Pharmaceutical Development with Focus
on Paediatric formulations
WHO/FIP Training Workshop
Hyatt Regency Hotel
Sahar Airport Road
Andheri East, Mumbai, India
28 April 2008 – 2 May 2008
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JM.AIACHE | April 2008
Bioavailability and bioequivalence
studies in paediatrics
Presented by: Jean-Marc AIACHE
Emeritus Professor,
Auvergne University,
Faculty of Pharmacy,
28 Place Henri Dunant
63000 Clermont-Ferrand,
France
jm.aiache@orange.fr
:
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JM.AIACHE | April 2008
In this presentation
 Introduction on B.A
*1-choice of subjects population
 B.A: when?
*2-choice of the dose
 B.A: how?
*3-design of studies: ways,,cross-over,dose
regimen, cond..of ad.,essay
 Design:2 ways, standard or population
kinetics.
 First Case: N.C.E.: Absolute B.A for
administration route
Relative B.A for best
formulation
 Second Case:" old” C.E.: Bioequivalence:
def, when, sampling on what ,how.
 Study design:
 .Bioequivalence and biowaivers:.,
 *choice of the reference D.P.
*parameters
*statistical analysis
*Ethics
*sampling
Conclusion
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JM.AIACHE | April 2008
General Definitions:Bioavailability
 The rate and extent to which the active ingredient or active moiety
is absorbed from a drug product and becomes available at the site
of action. (21 CFR 320.1. US)

(for drug product that are intended or not to be absorbed in the blood stream)
 Bioavailability means the rate and extent to which the active
substance or active moiety is absorbed from the pharmaceutical
form and becomes available at the site of action … (in the general
circulation) (EMEA CPMP/EWP/QWP)

(practical definition for substances intended to exhibit a systemic effect)
The evaluation of BA is made by data comparison of the BA
from tested product and the BA data from a solution,
suspension or IV dosage form.
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JM.AIACHE | April 2008
Drug Dosage
form
Type of DDF
Manufacturing
process
Technological
Factors of B.A
The technological factors have the same influence
Excipients
Liberation
in Adults
and children
except for dissolution rate due
Physical-chemical
crystals to the difference of volume of G.I tract liquids
Prop of API.
for example…and tasteDrug
of DFreleased
which increase the gastric secretion (Pavlov)
Solubility
Dissolution
Dissol. Rate
Absorbed drug
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Physiological factors influencing BD:
drug
They are fundamentallyDissolved
different from
adults.
Age ,race, metabolism state,
particularly
the A.D.M.E phenomena in children
Absorption
JM.AIACHE | April 2008
Subject, race, age,
sex, disease…,
What are the aims of the bioavailability
studies?
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First Case: New Chemical Entity (N.C.E)
 Determination of the best administration route:
Absolute Bioavailability
 Determination of the best formulation :
Relative Bioavailability and/or
Bioequivalence
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JM.AIACHE | April 2008
Absolute Bioavailability
 Compares the bioavailability (estimated as area under the
curve, or AUC) of the active drug in systemic circulation
following non-intravenous administration (i.e., after oral,
rectal, transdermal, subcutaneous administration), with
the bioavailability of the same drug following intravenous
administration( By definition, when a medication is
administered intravenously, its bioavailability is 100%).
 . For example, the formula for calculating F for a drug
administered by the oral route (po) is :
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JM.AIACHE | April 2008
Absolute Bioavailability: Results
ABA=1,same dose (solution), same AUC
Or
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Absolute Bioavailability: results about
different routes
Concentrations
I.V
I.M
S.C
Oral
Time
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Choice of the best formulation:
Relative Bioavailability
 It is used to choice the best formulation in a group of
DDF.
 It measures the bioavailability of a certain drug when
compared with another formulation of the same drug,
usually an established standard (solution or other one), or
through administration via a different route. The area
under the curve (AUC), Cmax and Tmax are used to
make comparisons.
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JM.AIACHE | April 2008
Results: Relative B.A
Same dose, same AUC ,but Cmax
and Tmax different:
onset and duration of action different!
What is the best one?
Tablet 1
Solution
Tablet 2
suspension
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JM.AIACHE | April 2008
Results: Relative Bioavailability
Solution
Concentration
Conventional
Tablet
New DDF
Same dose, same AUC, but Cmax
and Tmax different:
onset and duration of action different!
What is the best DDF for patients , child?
SR
0
Time
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JM.AIACHE | April 2008
Second Case: “Old C.E”:
Bioequivalence
 Based on the same principle of relative B.A.
 “Bioequivalence is the absence of a significant
difference in the rate and extent to which the
active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug
action when administered at the same molar dose
under similar conditions in an appropriately
designed study." :Bioavailabilities are similar
(Bioavailability and Bioequivalence Studies for Orally Administered Drug Products —FDA October
2000)
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Bioequivalence: When
 To compare a definitive dosage form (industrial batch!)
with the dosage form used in clinical trials developed and
evaluated ( Relative Bioavailability).
 To compare 2 dosage forms (containing “Old C.E”.)
administered by the same way, but with formulation or
Manufacturing Process different ,in the same company.
 To compare 2 dosage forms (containing “Old C.E” ) of
formulation and Manuf. Process unknown: ”Generics",
copies of an Innovator (considered as “reference”).
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JM.AIACHE | April 2008
Definition of Generics WHO
 The term generic product has somewhat different meanings in different jurisdictions. Use of
this term has therefore been avoided as far as possible, and the term multisource
pharmaceutical product is used instead (see the definition below). Multisource products
may be marketed either under the approved nonproprietary name or under a brand
(proprietary) name. They may be marketed in dosage forms and/or strengths different to
those of the innovator products.
 Multisource pharmaceutical products are pharmaceutically equivalent
products that may or may not be therapeutically equivalent. Multisource
pharmaceutical products that are therapeutically equivalent are
interchangeable.
 Where the term generic product is used, it means a pharmaceutical product,
usually intended to be interchangeable with the innovator product, which is
usually manufactured without a license from the innovator company and
marketed after expiry of the patent or other exclusivity rights.
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JM.AIACHE | April 2008
Methods for Bioequivalence : How? Methods for
1
1
assessing
BE
assessing BE
USA
 Pharmacokinetic study
EU
 Alternatively to classical BA studies
using pharmacokinetics end points to
 Pharmacodynamic study
 Comparative clinical study
 In vitro study
assess BE, other types of studies can be
envisaged, e.g. human studies with
clinical or pharmacodynamic end-points,
studies using animal models or in vitro
studies as long as they are appropriately
1.GUIDANCE FOR INDUSTRY
Bioavailability and Bioequivalence Studies for
Orally Administered Drug Products —
General Considerations
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JM.AIACHE | April 2008
justified and/or validated
1.Note for guidance on the investigation of BA and
BE (CPMP/EWP/QWP/1401/98, EU)
When PK-bioavailability determination or
bioequivalence studies have to be done in pediatric
population?.
 The answers can be found in the ICH topic E 11,
clinical investigation of medicinal products in
pediatric population, and in the note for guidance
on clinical investigation of medicinal products in
the paediatric population, CP M P/2711 /99.
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Paediatric Studies Decision Tree
if
the medicinal product is novel
Requisite
if
Relevant safety data come
from adult human exposure.
Repeated dose toxicity studies,
reproduction, toxicity studies
and genotoxicity tests
Unique paediatric indications or a
potential need for paediatric formulation
if
Medicinal products intended to treat serious
or life-threatening disease, occurring
in both adults and paediatric patient
yes
yes
Paediatric studies
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Pediatric Studies Decision Tree: PK-BA-BIE studies
Reasonable to assume (pediatrics vs adults)
 similar disease progression?
 similar response to intervention?
NO
YES TO BOTH
•Conduct PK studies
•Conduct safety/efficacy trials*
NO
Reasonable to assume similar
concentration-response (C-R)
in pediatrics and adults?
NO
Is there a PD measurement**
that can be use to predict
efficacy?
YES
•Conduct PK studies to achieve levels
similar to adults
•Conduct safety trials
YES
•Conduct PK/PD studies to get
C-R for PD measurement
•Conduct PK studies to achieve
target concentrations based on C-R
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•Conduct safety trials
These PK-BA-BIE Studies
 Should be performed to support formulation
development
 and determine pharmacokinetic
parameters
 in different age group to support dosing
recommendations.
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Studies design
 In general, pharmacokinetic studies in the
pediatric population should determine how the
dosage regimen in the pediatric population
should be adjusted to achieve approximately
the same level of systemic exposure that is
safe and effective in adults.
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Study design:
Choice of subjects population
 Definitive pharmacokinetic studies for dose selection across the
age ranges of paediatric patients in whom the medicinal product
is likely to be used shall be conducted in the paediatric
population.
 They are conducted in patients with the disease, even this may
lead to high inter subject variability than the studies in normal
volunteers, but the data better reflect clinical use.
 Phenotyping of subjects (possible side effects with “poor
metabolisers”) may cause drop-outs; variability
reduction/explanation
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Study design:
Choice of the doses
 Dosing recommendations for products used in the
paediatric population are usually based on
milligram/kilogram body weight up to a maximum dose.
 The dosing based on milligram/ square meter body
surface present numerous errors in measuring height or
length.
 In oncology surface/area guided dosing may be
necessary but extra care should be taken to ensure
proper for dose calculation
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JM.AIACHE | April 2008
Study design:
Choice of the doses
 Doses in initial studies require :
1)The Knowledge of ADME in an adult population combined with the physiologic development
of the intended pediatric study to modify the initial dose estimate.
(1) the relative bioavailability of the new formulation compared to the adult formulation;
(2) the age of the pediatric population;
(3) the therapeutic index of the drug;
( 4) pharmacokinetic data from the adult population; and
(5) body size of the pediatric study population
6)Subsequent clinical observations and prompt assay of biological fluids for the drug and/or its
metabolites should permit subsequent dose adjustment population..
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JM.AIACHE | April 2008
Study design: case of absolute B.A for
N.C.E
 Choice of Ad. route :
*1)For N.C.E. it is necessary to use for IV administration a true solution(in
appropriate drug concentrations for accurate and safe administration of
the dose) or a very fine emulsions or dispersion of the active ingredients
(in liposome) in an adequate and non-toxic solvent .This is the case also
when adult solution is not usable for children: very difficult to prepare!
*2)If I.V not possible, a solution has to be formulated administered either by
the oral route either by the chosen route.
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JM.AIACHE | April 2008
Example of Quinine
 Comparative in vitro-in vivo study of two quinine rectal gel
formulations.
 Fawaz F, Koffi A, Guyot M, Millet P.
 The main objective of this work was to develop and evaluate rectal
quinine paediatric formulations to treat acute uncomplicated
malaria attack in some African countries. Developed dosage forms
must be able to assure a prolonged release in the rectum but not
too much so as to avoid product expulsion by the child anus. Two
quinine rectal gels, namely mucoadhesive (MA) gel and
thermosensitive (TS) gel, containing 20 mg quinine base/g were
developed and evaluated in vitro and in vivo in the rabbit.
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JM.AIACHE | April 2008
Relative BA for N.C.E.:
choice of best formulation
For oral administration, different types of formulations,
flavors, and colors (, such as liquids, suspensions, and
chewable tablets) with different drug concentrations
Issues: the palatability of formulation must be studied in?
Adults?
Children?: school of taste
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JM.AIACHE | April 2008
Learning taste and testing for children
acid
bitter
Taste class-room
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JM.AIACHE | April 2008
sweet
salted
Design of Studies:2 ways
 The Standard Pharmacokinetic Approach
. It involves administering either single (if linear ) or multiple doses (steadystate, if non linear )of a drug to a relatively small (e.g., 6-12) group of subjects
with relatively frequent blood and sometimes urine sample collection. Both model
independent and model-dependent approaches can be used.
The Population PK Approach
A preferable approach in many pediatric situations: the population PK approach,
or study. This approach relies on infrequent (sparse) sampling (as few as 2-4)
samples per subject of blood from a larger population than would be used in a
standard pharmacokinetic study to determine pharmacokinetic measures and/or
parameters. The population PK approach is generally used in patients being
given the drug therapeutically.
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Design of studies: cross-over
 “The study should be designed in such a way that the formulation
effect can be distinguished from other effects. If the number of
formulations to be compared is two, a two-period, two sequence
crossover design is often considered to be the design of choice.
 Basic Postulate: each subject is his own reference, there is a wash
out period between the 2 administrations.
 Numerous types :latin square, incomplete block, balance design
(BIBD), sequential, etc.
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Study design:
Dose regimen
 For medicinal product with linear pharmacokinetics
in adults, single dose pharmacokinetic studies in
the paediatric population may provide sufficient
information for dosage selection.
 Any nonlinearity in absorption, distribution, and
elimination in adults, and any duration-of-effect related
changes would suggest the need for steady state studies
in the pediatric population
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JM.AIACHE | April 2008
Study design :
Conditions of administration
 For adults: fasten state or after a standardized meal: normal ,high
fat or…at a time perfectly determined.
 Full amount of water strictly fixed, no grapefruit nor other fruit juice
 No tobacco, nor other drugs (contraceptives).
 For children :depending of the age! From 3 to 8-10 years?
 Above, adults conditions
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General issues :
Conditions of administration
 From 0 to 3 years :fasten state ?method of administration
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General issues :
Conditions of administration
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JM.AIACHE | April 2008
General issues :
Conditions of administration
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JM.AIACHE | April 2008
Study design :
Conditions of administration and Food effect
 Bioequivalence studies for Food –effect on
formulation or food-drug interaction on adults,
children, in relation to Physiological factors.
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JM.AIACHE | April 2008
Exemple:Food-Effect in Bio study
 Sponsored by:National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK)Information provided by:National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK)ClinicalTrials.gov
Identifier:NCT00436878Purpose
 The purpose of this study is to test the effects of large food portions on children's
eating. Experiment 1 will test the effect of portion size on children's consumption
of sweetened beverages; we hypothesize that serving large beverage portions
will increase the amount of energy children consume from this food. Experiment
2 will test the effects of portion size on children's intake of fruits and vegetables
(FV) affect intake whether such effects are moderated by children's FV
preferences and; we hypothesize that serving large fruit and vegetable portions
will produce increases in children's intake of these foods, particularly for children
who like fruit and vegetables. Experiment 3 will evaluate how food energy density
affects children's response to large portions; we hypothesize that large portions
will have the greatest influence on children's energy consumption when foods are
energy dense. Experiment 4 will begin to address perceptual mechanisms by
which large portions affect children's eating.
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methodology: Essay of API or metabolites.
 Application of GLP;
 The methods should meet the requirements of specificity,
sensitivity, accuracy, precision reproducibility.
 The unchanged API has to be evaluated
 Or its active moiety or principal metabolite, or isomeric
parts.
 Issues of minimum dosing to essay the API
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JM.AIACHE | April 2008
i.e: Nevirapine: Doses
 PK profile:9 patients aged between 9 months and 14 years
administered after an overnight fast( 3 patients per dose level
equivalent to 7.5mg/m²,30.0mg/m² and 120mg/m²).
 Rapidly absorbed :peaks of 0.3,0.7 ,2.9 µg/ml respectively. AUC
and Cmax increase proportionally with the dose. Clearance was
0.91l/m²/h and T ½ 30.6+/-10.2h(adults 45 h)
 Population PK profile including 37 children: BSA and BW explain
the interpatient variation. Clearance increased non-linearly with
BW.
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JM.AIACHE | April 2008
Doses :Nevirapine
 Based on adult experience, a comparable lead-in period of two
weeks was suggested for paediatric population. A 4 mg/kg dose
is proposed for all children regardless the age. Although no
particular study has been performed to find the optimal lead-in
dose, this dose was considered acceptable considering the
enzyme induction to achieve initial antiretroviral activity.
The final recommended doses for the different ages are therefore
the following:
 Patients from 2 months to 8 years, 4 mg/kg once daily for 2
weeks followed by 7 mg/kg bid
 Patients from 8 years to 16 years are 4 mg/kg once daily
followed by 4-mg/kg bids.
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JM.AIACHE | April 2008
Relative BA and Bioequivalence
 Close methodology and design.
 Must be done for ALL GENERIC DRUG PRODUCTS and for all
dosage forms for routes of administration!!
 BUT there are dosage form exemptions.
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When Bioequivalence studies are not
necessary
.
 The following types of multisource pharmaceutical product are considered to
be equivalent without the need for further documentation:
 (a) when the pharmaceutical product is to be administered parenterally (e.g.
intravenously, subcutaneously or intramuscularly) as an aqueous solution
containing the same API in the same molar concentration as the comparator
product and the same or similar excipients in comparable concentrations as
in the comparator product.
 Certain excipients (e.g. buffer, preservative and antioxidant) may be
different provided it can be shown that the change(s) in these excipients
would not affect the safety and/or efficacy of the pharmaceutical product;
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JM.AIACHE | April 2008
When equivalence studies are not necessary
 (b) when pharmaceutically equivalent products are
solutions for oral use (e.g. syrups, elixirs and tinctures),
contain the API in the same molar concentration as the
comparator product, and contain essentially the same
excipients in comparable concentrations.
 Excipient(s) known to affect gastrointestinal (GI) transit,
GI permeability and hence absorption or stability of the
API in the GI tract should be critically reviewed
 i.e:aspirine:
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JM.AIACHE | April 2008
What are the best aspirin
effervescent tablets?
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JM.AIACHE | April 2008
When equivalence studies are not necessary
 (c) when pharmaceutically equivalent products are in the form of
powders for reconstitution as a solution and the resultant solution
meets either criterion (a) or criterion (b) above;
 (d) when pharmaceutically equivalent products are gases;
 (e) when pharmaceutically equivalent products are otic or
ophthalmic products prepared as aqueous solutions and contain
the same API(s)……
 (f) when pharmaceutically equivalent products are topical products
prepared as aqueous solutions and contain the same API(s) in the
same molar concentration and essentially the same excipients in
comparable concentrations
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When equivalence studies are not necessary
 (g) when pharmaceutically equivalent products are
aqueous solutions for nebulizer inhalation products or
nasal sprays, intended to be administered with essentially
the same device, and contain the same API(s) in the
same concentration and essentially the same excipients
in comparable concentrations.
 Some special dosage form where the physiological
factors are more important than technological factors:
enteric-coated DF depending on gastric emptying rate!
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JM.AIACHE | April 2008
When equivalence studies are not necessary
 Proportionally similar formulations
 (i) All active and inactive ingredients are exactly in the same proportions in
the different strengths (e.g. a tablet of 50 mg strength has all the active and
inactive ingredients exactly half that of a tablet of 100 mg strength, and
twice that of a tablet of 25 mg strength).
 (ii) For a high potency API, where the amount of the API in the dosage form
is relatively low (up to 10 mg per dosage unit), the total weight of the dosage
form remains nearly the same for all strengths (within ± 10% of the total
weight), the same inactive ingredients are used for all strengths, and the
change in strength is obtained by altering essentially only the amount of the
API(s).
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JM.AIACHE | April 2008
When equivalence studies are not necessary:
dose-proportionality of formulations
 A prerequisite for qualification for a biowaiver based on dose-proportionality
of formulations is that the multisource product at one strength has been
shown in in vivo studies to be bioequivalent to the corresponding strength of
the comparator product.
 The second requirement is that the further strengths of the multisource
product are proportionally similar in formulation to that of the strength
studied.
 When both of these criteria are met and the dissolution profiles of the further
dosage strengths are shown to be similar to that of the strength studied on a
percentage released against time basis, the biowaiver procedure can be
considered for the further strengths.
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JM.AIACHE | April 2008
Issues:
1)Choice of the reference drug product:
 “Test products are normally compared with the corresponding
dosage form of an innovator (based on date of first marketing or
first authorization) medicinal product (reference product)
marketed in the country..
 For EU,the innovator can be registered and marketed in one
country of union.
 Such an application can be considered acceptable unless there
is a significant difference between the reference products
originating from the same manufacturer (or it
subsidiaries/licensees), in terms of the qualitative and
quantitative composition in excipients.”
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JM.AIACHE | April 2008
Issues:
1)Choice of the reference drug product:
 Where the innovator product is not available, the product that is the market leader may be
used as a reference product, provided that it has been authorized for marketing and its
efficacy, safety and quality have been established and documented.
 In case of doubt ,the authorities should ask to the first country where the innovator is
registered, and all the documents must be supplied.
 WHO comparator product (see list TRS 902)
 ICH et al. innovator
 In case of BIE study during DDF scale–up, in vitro tests have to be done and a sufficient
amount of the batch must be kept for all the stability time + 1 year for control.
 The choice of reference product should be justified by the applicant. For example ,is it
possible to use an approved generic DP yet marketed? That is the question????
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JM.AIACHE | April 2008
Issues:
1)Choice of the reference drug product:
 Fixed combinations products Combination products
should in general be assessed with respect to
bioavailability and bioequivalence of individual active
substances either separately (in the case of a new
combination) or as an existing combination….
 The study in case of a new combination should be
designed in such a way that the possibility of a
pharmacokinetic drug-drug interaction could be detected.”
 The two products being compared may be different
brands, or different batches of the same brand, for
example when manufactured by different methods, at
different sites or according to different formulations.
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Fixed combinations products
 Interpretation of the results of bioavailability and
bioequivalence tests involves both quality and medical
considerations. For example it is not acceptable that
bioavailability is reduced or variable, when compared with
that of single entity products, because of poor
formulation, but an interaction between two actives that
leads to an increased bioavailability may be one of the
advantages that is taken into account when balancing
advantages and disadvantages.
 See section6.4 Bioavailability and bioequivalence of WHO Guidelines for
registration of fixed-dose combination medicinal products
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Issues:
2)Parameters
 The classical parameters have to be determined:
 Both direct (in example rate constant, rate profile), indirect( for
example C Max , Tmax , mean absorption time, mean residence
time, C Max normalized to AUC)
 AUCt and AUC(0-infinite)
 Fluctuation: (Cmax - Cam)/Cav
 Swing: (Cmax - Cmin)/Cmin
 Early exposure, peak exposure, total exposure.
 (The bioequivalence criterions are described in the official recommendations in USA and
EU.)
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Issues:
3) Statistical analysis
 “The statistical method for testing. bioequivalence is based upon the 90%
confidence interval for the ratio of the population means (Test/Reference), for the
parameters under consideration.”
 “Pharmacokinetic parameters derived from measures of concentration, e.g. AUC,
Cmax should be analysed using ANOVA. The data should be transformed prior to
analysis using a logarithmic transformation
 Covariates
The following covariates should ordinarily be obtained for each subject: height,
weight, body surface area, gestational age and birth weight for neonates, and
relevant laboratory tests that reflect the function of organs responsible for drug
elimination.
Concomitant and recent drug therapy should also be recorded.
The relationship between these parameters and the pharmacokinetics of the drug of
interest should be examined using suitable statistical techniques and study
designs.
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Issues:
3) Statistical analysis
 “AUC-ratio
– The 90% confidence interval for this measure of relative bioavailability
should lie within an acceptance interval of 0.80-1.25. In specific cases of a
narrow therapeutic range the acceptance interval may need to be tightened.
– In rare cases a wider acceptance range may be acceptable if it is based on
sound clinical justification.”
 “Cmax-ratio
– The 90% confidence interval for this measure of relative bioavailability
should lie within an acceptance interval of 0.80-1.25. In specific cases of a
narrow therapeutic range the acceptance interval may need to be tightened.
– In certain cases a wider interval may be acceptable. The interval must be
prospectively defined e.g. 0.75-1.33 and justified addressing in particular
any safety or efficacy concerns for patients switched between formulations
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Example: anti-epileptic drug products
 In France (and probably in Europe soon!) it is considered
that ,it is not recommended to substitute anti-epileptic
DDF in patients in where the steady-state is difficult to
reach.
 The modification (reduction) of confidence interval ,even
adopted by some European countries would not be
useful.
Furthermore there are no clear relationships between
plasma levels and efficacy . Pharmacokinetic parameters
are highly variable.
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JM.AIACHE | April 2008
Choice of subjects for Bioequivalence
studies
 BIE study in adults: the performance of the DDF can be
appreciated if the API has not a special metabolism in child (or
infant!).
 However to increase the essay sensitivity it could be
necessary to administer 2 or more children DDF to adults
, that may induce some errors in LADME and in the BIE
results !!
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XXDFNevirapine: relative Bioavailability
Nevirapine was readily absorbed (> 90 %) after oral administration in healthy
volunteers and in adults with HIV-1 infection.
A 3-way crossover study compared the bioavailability from three
production/commercial scale batches with varying dissolution profiles. All three
batches were bioequivalent with respect to systemic exposure (AUC). The
significantly different values for Cmax and tmax were considered not to be clinically
relevant.
In studies 1100.1231 and 1100.896 in which the suspension was administered
directly using a syringe, it was demonstrated that the suspension and tablet
formulations were comparably bioavailable with respect to extent of absorption. In
study 1100.1213 the suspension was administered in a dosing cup without rinsing.
The suspension intended for marketing was bioequivalent to the suspension used
during clinical trials but was not bioequivalent to the marketed tablets. This could be
attributed to incomplete dosing of the two suspensions since there was about 13 %
of the dose remaining in the cup.
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ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON MEDICINAL
PRODUCTS CONDUCTED WITH THE PAEDIATRIC POPULATION
 Recommendations of the ad hoc group for the
development of implementing guidelines for Directive
2001/20/EC relating to good clinical practice in the
conduct of clinical trials on medicinal products for
human use
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Issues:
7) Ethics in pediatric studies
 The paediatric population represents a vulnerable subgroup and it is
necessary to protect the rights of the study participants.
 The recruitment of study participants should occur in a manner free from
inappropriate inducement either to the parent is or the study participant.
 As a rule the paediatric subject is legally unable to provide informed
consent.
So they are dependent on their parents to assume responsibility for their
participation in the study, who will give their fully informed consent.
 Participants of appropriate intellectual maturity should personally sign
and date either a separately designed written assent form or the
written informed consent.
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Issues:
7) Ethics in pediatric studies
 It is important to minimize the distress and discomfort :
 use of topical anesthesia to place IV catheters, which have to be
indwelling catheters.
 Personnel knowledgeable and skilled in dealing with
the paediatric population.
 A physical setting with furniture, play equipment,
activity, and food appropriate to the age of population.
 A familiar environment such as the hospital or clinic where
participants is normally receive their care.
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Issues :
8) Sampling
 Normally:3 samples for each phase and 3 for
curve changes.
 For a one compartment model:9 samples (most
generally close to 12 to be sure to have
Cmax/Tmax
 For a 2 compartments model :15 samples to 24
(for modified release).
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Issues:
8 )Sampling Protocol
 The volume of blood withdrawn should be minimized in paediatric
studies.
 Use of sensitive essays.
 Use of laboratories experienced in handling small volume of blood.
 Use of indwelling catheters to minimize distress.
 Use of population pharmacokinetics and sparse sampling
based on optimal sampling theory to minimize the number of samples
obtained from each patient.
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Theorically!
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What to do for BIE studies in children??
 Use of BCS for API to waive the BIE study!
 :i.e anti-tuberculosis: fixed combination products of 4 molecules associated to fight
the resistance
 1) ethambutol (400mg) table p. 16), high solubility ,low permeability

2) pyrazinamide (table p. 24), high solubility, medium permeability.

3) rifampicine (150 mg) isoniazide (75 mg) (table p. 24 ): low solubility for rifampicine
high solubility for isoniazide, high permeability for rifampicine, and medium
permeability for isoniazide.
 4) rifampicine( 150 mg), isoniazide (75 mg) and pyrazinamide (400 mg)
 5) rifampicine (150 mg), isoniazide (75 mg), pyrazinamide (400 mg) and ethambutol
(275 mg).
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What to do for BIE studies in children??
 For anti tuberculosis drugs
 BIE for Isoniazide: metabolism problem and need to
“phenotype” the patients: high or low metabolism)
Rifampicine could be evaluated in vivo but !!!
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What to do for BIE studies in children??
 Study of the dosage form in vitro whatever the
BCS of the API if there is a reference as the
innovator and comparison with sharpness of
the dissolution curves and results. There is a
dissolution device for all the dosage form and
a lot of possibility for media!!
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JM.AIACHE | April 2008
What to do for BIE studies in children??
 It seems better to privilege the PD bioassays than PK
with sampling in children if it possible and so to
facilitate the determination of exposure /activity with
M.AC. than exposure /plasmatic levels, essentially for
antibiotics ,antiviral, anticancer drugs.
 Correlation IVIVC to be developed, as well as
extrapolation if there is a proof!!!
 CONCLUSION!!!!!!!!!
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Extrapolation of DATA
 A ).When a medicinal product is studied in paediatric patients in one region, the
intrinsic (for example pharmacogenetic) and extrinsic ( for example diet), factors
that could impact on the extrapolation of data to other regions should be
considered
 B.)When a medicinal product is to be used in the paediatric population for the
same indication as those studied and approved in adults, the disease process is
similar in adults and paediatric patients, and the outcome of therapy is likely to be
comparable, extrapolation from adult efficacy data may be appropriate. In such
cases, pharmacokinetic studies in all the age ranges of paediatric patient likely to
receive the medicinal product, together with safety studies, may provide
adequate information for used by allowing selection of paediatric doses that
will produce blood levels similar to those observed in adult
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Extrapolation of DATA
 C.) When a medicinal product is to be used in younger paediatric patient for the
same indication as those studied in older paediatric patient, the disease process
is similar, and the outcome of therapy is likely to be comparable, extrapolation of
efficacy from older to younger paediatric patient may be possible. In such cases,
pharmacokinetic studies in the relevant age groups of paediatric patients likely to
receive the medicinal product, together with safety studies may be sufficient to
provide adequate information for paediatric use.
 D.) This approach should be insufficient for medicinal product where blood levels
are known or expected not to correspond with efficacy or where there is concern
that the concentration-response relationship may differ between the adult and
paediatric population.
 E.) When the comparability of the disease course or outcome of therapy in
paediatric patient is expected to be similar to adults, but the appropriate blood
levels are not clear, it may be possible to use measurements of
pharmacodynamic effect related to clinical effectiveness to confirm the
expectation of effectiveness and to define the dose and concentration needed to
obtain that pharmacodynamic effect( example of analgesics, Ibuprofen)
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How to extrapolate?
 The answer:Simcyp Paediatric Simulator
 The Simcyp Paediatric Simulator allows pharmacokinetic behaviour
to be modelled in infants, neonates and children. This provides
valuable information relevant to first-time dosing decisions and the
design of clinical studies.
 The Simulator includes a full physiologically-based pharmacokinetic
(PBPK) model together with extensive libraries on demographics,
developmental physiology and the ontogeny of drug elimination
pathways. It allows population variability in pharmacokinetics to be
simulated over any age range and potential drug-drug interactions
to be quantified.
 Predictions can be made either from in vitro data, or from adult in
vivo values by retrograde modelling.
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 Simcyp Paediatric 2008 models pharmacokinetic
behaviour over any age range using in vitro data routinely
generated during drug discovery and development. This
allows ‘what-if’ questions to be explored in the safety of a
computer. The flexibility of the platform also allows
predictions to be made from adult in vivo values by
retrograde modelling.
 The Simcyp simulations are carried out in virtual
populations of children, rather than a single individual.
This produces ‘real world’ predictions and can identify the
characteristics of patients at the extremes of exposure.
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Many THANKS for Your Attention
Dziękuję Ďakujem dhanya-waad Дякую
bedankt ありがとう go raibh maith agat
tesekkürle Спасибо ‫ شكرا‬Thank yu
ً
Merci köszi tack så mycket
Thank you faleminderit
Shukriyâ Danke hvala díky kiitos
takk Obrigada
Mulţumesc nandri
Ευχαριστώ Grazie anugurihiitosumi ‫תודה‬
dhanya-waad
Muchas gracias
tack
너를 감사하십시요 ačiû Terima Kasih
mange
tak
aitäh děkuji vam
salamat
谢谢
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