jm.aiache | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations...

JM.AIACHE | April 20081 |

Pharmaceutical Development with Focus on Paediatric formulations

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


Bioavailability and bioequivalence studies in paediatrics

Bioavailability and bioequivalence studies in paediatrics

Presented by: Jean-Marc AIACHEEmeritus Professor,

Auvergne University,

Faculty of Pharmacy,

28 Place Henri Dunant

63000 Clermont-Ferrand,

France

[email protected]

:


In this presentationIn this presentation

Introduction on B.A

B.A: when?

B.A: how?

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:

*1-choice of subjects population

*2-choice of the dose

*3-design of studies: ways,,cross-over,dose regimen, cond..of ad.,essay

.Bioequivalence and biowaivers:.,

*choice of the reference D.P.

*parameters

*statistical analysis

*Ethics

*sampling

Conclusion


General Definitions:Bioavailability 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.


Drug Dosage form

Liberation

Drug released

Dissolution

Dissolved drug

AbsorptionAbsorbed drug

Type of DDF

Manufacturing process

Excipients

Physical-chemical Prop of API.

Solubility

Dissol. Rate

crystals

Subject, race, age, sex, disease,…

Technological Factors of B.A

The technological factors have the same influence in Adults and children

except for dissolution rate due to the difference of volume of G.I tract 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


What are the aims of the bioavailability studies?


First Case: New Chemical Entity (N.C.E)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


Absolute Bioavailability 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 :


Absolute Bioavailability: Results

ABA=1,same dose (solution), same AUC

Or


Absolute Bioavailability: results about different routes

Absolute Bioavailability: results about different routes

I.V

I.M

S.C

Oral

Concentrations

Time


Choice of the best formulation:Relative Bioavailability

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.


Results: Relative B.AResults: 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

Tablet 2

Solution

suspension


Results: Relative BioavailabilityResults: Relative Bioavailability

0

Time

Concentration

Solution

Conventional Tablet

SR

New DDFSame dose, same AUC, but Cmax

and Tmax different:onset and duration of action different!

What is the best DDF for patients , child?


Second Case: “Old C.E”:Bioequivalence

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)


Bioequivalence: WhenBioequivalence: 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”).


Definition of Generics WHODefinition 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.


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

EU

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 or in 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)

Bioequivalence : How?


When PK-bioavailability determination or bioequivalence studies have to be done in pediatric

population?.

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.


Paediatric Studies Decision Tree

the medicinal product is novel

Unique paediatric indications or a

potential need for paediatric formulation

yes

yes

Paediatric studies

Relevant safety data come from adult human exposure.

Repeated dose toxicity studies, reproduction, toxicity studies

and genotoxicity tests Medicinal products intended to treat serious

or life-threatening disease, occurring in both adults and paediatric patient

if

if

ifRequisite


Reasonable to assume (pediatrics vs adults) similar disease progression? similar response to intervention?

Pediatric Studies Decision Tree: PK-BA-BIE studiesPediatric Studies Decision Tree: PK-BA-BIE studies

NO

Is there a PD measurement**that can be use to predictefficacy?

NO

•Conduct PK studies•Conduct safety/efficacy trials*

NO

•Conduct PK studies to achieve levels similar to adults•Conduct safety trials

YES

Reasonable to assume similarconcentration-response (C-R)in pediatrics and adults?

YES TO BOTH

•Conduct PK/PD studies to getC-R for PD measurement•Conduct PK studies to achievetarget concentrations based on C-R

YES

•Conduct safety trials


These PK-BA-BIE StudiesThese PK-BA-BIE Studies

Should be performed to support formulation development

and determine pharmacokinetic parameters

in different age group to support dosing recommendations.


Studies designStudies 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.


Study design:Choice of subjects population

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


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




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..


Study design: case of absolute B.A for N.C.E

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.


Example of QuinineExample 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.


Relative BA for N.C.E.:choice of best formulation

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


Learning taste and testing for childrenLearning taste and testing for children

Taste class-room

acid bitter

sweet salted


Design of Studies:2 waysDesign of Studies:2 ways

The Standard Pharmacokinetic Approach

. It involves administering either single (if linear ) or multiple doses (steady-state, 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.


Design of studies: cross-overDesign 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.


Study design:Dose regimenStudy 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


Study design :Conditions of administration

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


General issues :Conditions of administration


From 0 to 3 years :fasten state ?method of administration


Study design :Conditions of administration and Food effect

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.


Exemple:Food-Effect in Bio study 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.


methodology: Essay of API or metabolites. 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


i.e: Nevirapine: Dosesi.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.


Doses :NevirapineDoses :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.


Relative BA and BioequivalenceRelative 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.


When Bioequivalence studies are not necessary

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;


When equivalence studies are not necessaryWhen 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:


What are the best aspirin

effervescent tablets?



(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



(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!



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).


When equivalence studies are not necessary:

dose-proportionality of formulations 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.


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.”




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????




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.


Fixed combinations productsFixed 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


Issues: 2)Parameters

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.)


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.




“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


Example: anti-epileptic drug productsExample: 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.


Choice of subjects for Bioequivalence studies

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 !!


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.

XXDFNevirapine: relative BioavailabilityXXDFNevirapine: relative Bioavailability


ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON MEDICINAL PRODUCTS CONDUCTED WITH THE PAEDIATRIC POPULATION

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


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.




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.


Issues :8) Sampling

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).


Issues:8 )Sampling Protocol

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.


Theorically!


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!

: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).



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 !!!



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!!



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!!!!!!!!!


Extrapolation of DATAExtrapolation 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


Extrapolation of DATAExtrapolation 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)


How to extrapolate?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.


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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mange takmange tak

díkydíky

tack så mycket tack så mycket Thank you

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dhanya-waaddhanya-waad

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ačiûačiû Terima Kasih

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jm.aiache | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations...

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