Bio Availability Bio Equivalence En

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Training Workshop on PharmaceuticalDevelopmentwith a Focus on Paediatric Medicines /

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Training Workshop onPharmaceutical Development

with focus on PaediatricFormulations

Tallinn, Estonia

Date: 15-19 October 2007

Pharmaceutical DevelopmentPharmaceutical Development


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Pharmaceutical Development:Pharmaceutical Development:

Bioavailability and bioequivalence in Paediatric medicine

Presenter: Jean-Marc AIACHEEmeritus Professor,

Auvergne University,

Faculty of Pharmacy,

28 Place Henri Dunant

63000 Clermont-Ferrand, France

[email protected]


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Pharmaceutical DevelopmentPharmaceutical 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 bioavailabilitystudies in children


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Definitions and relevance to paediatric

medicines


medicines

Bioavailability

Bioavailability means the rate and extent to

which the active substance or active moiety isabsorbed 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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medicines


medicines

Bioavailability

The rate and extent to which the active

ingredient or active moiety is absorbed from adrug product and becomes available at the

site of action.

(21 CFR 320.1. US)


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Comparison of definitionsComparison of definitions

The rate and extent to which the active ingredient or active moiety isabsorbed 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)

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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DeterminationDetermination

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.

So this determination must be considered as a

value of the performance of the drug dosage

form, quite as a parameterof the dosage form.


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Bioavailability: why?Bioavailability: why?

Where is the place ofBioavailability in the future of a

dosage form in the human being?


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L.A.D.M.E.R. systemL.A.D.M.E.R. system


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Technological (galenicals!) Factors of B.ATechnological (galenicals!) Factors of B.A

DDF

Liberation

Free APIDissolution

Dissolved API Absorbed drug

Absorption


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Drug Dosage

form

Liberation

Drug released

Dissolution

Dissolved drug

AbsorptionAbsorbed drug

Type of DDF

Manufacturing

processExcipients

Physical-chemical

Prop of API.

Solubility

Dissol. Rate

crystals

Subject, race, age,

sex, disease,


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Relevance to paediatric medicinesRelevance to paediatric medicines

The technological factors have the same influence in Adultsand children ,except for dissolution rate due to the difference

of volume of G.I tract liquids for exampleand 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 phenomenaModification 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 sixyears.

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 RouteOral Route

Gastric emptying rate is decreased in the newborn

The half- life is about 90 minutes. At six to eight months this valuereach the adults value,80 min.

the synthesis of biliary acid is quite of the half of adult value: This can

explain the low absorption of lipid soluble substances, essentiallyvitamins A.,E,.D and K.

The bacteria in the colon come later after the birth and depend onthe type of food.

The milk which is used largely generally reduces the absorption ofsome products by adsorption;


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Rectal routeRectal route

The absorption is convenient in case of oral intoleranceand 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 routeIntramuscular route

The absorption rate is low and hazardous in the newborndue to low blood flow rate in the muscles, to low amount

of muscle masses and low motor function of the baby.


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Cutaneous administrationCutaneous 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 (except for pain treatment)

The dosage form must be a administered

on a non injured skin .


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Other ModificationsOther Modifications

Distribution Volume:

The water soluble drugs will be prescribed at high doses (aminoglycosides, theophyllin, aminosides, penicillin, cephalosporin,phnyton, vancomycin, btalactamines ) in prematurenewborn.

The lipid soluble drug (diazepam, Phenobarbital) will beprescribed at lower doses (high peak ,low VD)

Protein Binding

Evolution of metabolism organs.


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ConsequencesConsequences

i.e., in the newborns absorption and elimination arereduced, 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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QuestionQuestion

Do we have to do Bioavailability studies in babies and ingeneral in children?

yes


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QuestionQuestion

Study of all dosage forms?

yes


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Question:

When these studies are needed?

Question:

When these studies are needed?

For new drugs, and new drug product or dosageform: clinical studies ,pharmacokinetics studies

and/or BA studies

For generics: only Bioequivalence studies basedon BA evaluation or pharmacologic or therapeutic

comparisons.


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New drugsNew drugs

ICH Topic E 11

Clinical Investigation of Medicinal Products in the

Paediatric Population

NOTE FOR GUIDANCE ON CLINICAL INVESTIGATIONOF MEDICINALPRODUCTS IN THE PAEDIATRIC

POPULATION

(CPMP/ICH/2711/99)


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General principles.

Drug development programs should usually include the

paediatric patient population when a product is being

developed for a disease or condition in adults and it is

anticipated the product will be used into paediatric

population.


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Clinical InvestigationClinical Investigation

The decision to proceed with the Paediatric development program for a medicinalproduct involve consideration of many factors, including :

the prevalence of the condition to be treated in the Paediatric population

the seriousness of the condition to be treated

whether the medicinal product is novel or one of a class of compounds withknown properties

whether there are unique Paediatric indications for the medicinal product

the age range of pediatric patients likely to be treated with the medicinal product

unique Paediatric (developmental) safety concern with the medicinal product,including any nonclinical safety issue

potential need for paediatric formulation development


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Clinical InvestigationClinical Investigation

Of these factors, the most important is the presence of seriousor life-threatening disease for which the medicinal productsrepresent a potentially important advance in therapy.

It should be noted that the most relevant safety data for

paediatric studies ordinarily come from adults humanexposure. Repeated dose toxicity studies, reproduction toxicitystudies and genotoxicity tests would generally be available.

All these studies requires adequate dosage forms: solutions

etc..


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Clinical Investigation: Timing of studiesClinical Investigation: Timing of studies

. The timing of paediatric studies will depend on the medicinal product,the type of disease being treated, safety considerations, and the

efficacy and safety of alternative treatments.

First case: Medicinal products for disease dominantly or

exclusively affecting paediatric patient.

The entire development program will be conducted in the paediatric

population except for initial safety and tolerability data, which will

usually be obtained in adults. Some products may reasonably be

studied only in the paediatric population even in the initial phase, forexample when studies in adults who yield little useful information or

expose them to inappropriate to risk


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Clinical Investigation: Timing of studiesClinical Investigation: Timing of studies

Second case. :Medicinal products intended to treatserious or life-threatening disease, occurring in bothadults and paediatric patient, for which there arecurrently no or limited therapeutic options.

If the product represents a potentially important advance in therapy,

there is a need for relatively urgent and early initiation of paediatricstudies.

Third case. :Medicinal products intended to treat otherdisease and conditions.

There is less urgency than in the previous cases and studies wouldusually begin at later phases of clinical development


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Clinical Investigation: Type of studies:Clinical Investigation: Type of studies:

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.


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When a medicinal product is to be used in the paediatric populationfor the same indication as those studied andapproved in adults, the disease process is similar in adults andpaediatric patients, and the outcome of therapy is likely to be

comparable, extrapolation from adult efficacy data may

be appropriate. In such cases, pharmacokinetic studiesin all the age ranges of paediatric patient likely toreceive the medicinal product, together with safetystudies, may provide adequate information for used byallowing selection of paediatric doses that will produce blood levelssimilar to those observed in adult. If this approach is taken, adultspharmacokinetic data should be available to plan the paediatricstudies


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When a medicinal product is to be used in younger paediatric patient for the

same indication as those studied in older paediatric patient, the diseaseprocess is similar, and the outcome of therapy is likely to be comparable, extrapolationof efficacy from older to younger paediatric patient may be possible. Insuch cases, pharmacokinetic studies in the relevant age groups of paediatricpatients likely to receive the medicinal product, together with safety studies may besufficient to provide adequate information for paediatric use.

This approach should be insufficient for medicinal product where bloodlevels are known or expected not to correspond with efficacy or wherethere is concern that the concentration-response relationship may differbetween the adult and paediatric population.

.


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When the comparability of the disease course or outcome of therapyin 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 theexpectation of effectiveness and to define the dose andconcentration needed to obtain that pharmacodynamic effect.

Thus a PK/PD approach combined with safety and other relevantstudies could avoid the need for clinical efficacy studies.


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Fortopical active product, extrapolation of efficacyfrom one patient population to anothermay be based

on studies that include pharmacodynamic

and / or appropriate alternative assessment.

Local tolerability studies may be needed. It may beimportant to determine blood levels and systemic effects

to assess safety.


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PharmacokineticsPharmacokinetics

Pharmacokinetic studies should be performed to support formulationdevelopment and determine pharmacokinetic parameters in

different age group to support dosing recommendations.

Relative bioavailability comparisons of paediatric

formulation with the adults oral formulation typically shouldbe done in adults.

Definitive pharmacokinetic studies for dose selection acrossthe age ranges of paediatric patients in whom the medicinal product is likely

to be used shall be conducted in the paediatric population.


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PharmacokineticsPharmacokinetics

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.

For medicinal product with linear pharmacokinetics

in adults, single dose pharmacokinetic studies in

the paediatric population may provide sufficient

information for dosage selection.


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Pharmacokinetics: dosesPharmacokinetics: doses

Dosing recommendations for products used in the paediatricpopulation 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 butextra care should be taken to ensure proper for dose calculation


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Pharmacokinetics: ProtocolPharmacokinetics: Protocol

The volume ofblood withdrawn should be minimized in paediatricstudies.

Use ofsensitive essays.

Use oflaboratories experienced in handling small volume of blood.

Use ofindwelling catheters to minimize distress.

Use ofpopulation pharmacokinetics and sparse sampling

based on optimal sampling theory to minimize the number of samplesobtained from each patient.


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Ethical issues in pediatric studiesEthical issues in pediatric studies

The paediatric population represents a vulnerable subgroup and it isnecessary to protect the rights of the study participants.

The recruitment of study participants should occur in a manner free frominappropriate 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 theirparticipation in the study, who will give their fully informed consent.

Participants ofappropriate intellectual maturity should personally sign

and date either a separately designed written assent form or the writteninformed consent.


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Ethical issues in pediatric studiesEthical issues in pediatric studies

It is important to minimize the distress and discomfort : use oftopical 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 whereparticipants is normally receive their care.


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BioequivalenceBioequivalence

Bioequivalence is the absence of a significantdifference in the rate and extent to which theactive ingredient or active moiety inpharmaceutical equivalents or pharmaceuticalalternatives becomes available at the site of drug

action when administered at the same molar doseunder similar conditions in an appropriatelydesigned study.

Bioavailability and Bioequivalence Studies for Orally Administered Drug Products GeneralConsiderations Food and Drug Administration October 2000


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BioequivalenceBioequivalence

This definition emphasizes the use of pharmacokineticmeasures 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.

Bioavailability and Bioequivalence Studies for Orally Administered Drug Products General Considerations Food and

Drug Administration October 2000


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Comparison of definitionsComparison of definitions

Pharmaceutical equivalents or pharmaceutical alternatives whoserate 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

similarto 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)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

Bi i l Wh ?Bi i l Wh ?


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Bioequivalence : Why?Bioequivalence : Why?

Prescribability refers to the clinical setting in which a practitioner

prescribes a drug product to a patient for the first time.

Switchabilityrefers to the setting in which a practitioner transfersa patient from one drug product to another. This situation arises

with generic substitution,

Guidance for Industry Average, Population, and Individual Approaches to Establishing

Bioequivalence Aug 1999


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Bioequivalence: WhenBioequivalence: When

To compare 2 dosage forms administered by the sameway, 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 GenericWhat is a Generic

1st definition given in France(1963) by the Trade Ministry:

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 sametherapeutic effects and /or secondary and is administered

by the same route: TRUE COPY


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Definitions (CPMP/EWP/QWP/1401/98, EU)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???Bioequivalence on what???

On a general point of view for all dosage forms for routesof administration!!

For oral solutions, it is not compulsory except if there are

excipients which can modify the absorption.

For suspensions, capsules, tablets, these in vivo studies

have to be done in parallel with in vitro studies.


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Bioequivalence : How?Bioequivalence : How?

Methods for


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Methods for

assessing BE1

USA

Pharmacokinetic study

Pharmacodynamic study

Comparative clinical study

In vitro study

1.GUIDANCE FOR INDUSTRY

Bioavailability and Bioequivalence Studies for

Orally Administered Drug Products

General Considerations

Methods for

assessing BE1 UE

Alternatively to classical BA studies

using pharmacokinetics end points to

assess BE, other types of studies can be

envisaged, e.g. human studies with

clinical or pharmacodynamic end-points,

studies using animal models orin vitro

studies as long as they are appropriately

justified and/or validated1.Note for guidance on the investigation of BA and

BE (CPMP/EWP/QWP/1401/98, EU)


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ParametersParameters

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).

Early exposure, peak exposure, total exposure.

The bioequivalence criterions are described in the official

recommendations in USA and EU.


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Nevirapine was readily absorbed (> 90 %) after oral administration in healthyvolunteers 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 beattributed to incomplete dosing of the two suspensions since there was about 13 %

of the dose remaining in the cup.

Example: NevirapineExample: Nevirapine


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ExampleExample

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 to7.5 mg/m, 30.0 mg/m and 120.0 mg/m).

Based on adult experience, a comparable lead-in period of two weeks was suggested forpaediatric 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, thisdose was considered acceptable considering the enzyme induction to achieve initialantiretroviral 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/kgbid

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???Bioequivalence: Compulsory???

Drug dependence and DF dependence


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J P C=

PermeabilitySolubility and

Dissolution rate In vivo

Luminal degradationSame 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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Class I: HS/HP

Verapamil, PropranololMetoprolol

Class II: LS/HP

Carbamazepine, Ketoprofen,Naproxen

Class III: HS/LP

Ranitidine, Cimetidine, Atenolol

Class IV: LS/LP

Furosemide,HydrochlorothiazideP

ermeabi

lity

Volume of aqueous buffer to dissolve the highest dose

BCS classificationBCS classification

E i i i f IN VIVO di


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UE-EMEA

Rapid dissolution:

Demonstrate similarity of

dissolution profile between test

and reference in each of three

buffers within the range of pH 1-8at 37C (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.

Exemption criteria ofIN VIVO studies

USA-FDA

Rapidly dissolving

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 ofBiowaiver: permission to use dissolution test as a surrogate of


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Biowaiver: permission to use dissolution test as a surrogate of

pharmacokinetic data: Dissolution test: In vitro Bioequivalence

Biowaiver: permission to use dissolution test as a surrogate of

pharmacokinetic data: Dissolution test: In vitro Bioequivalence

High solubility, pH 1-8 (6.8)

Linear and completeabsorption

Rapid dissolution(T8590%)

Rapid dissolution(T85


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Classify WHO Essential DrugsClassify WHO Essential Drugs

Readily available data (solubility)

Easily Implemented Estimation (permeability)

Provisional Classification

WHO d US DWHO d US D


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WHO and US DrugsWHO and US Drugs

WHO

325 Medicines

260 Drugs

123 Oral IR

US

200 Drug Products

141 Oral

43 on WHO List

WHO E ti l DWHO E ti l D


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WHO Essential DrugsWHO 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

Wh t t d f BIE t di i hild ??Wh t t d f BIE t di i hild ??


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What to do for BIE studies in children??What to do for BIE studies in children??

Use of BCS for API to waive the BIE study 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!!

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 for issue of essay (sensitivity )it could be

necessary to administer 2 or more DDF, that may induce someerrors in LADME and bad BIE results !!

Wh t t d f BIE t di i hild ??Wh t t d f BIE t di i hild ??


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What to do for BIE studies in children??What to do for BIE studies in children??

Correlation IVIVC to be developed, but noextrapolation 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 tofacilitate the determination of exposure /activity with

M.AC. than exposure /plasmatic levels, essentially for

antibiotics ,antiviral, anticancer drugs.

R t E l f BA d BIE t i lR t E l f BA d BIE t i l


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Recent Examples of BA and BIE trialsRecent 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 andKidney Diseases (NIDDK)ClinicalTrials.gov Identifier:NCT00436878Purpose

The purpose of this study is to test the effects of large food portions on children'seating. Experiment 1 will test the effect of portion size on children's consumptionof sweetened beverages; we hypothesize that serving large beverage portionswill increase the amount of energy children consume from this food. Experiment2 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 FVpreferences and; we hypothesize that serving large fruit and vegetable portionswill produce increases in children's intake of these foods, particularly for childrenwho like fruit and vegetables. Experiment 3 will evaluate how food energydensity affects children's response to large portions; we hypothesize that largeportions will have the greatest influence on children's energy consumption when

foods are energy dense. Experiment 4 will begin to address perceptualmechanisms by which large portions affect children's eating.

Ibuprofen Effective for Acute Musculoskeletal Pain Relief in Children CME News Author: Laurie Barclay, MD

CME Author: Charles Vega MD FAAFP
http://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tcvLy%2FXy8tMSckGkhl66fll%2BgDZwzbIGQAAAA%3D%3D%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tcvLy%2FXy8tMSckGkhl66fll%2BgDZwzbIGQAAAA%3D%3D%0A&warn=false


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CME Author: Charles Vega, MD, FAAFPDisclosures

Release Date: March 13, 2007; Valid for credit through March 13, 2008

Credits Available

Physicians - maximum of 0.25AMA 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 mosteffective for treating the pain of acute musculoskeletal injuries, according to the results of a study reported in the March issue ofPediatrics.

"Our goal was to determine which of 3 analgesics, acetaminophen, ibuprofen, or codeine, given as a single dose, provides the mostefficacious analgesia for children presenting to the emergency department with pain from acute musculoskeletal injuries," write EricClark, MD, from the University of Ottawa in Ontario, Canada, and colleagues. "Although there have been studies comparing the painrelief provided by different oral analgesics in children postoperatively, there are no published randomized, controlled trials examiningthe 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 thatoccurred in the preceding 48 hours before presentation in the emergency department. These children were randomized to receive asingle oral dose of 15 mg/kg of acetaminophen, 10 mg/kg of ibuprofen, or 1 mg/kg of codeine. Children, parents, and evaluators wereblinded to group assignment, and the main endpoint was change in pain from baseline to 60 minutes after treatment with studymedication, 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 theibuprofen group, and 100 in the codeine group). Age, sex, final diagnosis, previous analgesic given, and baseline pain score weresimilar in the 3 groups.

At 60 minutes, improvement in pain score was significantly greater in the ibuprofen group (mean decrease, 24 mm) than in thecodeine group (mean decrease, 11 mm) and acetaminophen group (mean decrease, 12 mm). More patients in the ibuprofen groupachieved adequate analgesia (visual analog scale, < 30 mm) at 60 minutes than in the other 2 groups.
http://www.medscape.com/viewarticle/553522_authorhttp://www.medscape.com/viewarticle/553522_author


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HIV Pharmacology Workshop: The dangers of breaking up tablets for paediatric dosing

printer friendly versionsendtofriendglossarycommentYasmin Halima, Monday, May 01,2006Further evidence that dividing adult Triomune tablets for use by children may result in under-dosing was presented last week at the HIV Pharmacology Workshop in Lisbon, and the workshopalso heard the first bioequivalence data on a paediatric tablet formulation ofTriomune, calledPedimune.

Triomune (a fixed dose combination of stavudine (d4T), lamuvdine (3TC) and nevirapine) is thecheapest 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 theNetherlands, two African hospitals in Malawi and Zambia respectively and the UK Medical ResearchCouncil (MRC) was carried out. The aim of the study was to investigate whetherTriomune tablets thatare routinely divided for administration, deliver the same active ingredients, particularly in childrenwho are malnourished.

Tablets are difficult to split, the drugs are not equally distributed and there are no formalrecommendations on how to divide them with the distinct possibility of under-dosing.
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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 atthis conference and to date - has highlighted the lack of easily

stored, low cost, age appropriate antiretroviral formulations forchildren.

As an interim measure many programmes prescribe divided adultfixed dose combinations (FDCs) but this is not without problems, andcan yield suboptimal levels of nevirapine, particularly in very youngchildren (see below). Obviously FDCs for children will be a welcomedevelopment.

Paediatric FDCs

At the pharmacology (PK) workshop in Lisbon earlier this year, independent investigators presented


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t t e p a aco ogy ( ) o s op sbo ea e t s yea , depe de t est gato s p ese tedbioavailability data for Indian generic manufacturer Ciplas Pedimune Baby and Pedimune JuniorFDC tablets of NVP, 3TC and d4T, which led them to conclude that it would be acceptable to begintesting PK and dosing requirements of these formulations in African children even though the formalbioequivalence study by Cipla has not yet been completed. [1, 2]

Another Indian generic company, Ranbaxy has developed two new paediatric formulations of tabletsfor oral suspension (TFOS) designed to disintegrate quickly into a uniform suspension in smallvolume of liquid media like water.

A poster from Singla and co-workers from Ranbaxy described the formulation development of Triviro-LNS 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 companys bioavailability studyof a single dose of the Triviro-LNS kids DS formulation compared to reference propriety liquidformulations. [4]

The investigators reported that the tablet has: a break line, to enhance accuracy of dosing; apleasant orange flavour and requires no specific measuring device or refrigeration. Time todispersion is 40 seconds in a small amount of water.

The bioavailability study was an open label, single dose crossover study conducted in 36 fasting HIVnegative adult males.

The investigators reported that the geometric mean ratios (% Test/Reference) of log-transformedparameters 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 theyconcluded Ranbaxys novel paediatric triple ARV TFOS could be used in place of individual liquidformulations.


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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 BioequivalenceUsing TSH as a Marker in Children With Permanent Hypothyroidism

Further study details as provided by Children's Hospital Boston:

Primary Outcomes: Thyroid Stimulating Hormone MeasureExpected Total Enrollment: 40

Study start: June 2006; Expected completion: January 2008Last follow-up: January 2008; Data entry closure: January 2008

This study is an unblinded, randomized controlled cross-over study, which involves taking2 different forms of levothyroxine sequentially over a 16 week period. Subjects will have atotal of 3 visits over this time period. At the first visit, subjects are randomized to rec
http://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tcvLy%2FXy8vJ1cvLzNBLzy%2FTz01NycnMSy3IKS3WBwAKdDCLIwAAAA%3D%3D%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAAXBwQnAMAgAwI30n20KShTUhGoi3b53UrUHYndDmEOowFwXnck0eNtJLPnepUSa%0A%2FCQnSLn9xUV%2BkDcAAAA%3D%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tdPzyjSy8vJ1cvLzNBLzy8DAPXTBk4WAAAA%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tdPzyjSy8vJ1cvLzNBLzy%2FTT87PS8ksyczPcy%2FKLy2wLcmoLMrPTEnJ%0ALE5NLE4tBgB%2FMxLgNQAAAA%3D%3D%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tdPzyjSy8vJ1cvLzNBLzy%2FTT87PS8ksyczPcy%2FKLy2wLcmoLMrPTEnJ%0ALE5NLE4tBgB%2FMxLgNQAAAA%3D%3D%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tdPzyjSy8vJ1cvLzNBLzy8DAPXTBk4WAAAA%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAAXBwQnAMAgAwI30n20KShTUhGoi3b53UrUHYndDmEOowFwXnck0eNtJLPnepUSa%0A%2FCQnSLn9xUV%2BkDcAAAA%3D%0A&warn=falsehttp://clinicaltrials.gov/ct/visit?uid=7a3H4sIAAAAAAAAAMsoKSmw0tcvLy%2FXy8vJ1cvLzNBLzy%2FTz01NycnMSy3IKS3WBwAKdDCLIwAAAA%3D%3D%0A&warn=false


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Purpose
http://clinicaltrials.gov/ct/info/phasehttp://clinicaltrials.gov/ct/info/phasehttp://clinicaltrials.gov/ct/info/phase


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This is a randomized, double-blind, multi-centered study to compare 6 months of medicaltreatment with digoxin or propranolol in infants with SVT Background: SVT is the mostcommon sustained arrhythmia of infancy. Neither digoxin nor propranolol has beenevaluated for pediatric use in a controlled trial in the context of SVT, yet both medicationsare 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 ordigoxin

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 andpropranololPhaseIIIMedlinePlus consumer health information

Study Type: InterventionalStudy Design: Treatment, Randomized, Double-Blind, Active Control,

Single Group Assignment, Bio-equivalence Study

Official Title: Multicenter Study of Antiarrhythmic Medications for Treatment of Infants WithSupraventricular Tachycardia

Asthma and gastroesophageal reflux disease (GERD) are common disorders, which

lth h t ll l th l b th h hi h bidit d hi h h lth t
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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

co-existence 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 totreatment 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 PPIs, can be identified.

Ranbaxy presents bioequivalence data on two paediatric fixed dose triplecombination tablets


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printer friendly versionsendtofriendglossarycomment Edwin J. Bernard,Thursday, August 17, 2006Two fixed dose triple combination water-dispersible tablets produced by generic manufacturer Ranbaxy providing half-

and quarter-doses of nevirapine, lamivudine and stavudine for paediatric useare bioequivalent to their proprietrary liquid formulations in adults, accordingto a study presented to the Sixteenth International AIDS Conference inToronto on August 16th. The two formulations have already been approvedby 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 paediatricformulations in low-income countries, first highlighted two years ago at theFifteenth International AIDS Conference in Bangkok by Mdecins SansFrontires (MSF) director Daniel Berman.
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ConclusionConclusion


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ConclusionConclusion

A new way for the future and a long way to solve all theissues.

Further referencesFurther references


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T i i W k h Ph ti l

Further referencesFurther 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 ClassificationSystem- Implementation Challenges and Extension Opportunities. J Pharm Sci2004 93(6)

Vogelpoel H. et al. Biowaiver monographs for IR solid oral dosage forms basedon BCS literature data: Verapamil HCl, Propranolon HCL and Atenolol.2004 JPharm. Sci. 93(8)

Lindenberg et al.: Classification of orally administered drugs on the WHO modellist of essential medicines according to the biopharmaceutics classificationsystem. Eur. J. Pharm. Biopharm. 58: 265-278, 2004

Bio Availability Bio Equivalence En

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