Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Protea Hotel
Victoria Junction, Waterfront
Cape Town, South Africa
Date: 16 to 20 April 2007
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April 2007
Pharmaceutical Development:
Bioavailability and bioequivalence in Paediatric medicine
Presenter: Jean-Marc AIACHE
Emeritus Professor,
Auvergne University,
Faculty of Pharmacy,
28 Place Henri Dunant
63000 Clermont-Ferrand, France
jm.aiache@wanadoo.fr
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Pharmaceutical Development
Outline and Objectives of presentation
 Definitions and relevance to paediatric medicines
 Relevance of paediatric pharmacokinetics
 Measurement
 Regulatory Aspects
 Formulation Strategies
 Ethical considerations in design and conduct of bioavailability
studies in children
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Definitions and relevance to paediatric
medicines
Bioavailability
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 1401/88 date for coming in operation January 2002
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F.D.A definition
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Comparison of definitions
 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)
 The rate and extent to which the active ingredient or active moiety
is delivered from a pharmaceutical form and becomes available in
the general circulation (CPMP/EWP/QWP/1401/98, EU)
(practical definition for substances intended to exhibit a systemic effect)
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F.D.A(cont..)
So this determination must be considered as a value of the
performance of the drug dosage form, quite as a parameter
of the dosage form.
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F.D.A(cont..)
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F.D.A (cont..)
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Bioavailability: why?
Where is the place of
Bioavailability in the future of a
dosage form in the human being?
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L.A.D.M.E.R. system
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Technological (galenicals!) Factors of B.A
Release
DDF
Free API
Disintegration
Absorption
Dissolution
Disagregation
Dissolved API
Absorbed drug
Dissolution
Enzymes
Intestinal
Flora
Lumen
T ablet
En
Inte
w
pGp
“First Pass E
Biopharmaceutical steps
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Drug Product
Type of DDF
Manufacturing
process
Excipients
crystals
Release
Physical-chemical
Prop of API.
Drug released
Solubility
Dissolution
Dissol. Rate
Dissolved drug
Absorption
Subject, race, age,
sex, disease…,
Absorbed drug
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relevance to paediatric medicines
 The technological factors have the same influence in
Adults and children ,except for dissolution rate due to the
difference of volume of liquids for example…and taste of
DF which increase the gastric secretion (Pavlov …)
 Physiological factors influencing BD: They are
fundamentally different from adults.
Age ,race, metabolism state, particularly the A.D.M.E
phenomena in children
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Modification of absorption phenomena
 Oral Route :Rate of intestinal absorption decreased in the
newborn.
 Gastric pH:
* no HCl in the newborn until the end of the first month
** the level of gastric secretion of adults is reached only after four to
six years.
 This can explain:
*the low absorption of weak acid like Phenobarbital and Aspirin and
**a better absorption of weak basic substances.
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Oral Route
 Gastric emptying rate is decreased in the newborn
 The half- life is about 90 minutes. At six to eight months this value
reach the adults value,80 min.
 the synthesis of biliary acid is quite of the half of adult value.
 This can explain the law absorption of lipid soluble substances,
essentially vitamins A.,E,.D and K.
 The bacteria in the colon come later after the birth and depend on
the type of food.
 The milk which is used largely generally reduces the absorption of
some products by adsorption;
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Rectal route
 The absorption is convenient in case of oral intolerance
and overall if the drug is administered in solution, like
enema for the treatment of convulsions with diazepam or
midazolam.
 The absorption is not so good after suppositories
administration.
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Intramuscular route
 The absorption rate is low and hazardous in the newborn
due to low blood flow rate in the muscles, a low amount of
muscle masses and low motor function of the baby.
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Cutaneous administration
 The skin absorption is more important in the newborn
than in adults.
 This can be explain by the elevated ratio between the
skin area and the weight, and by the elevated hydratation
of the stratum corneum.
 But this route is essentially used for topical application
and not for systemic activity
 The dosage form must be a administered
on a non injured skin .
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Other Modifications
 Distribution Volume:
The water soluble drugs will be prescribed at high doses
(amino glycosides, theophyllin, aminosides, penicillin,
cephalosporin, phénytoïn, vancomycin, bétalactamines …) in
premature newborn.
The lipid soluble drug (diazepam, Phenobarbital…) will be
prescribed at lower doses (high peak ,low VD)
 Protein Binding
 Evolution of metabolism organs.
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Consequences
 i.e., in the newborns absorption and elimination are
reduced, distribution volume increased. So the time
between 2 doses is large and it is to be noted that highly
protein bounded drug must be discarded.
 i.e. in the babies, the metabolism is accelerated,
distribution volume is high. So the single dose must be
more elevated but dosing interval smaller than in adults
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Question
 Do we have to do Bioavailability studies in babies and in
general in children?
yes
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Question
 Study of all dosage forms?
yes
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Clinical Investigation
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Pharmacokinetics
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Pharmacokinetics
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Pharmacokinetics
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Dose calculation:
area/weight.
Normogram
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Protocol
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Protocol
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Subjects
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Ethical issues in pediatric studies
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Ethical issues in pediatric studies
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Ethical issues in pediatric studies
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Ethical issues in pediatric studies
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Ethical issues in pediatric studies
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Ethical issues in pediatric studies
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Ethical issues in pediatric studies
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Ethical issues in pediatric studies
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Bioequivalence
 “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.”
Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General
Considerations Food and Drug Administration October 2000
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Bioequivalence
 “This definition emphasizes the use of pharmacokinetic
measures in an accessible biological matrix such as
blood, plasma, and/or serum to indicate release of the
drug substance from the drug product into the systemic
circulation.
 This approach rests on an understanding that measuring
the active moiety or ingredient at the site of action is
generally not possible and, furthermore, that some
relationship exists between the efficacy/safety and
concentration of active moiety and/or its important
metabolite or metabolites in the systemic circulation.”
Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food
and Drug Administration October 2000
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Bioequivalence
 Pharmacodynamic studies are not recommended for
orally administered drug products when the drug is
absorbed into the systemic circulation and a
pharmacokinetic approach can be used to assess
systemic exposure and establish BE.”
Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General
Considerations Food and Drug Administration October 2000
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Comparison of definitions
 Pharmaceutical equivalents or pharmaceutical alternatives whose
rate and extent of absorption do not show a significant difference
when administered at the same molar dose of the therapeutic
moiety under similar experimental conditions, either single dose or
multiple dose. (27 CFR 320.1(e)).
 Two medicinal products are BE if they are pharmaceutical
equivalents or pharmaceutical alternatives and if their
Bioavailabilities after the administration of the same molar dose
are similar to such degree that their effects, with respect to both
efficacy and safety, will be essentially the same
(CPMP/EWP/QWP/1401/98, EU)
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Definitions (CPMP/EWP/QWP/1401/98, EU)
 Pharmaceutical equivalents:
– Same amount active substance
– Same dosage forms
 Pharmaceutical alternatives:
– Same amount of active moiety
– In different chemical form or
– Different dosage form
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Bioequivalence : Why?
 “Prescribability refers to the clinical setting in which a practitioner prescribes
a drug product to a patient for the first time. In this setting, the prescriber
relies on an understanding that the average performance of the drug
product has been well characterized and relates in some definable way to
the safety and efficacy information from clinical trials.
 Switchability refers to the setting in which a practitioner transfers a patient
from one drug product to another. This situation arises with generic
substitution, as well as with certain post approval changes by an innovator
or generic firm in the formulation and/or manufacture of a drug product.
Under these circumstances, the prescriber and patient should be assured
that the newly administered drug product will yield comparable safety and
efficacy to that of the product for which it is being substituted.”
“Guidance for Industry Average, Population, and Individual Approaches to Establishing
Bioequivalence” Aug 1999
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Bioequivalence: When
 To compare 2 dosage forms administered by the same
way, but with formulation or Manufacturing Process
different ,in the same company.
 To compare 2 dosage forms of formulation and M.P
unknown: ”Generics”
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What is a Generic
 1st definition given in France(1963) by the Trade Minister:
“Copy of a drug product ,the production and marketing of
which are allowed after the patent caducity”.
It contains the same API, the same excipients, has the same
therapeutic effects and /or secondary and is administered
by the same route: TRUE COPY
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Definitions (CPMP/EWP/QWP/1401/98, EU)
 Essentially similar products:
–
–
–
–
Same qualitative-quantitative composition in active substances
Same dosage form*
Bioequivalent
*By extension for IR products the concept also applies to
different oral forms (tablets and capsules) with same active
substance.
– In France all the Essentially similar product to an innovator are
classified in a Generic family of” XXX”
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Bioequivalence on what???
 On a general point of view for all dosage forms for routes
of administration!!
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FDA / EMEA recommendations
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FDA / EMEA recommendations
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Bioequivalence : How?
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Methods for
assessing BE1
Methods for
assessing BE1
USA
UE
 Pharmacokinetic study
 Alternatively to classical BA studies
using pharmacokinetics end points to
 Pharmacodynamic study
 Comparative clinical study
assess BE, other types of studies can be
envisaged, e.g. human studies with
clinical or pharmacodynamic end-points,
 In vitro study
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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justified and/or validated
1.Note for guidance on the investigation of BA and
BE (CPMP/EWP/QWP/1401/98, EU)
Parameters
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Parameters
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Parameters
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Parameters
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Parameters
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Parameters
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Example: Nevirapine
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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April 2007
Example
 It has been later determined in a single dose study in 9 patients aged between 9 months
and 14 years administered after an overnight fast (3 patients per dose level equivalent to
7.5 mg/m², 30.0 mg/m² and 120.0 mg/m²).
 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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Bioequivalence: Compulsory???
Drug dependence and DF dependence
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J  PC
Permeability
Solubility and
Dissolution rate In vivo
Luminal degradation
•Same dissolution profile
•Formulation components do not alter permeability or intestinal transit
Amidon GL. Lennernas H. Shah VP. Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation
of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12(3):413-20, 1995
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Permeability
BCS classification
Class I: HS/HP
Class II: LS/HP
Verapamil, Propranolol
Metoprolol
Carbamazepine, Ketoprofen,
Naproxen
Class III: HS/LP
Class IV: LS/LP
Ranitidine, Cimetidine,
Atenolol
Furosemide,
Hydrochlorothiazide
Volume of aqueous buffer to dissolve the highest dose
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April 2007
Permeability classification
 What is a good permeability?
 How can we estimate intestinal permeability?
F  Fa  (1  Eg )  (1  Eh )
Eg= gut first-pass effects
Eh= liver first-pass effects
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Fa  1  e
(2 An )
Absorption number An
 Peff
An  
R


Tres
  (Tres ) 
T
abs

A high Permeability value ensures that the drug is completely absorbed
during its residence time in intestine. (in absence of formulation factors)
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 Solubility: How much is enough?
 Dissolution and solubility in what?
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Average physiological pHs in GI tract.
Fasted/fed
Site
fasted
Stomach
1.4 - 2.1
Duodenum
4.9 - 6.4
Jejunum
4.4 - 6.5
Ileum
6.5 - 8.0
Average pH
8
6
4
2
0
fasted
ileum
jejunum
duodenum
stomach
Adapted from Dressman et al. Pharm.Res 15(1) 11-22(1998)
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April 2007
Average physiological pHs in GI tract.
Fasted/fed
fasted
Stomach
Duodenum
Jejunum
Ileum
1.4 - 2.1
4.9 - 6.4
4.4 - 6.5
6.5 - 8.0
fed
3.0 - 7.0
5.1 - 5.2
5.2 - 6.2
6.8 - 8.0
Adapted from Dressman et al. Pharm.Res 15(1) 11-22(1998)
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8
8
veraraggeeppHH
AAve
Site
6
6
4
4
2
2
0
0
fasted
fasted
fed
ileum
ileum
jejunum
jejunum
duodenum
duodenum
stomach
stomach
Exemption criteria of IN VIVO
studies UE
 High solubility:
– When the active substance is highly soluble, the product could
be in general exempted from in vivo BE studies.
– The amount contained in the highest dose strength of an IR
product is dissolved in 250 mL of each of three buffers within
the range of pH 1-8 at 37ºC (preferably pH 1.0, 4.6, 6.8)
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Solubility: Dose/solubility ratio and Do dose
number
 D/S Gives the volume necessary to dissolve the given
dose of the active substance
Dose
 Do
D

250


Do 
 Cs 


Drug solubility
High solubility ensures that solubility is not likely to limit the dissolution and
therefore absorption.
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Dissolution rate: Dn dissolution
number
Solubility mg/mL
Diffusivity
5*10-6 cm2/s
 3 D   Cs
Dn  

2   
r  
Particle radius
~25m
Residence time
in small intestine
~180 min
Tres


T



 res
Tdiss

Density
~1.2mg/mL
Time required for
Complete dissolution
Rapid dissolution ensures that in vivo dissolution is not likely to be the rate limiting step
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Exemption criteria of IN VIVO studies
UE-EMEA
USA-FDA
 Rapid dissolution:
 Rapidly dissolving
– Demonstrate similarity of
dissolution profile between test
and reference in each of three
buffers within the range of pH 1-8
at 37ºC (preferably pH 1.0, 4.6,
6.8).
– In cases where more than 85% of
the active substance are dissolved
within 15 minutes, the similarity of
dissolution profiles may be
accepted as demonstrated.
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April 2007
– When no less than the 85% of
the labeled amount of the drug
substance dissolves within 30
mins using USP apparatus I
(100 rpm) or II (50 rpm) in a
volume of 900 mL or less in
each of the following media 0.1
N HCL, (or SGF without
enzymes) pH4.5 buffer, pH 6.8
buffer or SIF (without enzymes).
Biowaiver: permission to use dissolution test as a surrogate of
pharmacokinetic data: Dissolution test: In vitro Bioequivalence
EMEA/CPMP and FDA/BCS
 High solubility, pH 1-7.5
 High solubility, pH 1-8 (6.8)
(6.8)
 Linear and complete
absorption
 High permeability
(Fabs>90%)
 Rapid dissolution
(T85<30min,
pH=1.0,4.6,6.8)
 Rapid dissolution
(T85<30min,
pH=1.2,4.5,6.8)
 Excipients well established
(not large doses)
 Excipients currently
approved for IR Dosage
Forms (FDA Inactive
Ingredients List)
 Risk of therapeutic failures
 Non-NTI drugs
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Classify WHO Essential Drugs
 Readily available data (solubility)
 Easily Implemented Estimation (permeability)
 Provisional Classification
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WHO and US Drugs
 WHO
 US
 325 Medicines
 200 Drug Products
 260 Drugs
 141 Oral
 123 Oral IR
 43 on WHO List
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Merck Solubilities
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Solubility
assigned,
Descriptive Term
Parts of solvent required for
Solubility range,
(Solubility Definition)
1 part of solute
mg/ml
mg/ml
Very soluble (vs)
Less than 1
1000 and over
1000
Freely soluble (fs)
From 1 to 10
100 to 1000
100
Soluble (s)
From 10 to 30
33 to 100
33
Sparingly soluble (sps)
From 30 to 100
10 to 33
10
Slightly soluble (ss)
From 100 to 1000
1 to 10
1
Very slightly soluble (vss)
From 1000 to 10,000
0.1 to 1
0.1
Practically insoluble (pi)
10,000 and over
Less than 0.1
0.01
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April 2007
Solubility Classification
D
Percentage of immediate-release oral drugs
80.0
250
Do 
Cs
High Solubility Drugs
70.0
60.0
WHO
US
50.0
40.0
30.0
20.0
10.0
0.0
Dose numbe r ≤ 1.0
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Solubility ≤ 0.1 mg/ml Solubility ≤ 0.01 mg/ml
No solubility
information
Solubility Conclusions
 Majority of Drugs of the WHO list are High Solubility
(Do<1)
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Human Jejunal Permeability Data Base
Human fraction absorbed (%)
120
100
80
60
40
20
0
0
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2
4
6
8
10
Human jejunum permeability (x10-4 cm/s)
April 2007
12
D-glucose
Verapamil
Piroxicam
Phenylalanine
Cyclosporin
Enalapril
Cephalexin
Losartan
Lisinopril
Amoxicillin
Methyldopa
Naproxen
Antipyrine
Desipramine
Propanolol
Amiloride
Metoprolol
Terbutaline
Mannitol
Cimetidine
Ranitidine
Enalaprilate
Atenolol
Hydrochlorothiazide
Trend line
WHO Essential Drugs
 67% of WHO IR drugs are High Solubility
 68% of US Top 200 drugs are HS
 In Vitro Dissolution BE standard is applicable to the
majority of WHO Drugs
 Easily implemented, routinely conducted
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What to do for children??
 Use of BCS for API
 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!!
 Correlation IVIVC to be developed, but no extrapolation of
adult data to children, except in case of proof!!!
 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.
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Proposed BE Dissolution
Drug Solubility pH 1.2
Drug Solubility pH 6.8
Drug Permeability
I
High
High
High
II-A
High
Low
High
BCS Class
Preferred Procedure
>85% Dissolution in 15 min., pH = 6.8.
>85% Dissolution in 15 min., pH = 1.2.
>15 min at pH=1.2, then 85% Dissolution in 30 min., pH = 6.8;
F2>50; 5 points minimum; not more than one point > 85%.
II-B
Low
High
High
II-C
Low
Low
High
>15 min at pH=1.2; then 85% Dissolution in 30 min., pH = 6.8
plus surfactant*; F2>50; 5 points minimum, not more than one
point > 85%.
III
High
High
Low
>85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8.
IV-A
High
Low
Low
>85% Dissolution in 15 min., pH = 1.2.
IV-B
Low
IV-C
High
Low
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Slide 98 of 25
Low
April 2007
Low
Low
>15 min. at pH = 1.2; then 85% Dissolution in 30 min., pH =
6.8,; F2>50; 5 points minimum.; not more than one point >
85%.
>15 min at pH=1.2; then 85% Dissolution in 30 min., pH = 6.8
plus surfactant*; F2>50; 5 points minimum, not more than one
point > 85%.
Recent Examples of BA and BIE trials
 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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Slide 99 of 25
April 2007

Ibuprofen Effective for Acute Musculoskeletal Pain Relief in Children CME

News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD, FAAFP
Disclosures

Release Date: March 13, 2007; Valid for credit through March 13, 2008

Credits Available

Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians

March 13, 2007 — In a group of children randomly assigned to ibuprofen, acetaminophen, or codeine, ibuprofen was the most
effective for treating the pain of acute musculoskeletal injuries, according to the results of a study reported in the March issue of
Pediatrics.

"Our goal was to determine which of 3 analgesics, acetaminophen, ibuprofen, or codeine, given as a single dose, provides the most
efficacious analgesia for children presenting to the emergency department with pain from acute musculoskeletal injuries," write Eric
Clark, MD, from the University of Ottawa in Ontario, Canada, and colleagues. "Although there have been studies comparing the
pain relief provided by different oral analgesics in children postoperatively, there are no published randomized, controlled trials
examining the use of common oral pain medications for children with acute musculoskeletal injury in the ED [emergency
department]."

This study enrolled 336 children age 6 to 17 years with pain from a musculoskeletal injury to the extremities, neck, and back that
occurred in the preceding 48 hours before presentation in the emergency department. These children were randomized to receive a
single oral dose of 15 mg/kg of acetaminophen, 10 mg/kg of ibuprofen, or 1 mg/kg of codeine. Children, parents, and evaluators
were blinded to group assignment, and the main endpoint was change in pain from baseline to 60 minutes after treatment with
study medication, measured with a visual analog scale.

Of 336 patients randomized, 300 were included in the analysis of the primary outcome (100 in the acetaminophen group, 100 in the
ibuprofen group, and 100 in the codeine group). Age, sex, final diagnosis, previous analgesic given, and baseline pain score were
similar in the 3 groups.

At 60 minutes, improvement in pain score was significantly greater in the ibuprofen group (mean decrease, 24 mm) than in the
codeine group (mean decrease, 11 mm) and acetaminophen group (mean decrease, 12 mm). More patients in the ibuprofen group
achieved adequate analgesia (visual analog scale, < 30 mm) at 60 minutes than in the other 2 groups.
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Slide 100 of 25
April 2007

HIV Pharmacology Workshop: The dangers of breaking up tablets for paediatric dosing

printer friendly versionsend to friendglossarycomment Yasmin Halima, Monday, May 01,
2006Further evidence that dividing adult Triomune tablets for use by children may result in underdosing was presented last week at the HIV Pharmacology Workshop in Lisbon, and the workshop
also heard the first bioequivalence data on a paediatric tablet formulation of Triomune, called
Pedimune.
Triomune (a fixed dose combination of stavudine (d4T), lamuvdine (3TC) and nevirapine) is the
cheapest regimen available in much of sub-Saharan Africa, and is commonly prescribed to adults.
Attempts have been made to estimate doses for children by halving and quartering tablets, but it is
unclear if these doses are correct.
A European-African study involving the Radboud University and Nijmegen University in the
Netherlands, two African hospitals in Malawi and Zambia respectively and the UK Medical Research
Council (MRC) was carried out. The aim of the study was to investigate whether Triomune tablets that
are routinely divided for administration, deliver the same active ingredients, particularly in children
who are malnourished.
Tablets are difficult to split, the drugs are not equally distributed and there are no formal
recommendations on how to divide them with the distinct possibility of under-dosing.
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April 2007
 Bioavailability study results for new paediatric tablets for oral
suspension, and caution against splitting adult doses
 Polly Clayden, HIV i-Base
 All discussion concerning obstacles to paediatric scale up - both at
this conference and to date - has highlighted the lack of easily
stored, low cost, age appropriate antiretroviral formulations for
children.
 As an interim measure many programmes prescribe divided adult
fixed dose combinations (FDCs) but this is not without problems,
and can yield suboptimal levels of nevirapine, particularly in very
young children (see below). Obviously FDCs for children will be a
welcome development.
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April 2007
 Paediatric FDCs
 At the pharmacology (PK) workshop in Lisbon earlier this year, independent investigators presented
bioavailability data for Indian generic manufacturer Cipla’s Pedimune Baby and Pedimune Junior FDC
tablets of NVP, 3TC and d4T, which led them to conclude that it would be acceptable to begin testing
PK and dosing requirements of these formulations in African children even though the formal
bioequivalence study by Cipla has not yet been completed. [1, 2]
 Another Indian generic company, Ranbaxy has developed two new paediatric formulations of tablets
for oral suspension (TFOS) “designed to disintegrate quickly into a uniform suspension in small
volume of liquid media like water”.
 A poster from Singla and co-workers from Ranbaxy described the formulation development of TriviroLNS kid (3TC 20mg /nevirapine 35mg/d4T 5mg) and Triviro-LNS kid DS (3TC40mg / nevirapine 70mg
/ d4T 10mg) – which will provide NIH recommended doses of the drugs for children weighing 9-31kg.
[3]
 And in an oral presentation Manish Vermer reported findings from the company’s bioavailability study
of a single dose of the Triviro-LNS kids DS formulation compared to reference propriety liquid
formulations. [4]
 The investigators reported that the tablet has: a break line, “to enhance accuracy of dosing”; “a
pleasant orange flavour” and requires no specific measuring device or refrigeration. Time to
dispersion is 40 seconds in a small amount of water.
 The bioavailability study was an open label, single dose crossover study conducted in 36 fasting HIV
negative adult males.
 The investigators reported that the geometric mean ratios (% Test/Reference) of log-transformed
parameters of AUC, Cmax and 90% confidence intervals were within 80 -125% interval, see Table 1.
 They wrote “Therefore the two treatments were considered to be similarly bioavailable and they
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Slide 103
of 25
April
2007 paediatric triple ARV TFOS could be used in place of individual liquid
concluded
“Ranbaxy’s
novel
formulations.”
 MedlinePlus related topics: Thyroid Diseases
Genetics Home Reference related topics: Thyroid Diseases
 Study Type: Interventional
Study Design: Treatment, Randomized, Open Label, Active Control,
Crossover Assignment, Bio-equivalence Study
 Official Title: Generic vs. Name-Brand Levothyroxine: Assessment of Bioequivalence
Using TSH as a Marker in Children With Permanent Hypothyroidism
 Further study details as provided by Children's Hospital Boston:
 Primary Outcomes: Thyroid Stimulating Hormone Measure
Expected Total Enrollment: 40
 Study start: June 2006; Expected completion: January 2008
Last follow-up: January 2008; Data entry closure: January 2008
 This study is an unblinded, randomized controlled cross-over study, which involves taking
2 different forms of levothyroxine sequentially over a 16 week period. Subjects will have a
total of 3 visits over this time period. At the first visit, subjects are randomized to rec
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Slide 104 of 25
April 2007
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Slide 105 of 25
April 2007
 Purpose
 This is a randomized, double-blind, multi-centered study to compare 6 months of medical
treatment with digoxin or propranolol in infants with SVT Background: SVT is the most
common sustained arrhythmia of infancy. Neither digoxin nor propranolol has been
evaluated for pediatric use in a controlled trial in the context of SVT, yet both medications
are used frequently.
 Specific aims of the study:
 To determine whether propranolol and digoxin differ in the:
 Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or
digoxin
 Time to first recurrence of SVT in infants treated with propranolol or digoxin.
 Incidence of adverse outcomes in infants treated with propranolol or digoxin.
 Condition InterventionPhaseSupraventricular Tachycardia in Infants Drug: digoxin and
propranololPhase IIIMedlinePlus consumer health information
 Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Active Control,
Single Group Assignment, Bio-equivalence Study
 Official Title: Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With
Supraventricular Tachycardia
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Slide 106 of 25
April 2007
Asthma and gastroesophageal reflux disease (GERD) are common disorders, which
although are not usually lethal, both have high morbidity, and high healthcare costs. Recent
studies have demonstrated that asthma and GERD often co-exists, and that this coexistence is more frequent than just chance. Therefore, studies that characterize
associations between these conditions, and, help in the development of interventions will
positively impact the outcomes of these patients, which are critically needed.
Subjects that participate in this study are required to be between the ages of 4-11 years
old. This protocol proposes to enroll 50 children with asthma, on inhaled steroids who have
poor asthma control, defined on the basis of frequent symptoms, excessive beta-agonists
use, or frequent asthma episodes.
The purpose of this research study is to:
Determine, whether children with symptomatic, poorly controlled, asthma assigned to
treatment with a PPI( Proton Pump Inhibitor), have fewer asthma episodes than similar
participants assigned to placebo for a similar duration of time
Determine whether children treated with Lansoprazole ( i.e., proton pump inhibitor) : have a
longer time to first exacerbation, have improved lung function, improved asthma symptom
scores, improved quality of life, decreased rescue inhaler use, or other asthma
medications, reduced emergency room/urgent care/ physician office visits that are asthma
related.
Determine whether a subgroup of symptomatic asthmatics, who show a greater benefit
from PPI’s, can be identified.
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Slide 107 of 25
April 2007
 Ranbaxy presents bioequivalence data on two paediatric fixed dose triple
combination tablets
 printer friendly versionsend to friendglossarycomment Edwin J. Bernard,
Thursday, August 17, 2006Two fixed dose triple combination waterdispersible tablets produced by generic manufacturer Ranbaxy providing
half- and quarter-doses of nevirapine, lamivudine and stavudine for
paediatric use are bioequivalent to their proprietrary liquid formulations in
adults, according to a study presented to the Sixteenth International AIDS
Conference in Toronto on August 16th. The two formulations have already
been approved by the Indian government, and have been submitted to the
World Health Organisation (WHO) for inclusion on their pre-qualification list.
Several recent initiatives have begun to address the issue of lack of
paediatric formulations in low-income countries, first highlighted two years
ago at the Fifteenth International AIDS Conference in Bangkok by Médecins
Sans Frontières (MSF) director Daniel Berman.
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Slide 108 of 25
April 2007
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Slide 109 of 25
April 2007
Conclusion
 A new way for the future and a long way to solve all the
issues….
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Slide 110 of 25
April 2007
Further references
 Yu LX et al. Biopharmaceutics Classification System: The scientific basis for
biowaiver extensions. Pharm Res 2002 19(7).
 Polli J.E et al. Summary Workshop Report: Biopharmaceutics Classification
System- Implementation Challenges and Extension Opportunities. J Pharm Sci
2004 93(6)
 Vogelpoel H. et al. Biowaiver monographs for IR solid oral dosage forms based
on BCS literature data: Verapamil HCl, Propranolon HCL and Atenolol. 2004 J
Pharm. Sci. 93(8)
 Lindenberg et al.: Classification of orally administered drugs on the WHO model
list of essential medicines according to the biopharmaceutics classification
system. Eur. J. Pharm. Biopharm. 58: 265-278, 2004
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Slide 111 of 25
April 2007