Transcript particularites pharmacocinetiques en rapport avec la mucoviscidose

Société Française de la Mucoviscidose
Fédération des C.R.C.M.
Journées annuelles
Paris, 6 décembre 2007
Particularités pharmacologiques
de la mucoviscidose
Pr Gérard PONS MD, PhD
Groupe Hospitalier Cochin - St Vincent de Paul
René Descartes Medical School - University Paris 5
France
I – QUELLES PARTICULARITES ?
- PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA
MUCOVISCIDOSE
- PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA
MATURATION
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MUCOVISCIDOSE
ABSORPTION INTESTINALE
- vitesse d’absorption diminuée
- variabilité importante
- biodisponibilité non modifiée
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MUCOVISCIDOSE
DISTRIBUTION
- liaison aux proteines plasmatiques non modifiée
- volume de distribution plus élevé
(disparaît en normalisant par rapport à la surface
corporelle ou au poids maigre)
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MUCOVISCIDOSE
METABOLISME
- augmentation de l’activité de certaines voies du
métabolisme :
- CYP1A2, CYP2C8, pas CYPEC9, ni
CYP3A4
- glycuronyl transférase, sulfotransférase
- augmentation de la clairance hépatique
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MUCOVISCIDOSE
ELIMINATION
- augmentation de la clairance rénale
- filtration glomérulaire non modifiée
- sécrétion tubulaire nette augmentée
sécrétion sup réabsorption
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MUCOVISCIDOSE
ELIMINATION
- régulation coordonnée CFTR ()- PgP ()
- similarités structurelles (protéines ABC)
- similarités de localisation (membrane
apicale des cellules épithéliales)
- gènes sur chr 7q et même promoteur
BECAUSE CHILDREN ARE DIFFERENT
AS COMPARED TO ADULTS
DATA OBTAINED IN ADULTS
CANNOT SIMPLY BE EXTRAPOLATED
TO CHILDREN
using a proportionality rule
based upon body size
(weight or body surface area)
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA
MATURATION
ABSORPTION INTESTINALE
- Ralentie / dimnuée (?) chez lez
nouveau-nés
- Profil de maturation ensuite : ?
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MATURATION
DISTRIBUTION
EAU EXTRACELLULAIRE AUGMENTEE :
PREMIERE ANNEE DE LA VIE
- CONTENU EN GRAISSES AUGMENTE CHEZ LE
NOURRISSON
LIAISON AUX PROTEINES DIMINUEE :
PREMIERE ANNEE DE LA VIE
ALBUMINE : ACIDES FAIBLES – BILIRUBINE
1-GLYCOPROTEINES : BASES FAIBLES
 AUGMENTATION DES VOLUMES DE DISTRIBUTION
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MATURATION
METABOLISME
1- PROFILS DE MATURATION DIFFERENTS :
-A LA NAISSANCE
LA PLUPART DES VOIES DU METABOLISME SONT IMMATURES
CERTAINES VOIES SONT MATURES
- AU COURS DE LA CROISSANCE
-DEMETHYLATION DE LA CAFEINE : 4ème MOIS
-ACETYLATION DE LA CAFEINE : 2ème ANNEE
DE L’ISONIAZIDE : 4ème ANNEE
- GLYCURO CONJ. PARACETAMOL : GRAND ENFANT
2- ELIMINATION CHEZ LE NOURRISSON/ENFANT > ADULTE
THEOPHYLLINE, DIAZEPAM, PHENYTOINE, CARBAMAZEPINE,
CICLOSPORINE, DIGOXINE, MIDAZOLAM, LAMIVUDINE
PARTICULARITES DE LA PHARMACOLOGIE
CHEZ L’ENFANT
I - MODIFICATIONS PHARMACOCINETIQUES AU COURS
DE LA MATURATION
I-4 MODIFICATIONS ATTENDUES DES CAPACITES D ’ELIMINATION
EN FONCTION DE L ’AGE
NOUVEAU-NE
- CLAIRANCES DIMINUEES
- POSOLOGIES PLUS FAIBLES
- RISQUE DE SURDOSAGE
NOURRISSON
- CLAIRANCES AUGMENTEES
- POSOLOGIES PLUS ELEVEES
- RISQUE DE DOSE INEFFICACE
PARTICULARITES PHARMACOCINETIQUES
EN RAPPORT AVEC LA MATURATION
ELIMINATION
II – QU’EN FAIRE EN PRATIQUE ?
- THERAPEUTIQUE
- RECHERCHE
THERAPEUTIQUE
Adaptation individuelle de la
posologie
THERAPEUTIQUE
Adaptation individuelle de la
posologie
- Quand ?
- Quelles molécules ?
- Comment ?
THERAPEUTIQUE
Adaptation individuelle de la
posologie
- Quand ?
- RELATION DEMONTREE ENTRE
CONCENTRATION PLASMATIQUE ET EFFETS
(EFFETS SOUHAITES ET/OU
EFFETS INDESIRABLES)
- INTERVALLE THERAPEUTIQUE ETROIT
- GRANDE VARIABILITE INTERINDIVIDUELLE
MEME DOSE  DIFFERENTES CONCENTRATIONS
PLASMATIQUES
THERAPEUTIQUE
Adaptation individuelle de la
posologie
- Quelles molécules ?
- Aminosides
RECHERCHE CLINIQUE
Obstacles à surmonter
CHILDREN ARE DIFFERENT
THEREFORE CLINICAL STUDIES HAVE TO BE
PERFORMED SPECIFICALLY IN CHILDREN
BUT THEY …
1/ are more difficult to perform
2/ take longer
3) are more costly
… than in adults
PK & PK / PD STUDIES ARE
MORE DIFFICULT TO PERFORM IN CHILDREN
WHY ?
1) the reluctance of manufacturers
2/ invasiness is a limiting factor and has to be restricted
as much as possible
3/ the recruitment is more difficult than in adults
4) the age-related changes have to be taken into
account
5) appropriate tools have to be developped for the
measurement of drug effect
RECHERCHE CLINIQUE
Quelques solutions pour
surmonter ces difficultés
1) REGULATORY INCENTIVES AND
GUIDELINES
MAIN PILLARS OF THE REGULATION
. an expert committee :
the Paediatric Committee (PDCO)
. an agreed (evolving) Pædiatric
development :
the Paediatric Investigation Plan (PIP)
. a set of rewards and incentives
- For new and on-patent products
- For off-patent products
. a series of other tools for information,
transparency, and simulation of research
PAEDIATRIC INVESTIGATION PLAN
. is the basis for the development and
authorisation of a medicinal product
population subsets :
. Includes details of the timing and the
measures proposed to demonstrate
- Quality
Marketing
- Safety
Authorisation
- Efficacy
Criteria
. is to be agreed upon and/or amended by
the Paediatric Committee (PDCO)
. is binding on company
NEW PRODUCTS
. Currently unauthorised products :
-Obligation tu submit results compliant with
agreed Paediatric Investigation Plan (PIP) at
time of marketing autorisation (or invalid
application)
- Reward : 6-month extension of the patent
protection (Supplementary Protection
Certificate) – if compliance, autorisation in all
Member States, and information in Product
Information
RECENT PRODUCTS
. Authorised products with a patent
- Obligation tu submit results compliant
with agreed Paediatric Investigation Plan
(PIP) at time of new indication, new route
of administration, or new formulation (or
invalid application)
- Reward : 6-month extension of the patent
protection (Supplementary Protection
Certificate) – if compliance, autorisation in
all Member States, and information in
Product Information
“OLD” PRODUCTS
Off-patent products (Optional Procedure)
- Paediatric Use Marketing Authorisation (PUMA)
• Covers
Paediatric
indication
and
Formulation
• Need for Paediatric Investigation Plan and
Compliance
- Reward :10 years data protection/exclusivity
- Brand name can be retained
AVAILABLE EU GUIDELINES
ICH E 11 on Clinical Investigation of
Medicinal Products in the
Paediatric Population
Issued January 2001
2) INVASIVENESS HAS TO BE
MINIMISED
ISSUES TO BE FACED
INVASIVENESS




pain, stress
blood deprivation
irradiation
exposure to clinical studies and to
investigational new drugs … should be
limited to the minimum required
INVASIVENESS HAS TO BE MINIMISED
PROPOSED / USED CLUES
1- PREVENT PAIN AND STRESS
- BLOOD SAMPLING
- local anesthesia (EMLA cream),
- catheters
- ASSESSMENT OF EFFICACY
- non invasive procedures
(transcutaneous methods) ()
INVASIVENESS HAS TO BE MINIMISED
2- MINIMISE BLOOD LOSS
- SMALL BLOOD VOLUMES
- micro-assays
INVASIVENESS HAS TO BE MINIMISED
PK STUDIES
BLOOD SAMPLING : INVASIVENESS
PAIN, BLOOD LOSS
Limited volumes of blood samples
during childhood
29
12 year s
15
6 year s
7
1 year
5
3 m onth
3
Term neonate
1
Pr eter m infant
0
5
10
15
20
blood volume [m l]
25
30
INVASIVENESS HAS TO BE MINIMISED
2- MINIMISE BLOOD LOSS
- SMALL BLOOD VOLUMES
- micro-assays
- SMALL NUMBER OF SAMPLES
- PK and PK/PD:
population approaches ()
INVASIVENESS HAS TO BE MINIMISED
ALTERNATIVES FOR PK STUDIES
1) POPULATION APPROACH (POP-PK)
- few blood samples/patient
- many patients
2) RICH DATA INDIVIDUAL APPROACH
- many blood samples
- few patients
INVASIVENESS HAS TO BE MINIMISED
3- AVOID IRRADIATION
•THE PROBLEM
- IRRADIATION FROM RADIO-ACTIVE ISOTOPES
•THE SOLUTIONS :
- USE OF STABLE ISOTOPES () :
- BIOAVAILABILITY STUDIES
- PK REPEATED DOSES
- METABOLIC STUDIES
- CO2 BREATH TEST
- COMPLIANCE
- USE OF MICRODOSING () :
INVASIVENESS HAS TO BE MINIMISED
4 - MINIMISE EXPOSURE TO
CLINICAL STUDIES AND
INVESTIGATIONAL NEW DRUGS whenever possible
- AVOID UNECESSARY STUDIES
- extrapolation from adult data to the
lowest possible age limit
- use of the already available paediatric
data (literature, data on file …)
- ALTERNATIVE APPROACHES
AVOID UNNECESSARY STUDIES
1- EXTRAPOLATION
A - DIRECT EXTRAPOLATION
FROM ADULT DATA
- adjust the dose for a similar drug
systemic « exposure »
AVOID UNNECESSARY STUDIES
B - MODELLING THE INFLUENCE OF MATURATION
the knowledge of the ontogeny of the processes
involved in drug elimination (renal, hepatic,
metabolic pathways)
to determine the lower age limit for direct
extrapolation
and plan the paediatric PK studies
(OPTIMISATION OF AGE DISTRIBUTION IN THE RECRUITMENT OF
PATIENTS)
AVOID UNNECESSARY STUDIES
to model the influence of maturation ()
(using
a model of the maturational profiles of:
- PK : model the dose-concentration (plasma
concentration, AUC) relationship as a function of
age:
- renal elimination
- metabolic pathways: SimCYP, PKSim
assuming …
- PK-PD: similar plasma concentration-effect
relationship
otherwise model the concentration-effect relationship
AVOID UNNECESSARY STUDIES
2- USE OF AVAILABLE DATA
-bio-avalability studies
- BIOAVAILABILITY OF
PAEDIATRIC FORMULATIONS
IN HEALTHY ADULT VOLUNTEERS
AVOID UNNECESSARY STUDIES
2- USE OF AVAILABLE DATA
- bio-avalability studies: in adults
- population PK on published data
- POPULATION PK
Anderson B, Pons G et al, Paediatr. Anaesth, 2005, 15, 282-92
3) THE RECRUITMENT HAS TO BE
FACILITATED
RECRUITMENT HAS TO BE FACILITATED
PROBLEMS
1- NUMBER OF PATIENTS OFTEN LIMITED
- RARE DISEASES
- INFORMED CONSENT
MORE DIFFICULT TO OBTAIN
 clinical trials takes longer
 clinical trials may cost more
RECRUITMENT HAS TO BE FACILITATED
PROBLEMS
2- EXPOSURE TO CLINICAL TRIALS AND TO
INVESTIGATIONAL NEW DRUGS SHOULD BE
LIMITED TO THE MINIMUM REQUIRED
 Ethical issue: smallest possible numbers
 Validity of scientific data / acceptance by
regulatory bodies: numbers not too small
RECRUITMENT HAS TO BE FACILITATED
PROPOSALS :
INNOVATIVE METHODOLOGICAL
APPROACHES
 decrease the number of patients
- Clinical trial modeling and in silico simulation
avenue to explore
() :
a relatively new effort to devise in silico simulations of
human physiology and genetic variation.
RECRUITMENT HAS TO BE FACILITATED
PROPOSALS :
NETWORKS
 facilitate the recruitment of patients
- CRCM
- RIPPS
Assoc.
Parents
Conseil
scientifiqu
e
Autres
Réseaux
Européen
s
EMEA
PEDC
O
Assoc.
Parents
AFSSAPS
COP
Comité d’Interface
INSERM
Société Française de Pédiatrie
Comité
d’Orientation
stratégique
Formation
LEEM
Recherch
e
Qualité
Promoteurs Publics
Cellule
Logistique
Réseaux
spécialisés
CIC et URC
pédiatriques
Promoteurs privés
(CeNGEPS)
Réseaux
ville
RIPPS
Gestion
des données
Centres de Ressources
Biologiques
(collections)
Centres de
Biologie Spécialisée
Comité d’Interface
« INSERM - Société Française de Pédiatrie »
Comité
d’Orientatio
n
stratégique
Comité d’Interface
INSERM
Société Française de Pédiatrie
GROUPES DE REFLEXION THEMATIQUES
Programme
Galénique
Pharmacologie
PharmacoMéthodologie
de
Dispositifs
épidémiologie biologique
formation
Ethique
PK & PK / PD STUDIES ARE
MORE DIFFICULT TO PERFORM IN CHILDREN
WHY ?
1) the reluctance of manufacturers
2/ invasiness is a limiting factor and has to be restricted
as much as possible
3/ the recruitment is more difficult than in adults
4) the age-related changes have to be taken into
account
4) AGE-RELATED CHANGES
ISSUES TO BE FACED
PROBLEM:
AGE-RELATED CHANGES
 Age classes
AGE CLASSES
(ICH E-11)
- NEONATES (0-28 DAYS)
* PREMATURE (<37 w G.A.) OR TERM
* 0-7 DAYS ; 8-28 JOURS
- INFANTS (29 DAYS-23 MONTHS)
- CHILDREN (2 YEARS – 11 ANS )
- ADOLESCENTS (12 YEARS - 16-18
YEARS )
ISSUES TO BE FACED
PROBLEM:
AGE-RELATED CHANGES
 Age classes
 unequal size : related to maturational rate
 Small age-classe for neonate due to rapid developmental
changes (absorption, distribution, metabolism, excretion)
tailor the study design
 Inluence of gestational age / postnatal age
Post-conceptional age = gestational age + postnatal age
 The onset of puberty differs between individual
children – possible stratification boys / girls
ISSUES TO BE FACED
PROBLEM:
AGE-RELATED CHANGES
 Age classes (landmarks)
 Age as a continuous variable (calculation)
 Cut-off points
 Dosing recommandations
 Recruitment evenly distributed in the
clinically relevant age range
French Paediatric drug investigation
network (RIPPS) – Inserm / SFP
Workshop on
Potential role of modelling in
paediatric drug development
Paris, 6 July 2007
CONCLUSION (I)
- INNOVATIVE METHODOLOGIES ARE
POTENTIAL USEFUL TOOLS TO FACILITATE
DRUG EVALUATION IN CHILDREN
WHENEVER NECESSARY
- ARE NOT EXPECTED TO REPLACE
CLASSICAL APPROACHES
- THE LIMITS OF THE VALIDITY OF THESE
APPROACHES ARE TO BE EVALUATED FOR
AN APPROPRIATE LEVEL OF PROOF OF
EFFICACY AND SAFETY
CONCLUSION (II)
-DUE TO THE CONSTRAINTS OF DRUG
EVALUATION IN CHILDREN PAEDIATRIC
CLINICAL PHARMACOLOGY REPRESENTS A
CHALLENGING AREA FOR
METHODOLOGICAL CREATIVITY
WHICH MAY ULTIMATELY BENEFIT TO
OTHERS AREA OF CLINICAL
PHARMACOLOGY INCLUDING TO ADULTS
MERCI DE
VOTRE ATTENTION !