NON CLINICAL DEVELOPMENT OF DRUG SPECIALITIES ________________________
2. Biopharmacie clinique
Bernard MARCHAND
Explo Explo
Preclinical Preclinical Stage Stage A A
Project Project
Bio Pharmaceutical Research
Phase Phase II
Preclinical Preclinical Stage Stage B B
Phase Phase II II
Toxicological and kinetics Expertises PK/PD
TOXICO ADME Salt Selection Phase I Formulation
Phase Phase III III
PK Interactions PB/PK
Up scaled Formulation
Population Kinetic Interspecies metabolism comparison Pharmaceutical File
NDA NDA
Post Post NDA NDA
New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis
PHASE 1 STUDIES Clinical Pharmacokinetics Phase I : dose tolerance 10000 20
AUC
15
Concentration
1000
10 5 0 0
30
60
90
120
Dose
100
10
1 0
6
12
18
Time (h)
Dosing 600-900 samples in real time
24
SINGLE DOSE PK GASTRO INTESTINAL TRACT
ORAL ROUTE
Administration
Bile First pass effect
Portal vein
LIVER TARGET ORGANS (TISSUES)
1000 Cmax Concentration
ABSORPTION 100
DISTRIBUTION + ELIMINATION
10
BLOOD CIRCULATION
AUC Exposure 1
0 tmax4
8
12 16 Time (h)
20
24
EXCRETION
Integration of physiological parameters and in vitro measurements
Kplung
Qheart Kpheart
Qtissues
Concentration
1000
100
10
1
Kptissues
0
4
Concentration
1000
12 16 20 24 Time (h)
Qmuscles
100
Kpmuscles
10
Q
1 0
8
4
8
12 16 20 24 Time (h)
Vmax Km
hepatic. a
Kp liver
Q portal v. fabs
DMPK ISSUES IN DRUG DEVELOPMENT
Bioavailability
Inter/intr Evaluation of simple Drug-drug a subject drug metabolism variability interaction parameters Intestinal absorption Metabolic stability Metabolic pathways P450 Isoenzymes Inhibition potential
Prediction of the main drug characteristics with respect to the entire population
Induction potential
Rebuild (predict) of the in vivo situation
PREDICTIONS IN VIVO Interindividual variability CYP1A1 CYP1A2
Concentration (µM)
CYP2C9
Extreme subjects of the simulation
Time (h)
IN VIVO PREDICTIONS Drug-drug interactions
1000
+ inhibitor Concentration
100
10
+
+ inductor 1 0
4
8
12 Time (h)
16
20
24
+
PHASE II PK/PD Pharmacokinetic / Pharmacodynamic Analysis 700
140
600
120
Effect
500
200 100
80
Plasma concentration Cp
40 20
0
50
Cp
1400 1200 1000 800 600
100
0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
2000 1800 1600
150
60
Effect
300
200
100
400
Direct effect Effect versus Cp
0 0 80 70
Ce
50
100
150
200
250
300
350
400
450
concentration
60
Effect
50 40 30 20
400 200 0
10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Delayed effect Effect versus Ce
Why a modelling approach?
Sustained release formulation
A clinical study per formulation
Pharmacodynamic objectives
PK/PD model : Relationship between plasma concentrations and effects PK model : Absorption, distribution, elimination Dissolution model : Relationship between In vitro and In vivo dissolution
Simulations
FORMULATION RESEARCH
Oral Route
Transmucosal Route Buccal Nasal Pulmonary
Injectable Route
Bolus and Infusion Slow Release Formulation
Tablets and Capsules Fast Dissolving Forms Slow Release Formulation Delayed Formulation
Transdermal Route
Patches Iontophoresis devices
ORAL ROUTE/PROLONGED RELEASE HYDROPHILIC MATRIX
Gastro intestinal fluids penetrate the polymer layer which, consequently, swells and forms a gel which controls the release kinetics of the drug substance
HPMC
H2 O
ORAL ROUTE / HYDROPHILIC MATRIX
In vitro dissolution profile
% 100
50 Prolonged Release Immediate Release
0 0
4
8
12
16
H
ORAL ROUTE / HYDROPHILIC MATRIX In Vivo 80
[ng/ml]
Immediate Release
60 Prolonged Release 40 20 0 0
24
48
72
H
ORAL ROUTE / PROLONGED RELEASE SEMI SOLID LIPOPHILIC MATRIX • Control of the release kinetics is obtained by the choice of the excipient and by its hydrophilic-lipophilic balance (HLB). • Manufacturing process, excipient melting, drug substance dispersion in the molten mass and, pouring into hard gelatin capsules
ORAL ROUTE / PROLONGED RELEASE MICROPARTICLES
• Multiparticulate dosage form as small spherical reservoir beads (0.5 à 1.5 mm diameter) • Dissolution rate controlled by a semipermeable membrane
PROLONGED RELEASE MICROPARTICLES Filters Semi permeable membrane Drug substance + Excipients
Coating solution
Hot air
ORAL ROUTE SUSTAINED RELEASE MICROPARTICLES
Steady-state plasma concentrations of the two different dosage forms IR 3 x day
100
Plasma concentration (ng/ml)
Drug Substance dissolved, %
In vitro dissolution rate of two different dosage forms
75 50
IR PR
25 0 0
4
8
12
Time (h)
16
20
24
PR 1 x day
90 80 70 60 50 40 30 20 10 0 72
78
84 Time (h)
90
96
102
ORAL ROUTE / DELAYED RELEASE
Drug substance released (%)
120 100 80 60 40 20 0 0
2
4
6
8
Time (h)
10
12
14
16
18
ORAL ROUTE / DELAYED RELEASE
plasma concentration (ng/ml)
8 7 6 5 4 3 2 1 0
IR DR
0
2
4
6
8
10
12
16
20
24
Time (h)
ORAL ROUTE DELAYED AND PROLONGED RELEASE MICROPARTICLES
Plasma Concentration
12 ng/ml
8
In vitro dissolution rate
Drug substance released (%)
100
4
50
0 0
4
8
12
16
Time (h)
0 0
4
8
12 Time (h)
16
20
24
Explo Explo
Preclinical Preclinical Stage Stage A A
Project Project
Bio Pharmaceutical Research
Phase Phase II
Preclinical Preclinical Stage Stage B B
Phase Phase II II
Toxicological and kinetics Expertises PK/PD
TOXICO ADME Salt Selection Phase I Formulation
Phase Phase III III
PK Interactions PB/PK
Up scaled Formulation
Population Kinetic Interspecies metabolism comparison Pharmaceutical File
NDA NDA
Post Post NDA NDA
New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis
POPULATION KINETIC
healthy subjects healthy subjects
Time Time
CL creat CL creat
Plasma concentration Plasma concentration
plasm a concentration plasm a concentration
renal impaired subjects renal impaired subjects
Plasma concentration Plasma concentration
CL CL
Population Analysis Analysis Population
Populationsimulations simulations Population (variability variability)) (variability variability))
Time Time
Bayesianfeedback feedback Bayesian
Time Time
Clearance Extrapolation
CL/F (L/h) 41 39 36 33 30 27 24 21 19 16 13 10 7 4 2 98
8
9
7 6 5 88
4 78
68
Age (Years)
58
3 48
38
28
2 18
1
CLcr (L/h)
Pharmacokinetics
Activity - Toxicity • • • • •
Therapeutic window Relation conc. / effects Side effects Toxicity Clinical etc.
• Absorption
PKcs
• • • •
Distribution Metabolism Elimination etc.
Regimen Clinical Factors • • • • • • •
Status of the patient Age, weight Stage of the illness Associated pathologies Associated treatments Compliance etc.
Other Factors • Administration routes
• Formulation • Tolerance - addiction • Drug interactions • Genetic Polymorphism • etc.
Explo Explo
Preclinical Preclinical Stage Stage A A
Project Project
Bio Pharmaceutical Research
Phase Phase II
Preclinical Preclinical Stage Stage B B
Phase Phase II II
Toxicological and kinetics Expertises PK/PD
TOXICO ADME Salt Selection Phase I Formulation
Phase Phase III III
PK Interactions PB/PK
Up scaled Formulation
Population Kinetic Interspecies metabolism comparison Pharmaceutical File
NDA NDA
Post Post NDA NDA
New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis
COHERENCE Analytical Methods Impurities Degradation products
REGULATORY CONSTRAINTS % Qualification
Pharmaceutical File
FORMULATION DESCRIPTION Diluting and lubrification agents Added excipients
PHARMACEUTICAL DEVELOPMENT
2 Definitions : Drug substance = Active substance (New Chemical Entity or existing drug substance ) Drug product = medicinal product = Finished product (tablets, capsules, …)
BEGINNING OF PHARMACEUTICAL DEVELOPMENT (1)
p
Physicochemical properties of the new drug substance qsolubility in water at different pH values qkinetics of dissolution as a function of particle size q........
p
Stability of the drug substance itself qstress conditions (acidic or basic pH, oxidation, temperature)
BEGINNING OF PHARMACEUTICAL DEVELOPMENT (2)
p Choice of salt and cristalin form for development - Solubility - Stability p Chemical compatibility drug substance/excipients p Formulations for phase I
Make crystals Microwell device (150 µl) with heating control for crystallization screening
Detected crystals
Measurement of their performances XR Diffractometry :
Proof of crystalline structure
Sorption gravimetry
(Dynamic Vapour Sorption – DVS)
Hygroscopicity
Dissolutest
Kinetic of dissolution
BEGINNING OF PHARMACEUTICAL DEVELOPMENT (2)
p Choice of salt and cristalin form for development - Solubility - Stability p Chemical compatibility drug substance/excipients p Formulations for phase I
TYPES OF FORMULATION / ORAL ROUTE
p Release of the drug substance qImmediate release (IR) qModified release (MR) qprolonged release qdelayed release
IMMEDIATE RELEASE TABLET
p Drug substance p Diluant (lactose, mannitol ....) p Binder (povidone,HPMC, maltodextrin ....) p Desintegrating agent (sodium starch glycolate,…) p Flowing agent (silica, talc ....) p Lubricant (magnesium stearate, stearic acid ....)
THE IDEAL FORMULATION (1)
p
Easy to manufacture, with a robust process giving always a quality product
p
Delivering the drug substance as needed according to its intrinsec pharmacokinetic properties (half-life, site of absorption......) and to the therapeutic needs : q prolonged release for a once-a-day formulation of a drug substance with a short half-life q quick Cmax to get an effect quickly q lower Cmax to decrease side effects q ......
p
Stable throughout the storage period q chemical stability of the drug q no evolution of the dissolution profile
INTERNATIONAL CONFERENCE OF HARMONISATION : I.C.H. PROCESS p
Since 1990
p
The aim: to standardize the studies to be performed for the registration of a new product in the 3 main geographical areas : • USA/Canada • Japon • European Union
p
3 topics • Safety (guidelines S) / Toxicology • Efficacy (guidelines E) / Clinical development • Quality (guidelines Q) / Pharmaceutical development
I.C.H. PROCESS Example : Stability for zone II p
p
Drug substance : q 3 batches q packaging representative of industrial packaging Drug product : q 3 batches (the size of 2 out of 3 is more than 1/10 that of industrial batches) q packaging chosen for the market
Conditions : q 25°C/60%RH throughout shelf-life q 30°C/60%RH (65%RH in 2005) 1 year q 40°C/75%RH 6 months p Time of analysis : q 0, 3 months, 6 months, 9 months, 1 year, 18 months, 2 years, 3 years p
MARKETING AUTHORISATION FILE DRUG SUBSTANCE
p
S.2 Preparation/synthesis
p
S.3 Characterisation (Physico-chemical properties, structure and qualification of impurities)
p
S.4 Control of drug substance
p
S.7 Stability
MARKETING AUTHORISATION FILE DRUG PRODUCT
p
P.1 Description and composition
p
P.2 Process development/validation
p
P.3 Manufacturing process
p
P.4 Excipients
p
P.5 Control of drug product
p
P.7 Container closure system
p
P.8 Stability B shelf-life and storage conditions
Change in Production Site
Up dating of the CMC File
New Specifications
) ) )
Improvment of Analytical Technics
Stability Solvants Impurities
SETTING THE SPECIFICATION OF THE ACTIVE PRINCIPLE
PHARMACOPEA
1st WAY
Consensus within competitors
2nd WAY
Before patent issue Monopole situation
COPIES AND COUNTERFEITS How to distinguish Real from False ? 1st pathway : Standard analysis criteria : ) ) )
purity profil dissolution content
2nd pathway : Qualitative and Quantitative Analysis of the Formulation
Which kind of products & results can be expected ? • “True” Counterfeit: looks exactly the same as drug company production (aspect, batch number,etc…) but everything is false
• Hybrid: True drug company tablets in a false packaging (even … a false blister)
•
Parallel Traffic: True durg company production but sold outside the right country ; illegal, except registered parallel importation (E.C)
• True/Authentic drug company product in the right area Not a counterfeit
Explo Explo
Preclinical Preclinical Stage Stage A A
Project Project
Bio Pharmaceutical Research
Phase Phase II
Preclinical Preclinical Stage Stage B B
Phase Phase II II
Toxicological and kinetics Expertises PK/PD
TOXICO ADME Salt Selection Phase I Formulation
Phase Phase III III
PK Interactions PB/PK
Up scaled Formulation
Population Kinetic Interspecies metabolism comparison Pharmaceutical File
NDA NDA
Post Post NDA NDA
New Formulation Pharmaceutical Support Regulatory Affairs Pharmacopoeia Copy Analysis
