Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

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

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

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

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

F.D.A definition

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)

F.D.A(cont..) So this determination must be considered as a value of the performance of the drug dosage form, quite as a parameterof the dosage form.

F.D.A(cont..)

F.D.A (cont..)

Bioavailability: why? • Where is the place of Bioavailability in the future of a dosage form in the human being?

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

Technological (galenicals!) Factors of B.A Release Absorption Dissolution DDF Dissolved API Free API Absorbed drug

Drug Product Type of DDF Manufacturing process Excipients Release crystals Physical-chemical Prop of API. Drug released Solubility Dissolution Dissol. Rate Dissolved drug Absorption Absorbed drug Subject, race, age, sex, disease…,

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

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.

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;

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.

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.

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 .

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.

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

Question • Do we have to do Bioavailability studies in babies and in general in children? yes

Question • Study of all dosage forms? yes

Clinical Investigation

Pharmacokinetics

Dose calculation:area/weight.Normogram

Protocol

Subjects

Ethical issues in pediatric studies

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

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