Samenvatting Pharmaceutical Medicine - KU LEUVEN

FARMACEUTICAL MEDICINE
INHOUDSOPGAVE

Introduction .......................................................................................................................................................... 13
definition ........................................................................................................................................................... 13
Farmaceutical medicine worldwide .................................................................................................................... 13
Authorization and administration of drugs .......................................................................................................... 13
FDA = FDA = food and drug administration ...................................................................................................... 13
The drug life cycle .............................................................................................................................................. 15
Drug discovery ............................................................................................................................................... 15
Three life periods:........................................................................................................................................... 15
Drug development.......................................................................................................................................... 16
1. Pre-clinical / non-clinical development........................................................................................... 16
2. Clinical development: Prof. J. de Hoon............................................................................................ 16
3. Post approval phase: ...................................................................................................................... 17
Guidelines that a farmaceutical company or researcher has to follow ......................................................... 17
Aim of the course ............................................................................................................................................... 17
Drug design and discovery (pt. 1) ......................................................................................................................... 19
Introduction ....................................................................................................................................................... 19
Management .................................................................................................................................................. 19
Objective Drug Discovery & Design ................................................................................................................. 19
Biology: target based or phenotypic discovery .................................................................................................... 20
Discovery & Design research antitumoral compounds .................................................................................... 20
In vitro antiproliferation assay (cells) .......................................................................................................... 20
In vivo antitumoral assay (animal)............................................................................................................... 20
In vitro kinase assay ................................................................................................................................... 20
In silico drug design (PC) ............................................................................................................................ 21
Phenotypic Drug Discovery (PDD) ................................................................................................................... 22
Target-based Drug Discovery (TDD) ................................................................................................................ 22
Loss-of-function vs inhibition ......................................................................................................................... 22
Opportunities and challenges in phenotypic drug discovery: an industry perspective ...................................... 23
Chain of translatability ............................................................................................................................... 23
improve ‘translatability’.............................................................................................................................. 23
Drug design and discovery (pt. 2) ......................................................................................................................... 25
Target deconvolution strategies in drug discovery ............................................................................................... 25
Affinity chromatography-based methods ........................................................................................................ 25
Expression-cloning-based methods ............................................................................................................... 27
Validation ...................................................................................................................................................... 27
Hit to lead .......................................................................................................................................................... 28


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, Objectives drug discovery and design ............................................................................................................. 28
Discovery testing (in TDD) ........................................................................................................................... 28
Pharmaceutical development .............................................................................................................................. 33
Introduction ....................................................................................................................................................... 33
Process of pharmaceutical development ........................................................................................................... 33
In the past vs. now.............................................................................................................................................. 34
Hurdles .......................................................................................................................................................... 34
STEP 1 in farmaceutical development = Pre-formulation: physicochemical and Biopharmaceutical aspects ....... 35
Currently available property predictions ......................................................................................................... 35
Solubility and in vitro dissolution rate ............................................................................................................. 35
Biopharmaceutics Classification System (BCS) .......................................................................................... 36
Dissolution rate .......................................................................................................................................... 36
Ionization behaviour ................................................................................................................................... 37
Partition coefficient / distribution coefficient: ............................................................................................. 37
Solid state properties of the API .................................................................................................................. 38
STEP 2 in farmaceutical development = formulation and process development .................................................. 41
Tablets ........................................................................................................................................................... 41
Immediate release tablets .......................................................................................................................... 41
Tablets in oral controlled drug delivery........................................................................................................ 41
Suspensions .................................................................................................................................................. 42
Creams and ointments ................................................................................................................................... 43
Gels ............................................................................................................................................................... 43
Transdermal therapeutic systems (TTS) ...................................................................................................... 44
Vaginal and intra uterine dosage forms ........................................................................................................... 44
Parenteral dosage forms ................................................................................................................................ 45
Injectable systems ..................................................................................................................................... 45
Controlled release ..................................................................................................................................... 45
Nano-sized drug delivery systems for drug targeting........................................................................................ 45
Requirements of an efficient drug targeting system ..................................................................................... 45
Passive vs active targeting .......................................................................................................................... 46
Clinical Drug Development: Part 1 ....................................................................................................................... 51
clinical research versus clinical trial? ................................................................................................................. 51
Phase I: from mice to man… ............................................................................................................................... 51
Non-clinical safety studies ................................................................................................................................. 52
What kind of information do you need to go into humans? ........................................................................... 52
These specific guidelines show us how long the study should last at least – in terms of species .................. 52
In non-clinical development we look at: ...................................................................................................... 52
Endpoints of non-clinical safety studies ..................................................................................................... 53
Maximal Recommended Starting Dose (MRSD) ................................................................................................... 53



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, Then it all went wrong ................................................................................................................................. 54
Maximal Anticipated Biological Effect Level (MABEL) – Pharmacological approach .............................................. 54
MRSD summary ................................................................................................................................................. 55
Phase I trial ........................................................................................................................................................ 56
Definition ....................................................................................................................................................... 56
Trial characteristics........................................................................................................................................ 56
Design ........................................................................................................................................................... 57
Types & timing ................................................................................................................................................ 58
Trial examples ................................................................................................................................................ 58
Clinical Drug Development: Part 2 ....................................................................................................................... 59
Phase II .............................................................................................................................................................. 59
What is a phase II clinical trial?....................................................................................................................... 59
study characteristics ...................................................................................................................................... 59
target selection for migraine ........................................................................................................................... 60
Target validation............................................................................................................................................. 61
Example os SAD/MAD phase I trial ...................................................................................................................... 62
Example of phase II trial: dose-finding ................................................................................................................ 62
Clinical Drug Development – Part 3 ...................................................................................................................... 63
Phase III ............................................................................................................................................................. 63
definition ....................................................................................................................................................... 63
clinical trials .................................................................................................................................................. 63
from study plan to protocol ................................................................................................................................ 63
Trial endpoints ............................................................................................................................................... 64
Clinical endpoint ........................................................................................................................................ 64
Surrogate endpoint .................................................................................................................................... 64
Biomarkers ................................................................................................................................................ 65
Trial design: RCT ............................................................................................................................................ 66
History ....................................................................................................................................................... 66
Procedure .................................................................................................................................................. 66
trial design ................................................................................................................................................. 67

• Treatment sequences ......................................................................................................................... 67

• Guarding validity ................................................................................................................................. 68
Phase IV ......................................................................................................................................................... 69
Real-life follow-up ...................................................................................................................................... 70
pharmacovigilance and rare events … ........................................................................................................ 70
Clinical drug development: part 4 ........................................................................................................................ 71
The classical approach: problems ...................................................................................................................... 71
Alternative approaches? .................................................................................................................................... 71
Exploratory Clinical Trial Applications (eCTAs) ................................................................................................ 71



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, What is it? .................................................................................................................................................. 71
characteristics OF Ecta’S ........................................................................................................................... 72
Added value ............................................................................................................................................... 72
microdosing or “phase 0” trials .................................................................................................................. 72
Biomarkers (human models / translational medicine) ..................................................................................... 74
Challenging trails ....................................................................................................................................... 74
A) Human challenging trials: controlled human infection model (CHIM) .............................................. 75
Platform trials & Master protocols .................................................................................................................. 76
umbrella trials ............................................................................................................................................ 77
basket / bucket trials .................................................................................................................................. 77
Clinical Drug Development: part 5 ....................................................................................................................... 79
Study design ...................................................................................................................................................... 79
hierarchy & level of evidence .......................................................................................................................... 79
observational/descriptive ............................................................................................................................... 79
Case report ................................................................................................................................................ 79
Case series ................................................................................................................................................ 79
observational/analytical study ....................................................................................................................... 80
case-control .............................................................................................................................................. 80
Cohort study .............................................................................................................................................. 81
experimental / analytical study ....................................................................................................................... 82
RCT ............................................................................................................................................................ 82
Summary/overview ........................................................................................................................................ 82
Meta analysis ................................................................................................................................................. 83
criteria for study classification........................................................................................................................ 83
explanatory versus pragmatic RCT .............................................................................................................. 83
centralized versus de-centralized trials ...................................................................................................... 85
Special populations.............................................................................................................................................. 87
Pediatrics .......................................................................................................................................................... 87
Learning objective .......................................................................................................................................... 87
developmental (dys)continuum throughout childhood .................................................................................... 87
developmental pharmacodynamics ............................................................................................................... 87
same concentration, different (magnitude) of effect ................................................................................... 88
same dose, other concentration ................................................................................................................. 88
Absorption, skin: BSA > permeability (integumentary development) ............................................................ 88
Absorption of drugs after oral administration .............................................................................................. 88
bio-availability............................................................................................................................................ 89
distribution volume .................................................................................................................................... 89
Covariates of drug metabolism ................................................................................................................... 89
Allometry matters to the BMW community ...................................................................................................... 90



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, drug-drug interactions (also) exist .................................................................................................................. 90
polymorphisms (individual genotypes for enzymes or receptors) matter ......................................................... 91
NAT-2, isoniazid ontogeny (slide 29) ........................................................................................................... 91
clearance &Excretion ................................................................................................................................. 91
how to conduct studies in this (and any special population) ............................................................................ 92
Methods (cf course Pharmacometrics) ....................................................................................................... 92
The legal setting has changed! .................................................................................................................... 92
ethics and logistics .................................................................................................................................... 92
Pregnancy .......................................................................................................................................................... 93
pregnancy-related physiological changes ....................................................................................................... 93
Example: amoxicillin clearance: T2 and T3 24 l/h, postpartum 13 l/h (+45%) ................................................ 94
Placenta-related drug transfer ........................................................................................................................ 94
‘active’ filter system + blood flows .............................................................................................................. 94
More than a passive filter!........................................................................................................................... 94
impact is time (gestational age) and organ specific: ‘teratology’ ...................................................................... 95
Examples ................................................................................................................................................... 96
lactation-related drug transfer ........................................................................................................................ 96
New labeling rules: descriptive instead of categorisation (FDA) ....................................................................... 96
Geriatrics ........................................................................................................................................................... 97
age-related organ changes affecting drug pharmacokinetics ........................................................................... 97
Drug-drug interactions ................................................................................................................................... 97
Pharmacodynamics and safety ...................................................................................................................... 97
Co-morbidity: Chronic kidney disease & Liver disease ........................................................................................ 98
pharmacokinetics of renal failure ................................................................................................................... 98
PK/PD in hepatic dysfunction ......................................................................................................................... 98
Physiologically-based pharmacokinetic (PBPK) modelling & simulation ............................................................ 99
introduction ....................................................................................................................................................... 99
Desired learning outcomes? ........................................................................................................................... 99
Biosimulation= using mathematics to understand biology .............................................................................. 99
Reculerpour mieuxsauter: : what is Modelling and Simulation (M&S)? ............................................................. 99
what is model-informed drug development (MIDD) ........................................................................................... 100
PMX (PKPD), QSP and PBPK… ....................................................................................................................... 100
Methodological aspects of PBPK modelling .................................................................................................. 100
Differences with other types of PK modelling ............................................................................................ 101
intrinsic/extrinsic factors on drug exposure .............................................................................................. 102
Overview of human PK prediction and evaluation methods ....................................................................... 103
Has there been an increase in throughput (HT) of PBPK models? ................................................................... 103
overview of common applications of physiologically based pharmacokinetic modelling in US FDA reguaroty
submissions ................................................................................................................................................ 104
CYP-specific Supersomes® .......................................................................................................................... 104


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, What did we learn from the experience with PBPK models in pharmaceutical industry? ..................................... 104
PBPK workflows consist of compiling system data and compound-specific data ........................................... 104
Model validation........................................................................................................................................... 105
PBPK modelling for paediatric populations ....................................................................................................... 106
Examples illustrating the use of PBPK modelling in paediatric populations? .................................................. 106
PBPK modelling to predict secretion of medicines to breastmilk? ..................................................................... 107
Model-informed drug development (MIDD) ........................................................................................................ 109
What’s all the fuss about? ................................................................................................................................ 109
What is MIDD? ............................................................................................................................................. 109
MIDD in practice .............................................................................................................................................. 109
Case 1: Caplacizumab ................................................................................................................................. 109
Schematic of the adult popPKPD model ................................................................................................... 110
Case 1: Caplacizumab (children) .............................................................................................................. 110
Take home messages ............................................................................................................................... 111
Case 2: Ocrelizumab .................................................................................................................................... 111
Take home messages ............................................................................................................................... 112
The ABCs of MIDD ............................................................................................................................................ 112
Scientific learning ........................................................................................................................................ 112
The MIDD wheel drives drug development .................................................................................................... 113
Top-down vs bottom-up modelling ............................................................................................................... 113
(semi-)mechanistic pharmacometrics models ............................................................................................. 113
Regulatory value of MIDD ............................................................................................................................. 114
Where is MIDD growing? ............................................................................................................................... 114
Challenges ahead ........................................................................................................................................ 114
Guidelines and Regulations in Clinical Research: an overview ......................................................................... 115
Guidelines and regulations: historical overview ................................................................................................ 115
1947: Nuremberg Code ................................................................................................................................ 115
1964: World Medical Association (WMA): Declaration of Helsinki .................................................................. 115
1997 ICH-Good Clinical Practice guidelines (GCP) ................................................................................ 117
2001 European Clinical Trial Directive (CTD) ......................................................................................... 117
The Belgian law on experiments in human beings (7 May 2004) ......................................................................... 118
The European perspective*: from CTD to CTR… ................................................................................................ 118
2014 European Clinical Trial Regulation: CTR… ..................................................................................... 118
2017 Belgian law: clinical trials on medicinal products .......................................................................... 119
2022 CTR implementation….................................................................................................................. 119
Summary and conclusions ............................................................................................................................... 120
Differences between small molecules and biologicals ..................................................................................... 121
Size and complexity ......................................................................................................................................... 121
Biologicals are not just “big chemicals” ............................................................................................................ 121



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, Biologicals – What’s in a name ......................................................................................................................... 122
Not 1 straight forward definition → multiple definitions................................................................................. 122
Different classes of biologicals ..................................................................................................................... 122
COVID-19 ................................................................................................................................................ 122
sAntibodies = Immunoglobulins (IgS) ................................................................................................................ 123
What’s different about antibodies? ............................................................................................................... 123
Mode of action ......................................................................................................................................... 123
Pharmacokinetics .................................................................................................................................... 124
Safety ...................................................................................................................................................... 125
Clinical development ............................................................................................................................... 126
A) Difference: study design ............................................................................................................... 126
B) Safety considerations when the IMP is an antibody ....................................................................... 127
C) PK and PD considerations when the IMP is an antibody ................................................................. 128
Conclusion: differences between small molecules and biologicals ................................................................... 129
Vaccine development......................................................................................................................................... 131
Introduction ..................................................................................................................................................... 131
What is a vaccine? ....................................................................................................................................... 131
difference between drugd and vaccines ........................................................................................................ 131
Why develop vaccines? ................................................................................................................................ 131
Vaccine types .................................................................................................................................................. 132
inactivated vaccines .................................................................................................................................... 132
Poliomyelitis – inactivated vaccine ........................................................................................................... 132
Toxoid vaccins: inactivated bacterial toxins .............................................................................................. 133
Whole pathogen vaccines: live attenuated ................................................................................................ 133
Subunit approach ........................................................................................................................................ 134
Example subunit vaccine: Nuvaxovid (NVX-CoV2373) ............................................................................... 134
The genetic approach (nucleic acid vaccine) ................................................................................................. 135
DNA vaccines........................................................................................................................................... 135
RNA vaccines ........................................................................................................................................... 135
Vector vaccines ....................................................................................................................................... 135
Preclinical studies............................................................................................................................................ 136
Clinical development: phase I ...................................................................................................................... 136
Clinical development: phase II ..................................................................................................................... 137
Clinical development: phase III .................................................................................................................... 137
Rotavirus vaccines: .................................................................................................................................. 137
Clinical development: phase IV .................................................................................................................... 137
Obstacles in vaccine development ............................................................................................................... 138
1. Choice of antigen/immunogen ..................................................................................................... 138
2. Overcoming pathogen diversity .................................................................................................... 139



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, 3. Defining correlate of protection .................................................................................................... 140
4. Delivery of antigen to immune system........................................................................................... 141
5. Route of immunization ................................................................................................................. 141
6. Antigen Dose ................................................................................................................................ 142
7. Number of vaccine doses ............................................................................................................. 142
8. Using adjuvants............................................................................................................................ 142
Therapeutic vaccines ....................................................................................................................................... 143
Recommendations: introduction of new vaccines......................................................................................... 144
In belgium: ............................................................................................................................................... 144
Implementation of vaccination programs ..................................................................................................... 145
Vaccine delivery to vaccinees: health care system .................................................................................... 145
Vaccine delivery to vaccinees: logistics .................................................................................................... 145
Regulations concerning marketing authorization (MA) and reimbursem........................................................... 147
Regulatory authorities for registration (MA/VHB) .............................................................................................. 147
Which regulatory and non-regulatory authorities have an impact on the availability of medicinal products in
EU/Belgium? ................................................................................................................................................ 147
Impact of regulations on MA? ....................................................................................................................... 147
practical requirements concerning the trail .................................................................................................. 147
Challenges for investigators ......................................................................................................................... 148
Within the EU: GDPR and impact on clinical trials ..................................................................................... 149
Process of MA – role of national agencies in the EU/EMA ................................................................................... 149
National Agencies: NCA = National Competent Authorities ........................................................................... 149
Critical Extrapolations –”bridging” ................................................................................................................ 150
European Medicines Agency ............................................................................................................................. 151
European Medicines Agency vs. European FDA ............................................................................................. 151
Role of EMA .................................................................................................................................................. 151
Human Medicines, HM ................................................................................................................................. 151
MA ............................................................................................................................................................... 151
phase III ....................................................................................................................................................... 152
CTD – Common Technical Document ............................................................................................................... 153
ICH guidelines.............................................................................................................................................. 153
Before CTD .................................................................................................................................................. 153
Common technical document ...................................................................................................................... 154
CTD triangle ................................................................................................................................................. 154
Central procedure: outcome of evaluation by CHMP..................................................................................... 154
Orphan medicines and “orphan designation” ................................................................................................... 155
Qualifying for a orphan designation .............................................................................................................. 155
Orphan medicinal products .......................................................................................................................... 155
Recent evolutions: CMA - ATMP – RMP – PRIME................................................................................................. 155
CMA............................................................................................................................................................. 155


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, Advanced Therapies = AT .............................................................................................................................. 156
Risk Management Plan = RMP....................................................................................................................... 156
Marketing and risks .......................................................................................................................................... 157
Biosimilars ................................................................................................................................................... 157
innovation ........................................................................................................................................................ 157
Definition ..................................................................................................................................................... 157
Value of innovation? Price for innovation? Affordability of innovation? .......................................................... 158
Conflict of interest (COI) and declaration of interest (DOI) ............................................................................ 158
Market ............................................................................................................................................................. 158
Pharmacovigilance ............................................................................................................................................. 159
Introduction ..................................................................................................................................................... 159
Some definitions .......................................................................................................................................... 159
Pre- and postmarketing ................................................................................................................................ 160
Pre-registration: GCP-requirements for pharmacovigilance ...................................................................... 160
When do you start with pharmacovigilance? ............................................................................................. 160
Definitions ............................................................................................................................................... 161

• Adverse event (AE) ............................................................................................................................ 161

• Adverse Drug Reaction (ADR) ............................................................................................................ 161

• Serious Adverse Event (SAE) .............................................................................................................. 162

• Unexpected Adverse Drug reaction ................................................................................................... 162

• Suspected unexpected serious adverse reaction (SUSAR) ................................................................. 162

• Adverse Event of Special Interest (AESI) ............................................................................................. 162

• Adverse drug event (ADE) .................................................................................................................. 163
Causality assessment ...................................................................................................................................... 163
Drafting a causality assessment ................................................................................................................... 163
But what can help?....................................................................................................................................... 164
Time of adverse event ............................................................................................................................... 164
dechallange ............................................................................................................................................. 164
Re-challenge ............................................................................................................................................ 165
Causality = YES ............................................................................................................................................ 165
Causality = NO or not clear ` ........................................................................................................................ 165
Pre-registration/GCP requirements regarding pharmacovigilance ..................................................................... 166
Clinical relevance and possible actions following an AE ................................................................................ 166
Determination of the clinical relevance/actions of an AE ............................................................................... 166
Impact of clinical relevance.......................................................................................................................... 166
Stopping rules – stopping criteria .................................................................................................................. 167
GCP/legal obligations for pharmacovigilance in clinical trials are the responsibility of…: ............................... 167
Data Safety Monitoring Board ........................................................................................................................... 169
Post-registration: requirements regarding pharmacovigilance .......................................................................... 170



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, Pre-registration pharmacovigilance is based on..: ......................................................................................... 170
Result can be market withdrawal: ................................................................................................................. 171
Reporting of ADR .......................................................................................................................................... 171
Post-registration: systematic follow up of safety .......................................................................................... 172
EudraVigilance Medicinal Product Dictionary (EVMPD) ............................................................................. 172
Periodic Safety Update Report (PSUR) ...................................................................................................... 172
Risk Management Plan (RMP) ................................................................................................................... 173
Post Authorization Safety Study (PASS) ..................................................................................................... 173
Drugs & society pt. I ............................................................................................................................................ 175
Introduction ..................................................................................................................................................... 175
from chemical comound … up to treatment .................................................................................................. 175
Regulatory agencies – national legislation..................................................................................................... 175
Regulatory aspects on drugs ............................................................................................................................ 176
Law on drugs 25 March 1964 - Updated pharmaceutical lesgislation 1 May 2006 ........................................... 176
Drug dispensed in the hospital – KB hospital pharmacy 4 march 1991 ........................................................... 176
Drugs can be used for their: .......................................................................................................................... 176
Nomenclature of drugs................................................................................................................................. 177
Conditions for nomenclature for drugs ..................................................................................................... 177
Classification of drugs (INN names).............................................................................................................. 178
Registered drugs .......................................................................................................................................... 178
How are brand names invented? .............................................................................................................. 179
Registered drugs and the danger of brand names ...................................................................................... 179
Indications of drugs ...................................................................................................................................... 179
Off-label use ................................................................................................................................................ 179
Why? ....................................................................................................................................................... 180
Advantages and disadvantages ................................................................................................................ 180
Conflict of interests .................................................................................................................................. 180
Registered drugs – different formulations ..................................................................................................... 181
Package ....................................................................................................................................................... 181
Cold chain management .............................................................................................................................. 182
Quality standards for drugs (and raw material).............................................................................................. 183
What is the pharmacopeia? ...................................................................................................................... 183
Extempore preparations/compounding ........................................................................................................ 183
Drugs & society pt. II ........................................................................................................................................... 185
Prescription ..................................................................................................................................................... 185
How are drugs dispensed in Belgium? .......................................................................................................... 185
Who is allowed to prescribe? ........................................................................................................................ 185
Prescription aspects .................................................................................................................................... 185
Drugs without prescription ........................................................................................................................... 186



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