pharmacokinetics

Theory (60 Hours)

Unit-1 (12 hours)

Drug Absorption from the Gastrointestinal Tract: Gastrointestinal tract, Mechanism of drug absorption, Factors affecting drug absorption, pH–partition theory of drug absorption. Formulation and physicochemical factors: Dissolution rate, Dissolution process, Noyes–Whitney equation and drug dissolution, Factors affecting the dissolution rate. Gastrointestinal absorption: role of the dosage form: Solution (elixir, syrup and solution) as a dosage form, Suspension as a dosage form, Capsule as a dosage form, Tablet as a dosage form, Dissolution methods ,Formulation and processing factors, Correlation of in vivo data with in vitro dissolution data. Transport model: Permeability-Solubility Charge State and the pH Partition Hypothesis, Properties of the Gastrointestinal Tract (GIT), pH Microclimate Intracellular pH Environment, Tight-Junction Complex.

Unit-2 (12 hours)

Biopharmaceutic Considerations in Drug Product Design and In Vitro Drug Product Performance: Introduction, biopharmaceutic factors affecting drug bioavailability, rate-limiting steps in drug absorption, physicochemical nature of the drug formulation factors affecting drug product performance, in vitro: dissolution and drug release testing, Compendial methods of dissolution, alternative methods of dissolution testing, meeting dissolution requirements, problems of variable control in dissolution testing performance of drug products. In vitro–in vivo correlation, dissolution profile comparisons, drug product stability, considerations in the design of a drug product.

Unit-3 (12 hours)

Pharmacokinetics: Basic considerations, pharmacokinetic models, compartment modeling: one compartment model- IV bolus, IV infusion, extra-vascular. Multi compartment model: two compartment-model in brief, non-linear pharmacokinetics: cause of non-linearity, Michaelis–Menten equation, estimation of k_max and v_max. Drug interactions: introduction, the effect of protein binding interactions, the effect of tissue-binding interactions, cytochrome p450-based drug interactions, drug interactions linked to transporters.

Unit-4 (12 hours)

Drug Product Performance, In Vivo: Bioavailability and Bioequivalence: Drug product performance, purpose of bioavailability studies, relative and absolute availability. Methods for assessing bioavailability, bioequivalence studies, design and evaluation of bioequivalence studies, study designs, crossover study designs, evaluation of the data, bioequivalence example, study submission and drug review process. Biopharmaceutics classification system, methods. Permeability: In-vitro, in-situ and In-vivo methods. Generic biologics (biosimilar drug products), clinical significance of bioequivalence studies, special concerns in bioavailability and bioequivalence studies, generic substitution.

Unit-5 (12 hours)

Application of Pharmacokinetics: Modified-Release Drug Products, Targeted Drug Delivery Systems and Biotechnological Products. Introduction to Pharmacokinetics and pharmacodynamic, drug interactions. Pharmacokinetics and pharmacodynamics of biotechnology drugs. Introduction, Proteins and peptides, Monoclonal antibodies, Oligonucleotides, Vaccines (immunotherapy), Gene therapies.

Contents

Unit I Chapter 1: Drug Absorption from the Gastrointestinal Tract
1.1.	Gastrointestinal Tract	13
1.2.	Mechanism of Drug Absorption	17
1.2.1.	Introduction	17
1.2.2.	Transcellular/Intracellular Transport	18
1.2.2.1.	Passive Diffusion	19
1.2.2.2.	Pore Transport	20
1.2.2.3.	Ion-Pair Transport	20
1.2.2.4.	Facilitated or Carrier-Mediated Transport	21
1.2.2.5.	Active Transport	23
1.2.3.	Paracellular/Intercellular Transport	26
1.2.4.	Vesicular/Corpuscular Transport - Endocytosis	26
1.2.5.	Role of Transporters in Drug Absorption	28
1.3.	Factors Affecting Drug Absorption	29
1.3.1.	Introduction	29
1.3.2.	Chemical Factors	29
1.3.3.	Physicochemical Factors	30
1.3.4.	Formulation Factors	40
1.3.5.	Physiological Factors	45
1.3.6.	Patient-Related Factors	50
1.4.	Dissolution Rate	52
1.4.1.	Introduction	52
1.4.2.	Noyes-Whitney Theory or Stagnant Film Theory	53
1.4.3.	Diffusion Layer Model or Film Theory	54
1.4.4.	Danckwert’s Model or Penetration or Surface Renewal Theory	55
1.4.5.	Interfacial Barrier Model or Double Barrier or Limited Solvation Theory	56
1.4.6.	Factors Affecting the Dissolution Rate	56
1.5.	Role of the Dosage Form in Gastrointestinal Absorption	61
1.5.1.	Introduction	61
1.5.2.	Solution (Elixir and Syrup) as a Dosage Form	61
1.5.3.	Suspension as a Dosage Form	62
1.5.4.	Capsule as a Dosage Form	63
1.5.5.	Tablet as a Dosage Form	64
1.6.	*Correlation of In Vivo* Data with In Vitro (IVIVC) Dissolution Data**	65
1.6.1.	Introduction	65
1.6.2.	Purpose of IVIVC	65
1.6.3.	Levels of IVIVC	66
1.6.3.1.	Level A Correlation	66
1.6.3.2.	Level B Correlation	67
1.6.3.3.	Level C Correlation	67
1.6.3.4.	Multiple Level C Correlations	67
1.6.3.5.	Level D Correlation	68
1.6.4.	Applications of an IVIVC	68
1.6.5.	Limitations in the IVIVC Arising from In Vivo Data	70
1.7.	Exercise	71
	Chapter 2: Transport Model
2.1.	Transport Model	76
2.1.1.	Introduction	76
2.1.2.	Permeability-Solubility-Charge State and the pH-Partition Hypothesis	77
2.1.3.	Properties of Gastrointestinal Tract (GIT)	81
2.1.4.	pH Microclimate	85
2.1.5.	Intracellular pH Environment	86
2.1.6.	Tight-Junction Complex	86
2.1.7.	Physiological Barriers	88
2.2.	Exercise	92
Unit II Chapter 3: Biopharmaceutic Considerations in Drug Product Design
3.1.	Biopharmaceutic Considerations in Drug Product Design	93
3.1.1.	Introduction	93
3.1.2.	Bioavailability	94
3.1.2.1.	Objectives of Bioavailability Studies	95
3.1.2.2.	Types of Bioavailability	95
3.1.2.3.	Biopharmaceutic Factors Affecting Drug Bioavailability	95
3.1.3.	Rate-Limiting Steps in Drug Absorption	99
3.1.4.	Physicochemical Nature of the Drug	102
3.1.5.	Factors Affecting Drug Product Performance	102
3.1.5.1.	Physicochemical Factors	102
3.1.5.2.	Biological Factors	106
3.1.5.3.	Formulation and Manufacturing Factors	106
3.2.	Exercise	108
	*Chapter 4: In Vitro* Drug Product Performance**
4.1.	*In Vitro* Dissolution and Drug Release Testing	110
4.1.1.	Introduction	110
4.1.2.	Need for Dissolution Testing	110
4.1.3.	In vitro Drug Dissolution Methods	111
4.1.4.	Drug Release Testing from Different Dosage Forms	111
4.1.5.	Significance of In vitro Dissolution and Drug Release Testing	114
4.2.	*Sink and Non-Sink Methods of In vitro* Dissolution Testing**	115
4.2.1.	Introduction	115
4.2.2.	Forced Convection Sink Methods	115
4.2.3.	Continuous Flow/Flow-Through Methods	117
4.2.4.	Natural Convection Non-Sink Methods	118
4.2.5.	Forced Convection Non-Sink Methods	119
4.3.	Compendial Methods of Dissolution	119
4.3.1.	Introduction	119
4.3.2.	Rotating Basket Apparatus (Apparatus 1)	121
4.3.3.	Rotating Paddle Apparatus (Apparatus 2)	123
4.3.4.	Reciprocating Cylinder Apparatus (Apparatus 3)	124
4.3.5.	Flow-Through Cell Apparatus (Apparatus 4)	125
4.3.6.	Paddle Over Disc Apparatus (Apparatus 5)	127
4.3.7.	Rotating Cylinder Apparatus (Apparatus 6)	128
4.3.8.	Reciprocating Holder Apparatus (Apparatus 7)	129
4.4.	Alternative Methods of Dissolution Testing	130
4.5.	Meeting Dissolution Requirements	132
4.6.	Problems of Variable Control in Dissolution Testing Performance of Drug Products	133
4.7.	*In Vitro-In Vivo* Correlation	135
4.8.	Dissolution Profile Comparisons	135
4.8.1.	Introduction	135
4.8.2.	Objectives of Dissolution Profile Comparison	135
4.8.3.	Methods to Compare Dissolution Profile	136
4.8.3.1.	Graphical Method	136
4.8.3.2.	Statistical Analysis	137
4.8.3.3.	Model Dependent Method	138
4.8.3.4.	Model Independent Method	144
4.9.	Drug Product Stability	149
4.9.1.	Introduction	149
4.9.2.	Adverse Effects of Instability of Drugs	149
4.9.3.	Factors Affecting Drug Stability	149
4.9.4.	Types of Drug Stabilities	151
4.9.5.	Importance of Stability Studies	153
4.10.	Considerations in the Design of a Drug Product	153
4.10.1.	Biopharmaceutic Considerations	153
4.10.2.	Pharmacodynamic Considerations	154
4.10.3.	Drug Substance Considerations	155
4.10.4.	Pharmacokinetics of the Drug	155
4.10.5.	Bioavailability of the Drug	156
4.10.6.	Dose Considerations	157
4.10.7.	Dosing Frequency	158
4.10.8.	Patient Considerations	158
4.10.9.	Route of Drug Administration	159
4.11.	Exercise	159
	Unit III Chapter 5: Pharmacokinetics
5.1.	Pharmacokinetics	161
5.1.1.	Introduction	161
5.1.2.	Objectives of Pharmacokinetics	162
5.1.3.	Basic Considerations of Pharmacokinetics	162
5.1.3.1.	Pharmacokinetic Parameters	163
5.1.3.2.	Pharmacodynamic Parameters	164
5.1.4.	Applications of Pharmacokinetics	165
5.2.	Pharmacokinetic Models	165
5.2.1.	Introduction	165
5.2.2.	Compartment Modeling	166
5.2.3.	Non-Compartmental Model	169
5.2.4.	Physiological Model	171
5.3.	One Compartment Model	172
5.3.1.	Introduction	172
5.3.2.	Assumptions of One Compartment Model	173
5.3.3.	Intravenous Injection (IV Bolus)	173
5.3.3.1.	Elimination Rate Constant (K_E)	174
5.3.3.2.	Elimination Half-Life (t_1/2)	176
5.3.3.3.	Apparent Volume of Distribution (V_d)	176
5.3.3.4.	Clearance (Cl_R)	177
5.3.3.5.	Total Body Clearance (Cl_T)	177
5.3.3.6.	Organ Clearance	178
5.3.3.7.	Area Under Curve (AUC)	180
5.3.4.	Intravenous (IV) Infusion	181
5.3.5.	Extravascular Administration	184
5.3.5.1.	Determination of Pharmacokinetic Parameters - C_max and t_max	186
5.3.5.2.	Elimination Rate Constant	186
5.3.5.3.	Absorption Rate Constant (K_a)	187
5.3.6.	Urinary Excretion Data	192
5.3.6.1.	Determination of Pharmacokinetic Parameters from Urine Data after Intravenous Bolus Administration	193
5.3.6.2.	Determination of Pharmacokinetic Parameters from Urine Data after Intravenous Infusion	196
5.3.6.3.	Determination of Pharmacokinetic Parameters from Urine Data after Extravascular Administration	196
5.3.7.	Advantages of One Compartment Model	197
5.3.8.	Limitations of One Compartment Model	198
5.4.	Multi-Compartment Model	198
5.4.1.	Introduction	198
5.4.2.	Two Compartment Open Model	200
5.4.3.	Two Compartment Open Model - IV Bolus	202
5.4.4.	Two Compartment Open Model - IV Infusion	206
5.4.5.	Two Compartment Open Model - Extravascular Administration	206
5.5.	Kinetics of Multiple Dosing	207
5.5.1.	Introduction	207
5.5.2.	Steady State Drug Levels	209
5.5.3.	Calculation of Loading and Maintenance Doses and their Significance in Clinical Settings	210
5.6.	Exercise	212
Chapter 6: Non-Linear Pharmacokinetics and Drug Interactions
6.1.	Non-Linear Pharmacokinetics	219
6.1.1.	Introduction	219
6.1.2.	Causes of Non-Linearity	220
6.1.3.	Michaelis-Menten Equation for Estimation of K_m and V_max	222
6.2.	Drug Interactions	227
6.2.1.	Introduction	227
6.2.2.	Types of Drug Interactions	227
6.2.3.	Mechanism of Drug Interactions	228
6.2.3.1.	Pharmaceutical Interactions	229
6.2.3.2.	Pharmacokinetic Interactions	229
6.2.3.3.	Pharmacodynamic Interactions	235
6.2.4.	Protein-Binding Interactions	237
6.2.4.1.	Plasma Protein Binding Sites	239
6.2.4.2.	Effect of Protein-Binding Interactions	241
6.2.4.3.	Kinetics of Protein Binding	243
6.2.4.4.	Clinical Significance of Protein-Binding of Drugs	245
6.2.5.	Effect of Tissue-Binding Interactions	246
6.2.6.	Cytochrome p450-Based Drug Interactions	247
6.2.7.	Drug Interactions Linked to Transporters	253
6.3.	Exercise	257
	Unit IV Chapter 7: Bioavailability and Bioequivalence
7.1.	Bioavailability	260
7.1.1.	Introduction	260
7.1.2.	Drug Product Performance, In Vivo	260
7.1.3.	Purpose of Bioavailability Studies	261
7.1.4.	Types of Bioavailability	261
7.1.4.1.	Absolute Bioavailability	261
7.1.4.2.	Relative Bioavailability	263
7.1.5.	Methods for Assessing Bioavailability	265
7.1.6.	Methods to Enhance Bioavailability of Poorly Soluble Drugs	269
7.1.7.	Significance of Bioavailability Studies	276
7.2.	Bioequivalence Studies	277
7.2.1.	Introduction	277
7.2.2.	Purpose of Bioequivalence Studies	278
7.2.3.	Types of Bioequivalence Studies	278
7.2.4.	Clinical Significance of Bioequivalence Studies	279
7.2.5.	Special Concerns in Bioavailability and Bioequivalence Studies	280
7.3.	Design and Evaluation of Bioequivalence Studies	282
7.3.1.	Introduction	282
7.3.2.	Protocol for Bioequivalence Studies	282
7.3.3.	Study Design	289
7.3.4.	Cross-Over Study Designs	290
7.3.4.1.	Latin-Square Cross-Over Study Design	292
7.3.4.2.	Balanced Incomplete Block Design (BIBD)	293
7.3.4.3.	Replicate Cross-Over Study Design	294
7.3.5.	Evaluation of the Data	295
7.3.6.	Bioequivalence Examples	297
7.3.7.	Study Submission and Drug Review Process	300
7.3.8.	Waivers of In vivo Bioequivalence Studies	302
7.4.	Biopharmaceutics Classification System (BCS)	304
7.4.1.	Introduction	304
7.4.2.	Objectives of BCS	304
7.4.3.	Classes of Drugs as per BCS	305
7.4.4.	Methods to Overcome Bioavailability Problems	306
7.4.5.	Permeability	307
7.4.5.1.	In vitro Methods of Permeability Assessment	307
7.4.5.2.	In situ Methods of Permeability Assessment	310
7.4.5.3.	In vivo Methods of Permeability Assessment	311
7.4.6.	Dissolution	311
7.4.7.	Significance of BCS	312
7.5.	Generic Biologics (Biosimilar Drug Products)	313
7.5.1.	Introduction	313
7.5.2.	Manufacturing Biosimilars	314
7.5.3.	Applications of Biosimilars	316
7.5.4.	Generic Substitution	316
7.6.	Exercise	318
	Unit V Chapter 8: Application of Pharmacokinetics
8.1.	Pharmacokinetics and Pharmacodynamics	323
8.1.1.	Introduction	323
8.1.2.	Relationship between Pharmacokinetics and Pharmacodynamics	324
8.2.	Modified-Release Drug Products	324
8.2.1.	Introduction	324
8.2.2.	Types of Modified-Release Drug Products	325
8.2.3.	Kinetics of Extended Release Dosage Forms	326
8.2.4.	Pharmacokinetics of Modified-Release Drug Products	327
8.2.5.	Pharmacodynamics of Modified-Release Dosage Products	328
8.3.	Targeted Drug Delivery Systems	329
8.3.1.	Introduction	329
8.3.2.	Types of Targeted Drug Delivery Systems	330
8.3.3.	General Considerations in Targeted Drug Delivery Systems	331
8.3.4.	Pharmacokinetics of Targeted Drug Delivery Systems	333
8.3.5.	Pharmacodynamics of Targeted Drug Delivery Systems	335
8.4.	Drug Interactions	336
8.5.	Biotechnology Drugs	336
8.5.1.	Introduction	336
8.5.2.	Pharmacokinetics and Pharmacodynamics of Biotechnology Drugs	336
8.6.	Proteins and Peptides	339
8.6.1.	Introduction	339
8.6.2.	Pharmacokinetics of Proteins and Peptides	340
8.6.3.	Pharmacodynamics of Proteins and Peptides	345
8.7.	Monoclonal Antibodies	346
8.7.1.	Introduction	346
8.7.2.	Production of Monoclonal Antibodies	346
8.7.3.	Pharmacokinetics of Monoclonal Antibodies	348
8.7.4.	Pharmacodynamics of Monoclonal Antibodies	350
8.7.5.	Applications of Monoclonal Antibodies	351
8.8.	Oligonucleotides	352
8.8.1.	Introduction	352
8.8.2.	Pharmacokinetics of Oligonucleotides	353
8.8.3.	Pharmacodynamics of Oligonucleotides	354
8.8.4.	Applications of Oligonucleotides	354
8.9.	Vaccines (Immunotherapy)	355
8.9.1.	Introduction	355
8.9.2.	Classification of Vaccines	356
8.9.3.	Pharmacokinetics of Vaccines	358
8.9.4.	Pharmacodynamics of Vaccines	359
8.9.5.	Applications of Vaccines	359
8.10.	Gene Therapy	359
8.10.1.	Introduction	359
8.10.2.	Types of Gene Therapy	360
8.10.3.	Strategies of Gene Therapy	360
8.10.4.	Pharmacokinetics of Gene Therapy	360
8.10.5.	Pharmacodynamics of Gene Therapy	361
8.10.6.	Applications of Gene Therapy	362
8.11.	Exercise	363

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