Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn, Estonia Date: 15-19 Octob

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn, Estonia Date: 15-19 October 2007

2. 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

3. 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

4. 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

5. Definitions and relevance to paediatric medicines 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)

6. 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) (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)

7. Determination 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.

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

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

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

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

12. 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 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

13. 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.

14. 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 low 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;

15. 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.

16. Intramuscular route • The absorption rate is low and hazardous in the newborn due to low blood flow rate in the muscles, to low amount of muscle masses and low motor function of the baby.

17. 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 (except for pain treatment) • The dosage form must be a administered on a non injured skin .

18. 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.

19. 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

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

21. Question • Study of all dosage forms? yes

22. Question: When these studies are needed? • For new drugs, and new drug product or dosage form: clinical studies ,pharmacokinetics studies and/or BA studies • For generics: only Bioequivalence studies based on BA evaluation or pharmacologic or therapeutic comparisons.

23. New drugs ICH Topic E 11 • Clinical Investigation of Medicinal Products in the Paediatric Population • NOTE FOR GUIDANCE ON CLINICAL INVESTIGATION OF MEDICINALPRODUCTS IN THE PAEDIATRIC POPULATION (CPMP/ICH/2711/99)

24. 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”.

25. Clinical Investigation The decision to proceed with the Paediatric development program for a medicinal product 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 with known 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

26. Clinical Investigation • “Of these factors, the most important is the presence of serious or life-threatening disease for which the medicinal products represent 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 toxicity studies and genotoxicity tests would generally be available”. • All these studies requires adequate dosage forms: solutions etc..

27. Clinical 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, for example when studies in adults who yield little useful information or expose them to inappropriate to risk

28. Clinical Investigation: Timing of studies • Second case. :Medicinal products intended to treat serious or life-threatening disease, occurring in both adults and paediatric patient, for which there are currently 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 paediatric studies. • Third case. :Medicinal products intended to treat other disease and conditions. There is less urgency than in the previous cases and studies would usually begin at later phases of clinical development

29. 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.

30. Clinical Investigation: Type of studies: 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. If this approach is taken, adults pharmacokinetic data should be available to plan the paediatric studies

31. Clinical Investigation: Type of studies: • 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. • 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. .

32. Clinical Investigation: Type of studies: • 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. • Thus a PK/PD approach combined with safety and other relevant studies could avoid the need for clinical efficacy studies.

33. Clinical Investigation: Type of studies: • For topical active product, extrapolation of efficacy from one patient population to another may be based on studies that include pharmacodynamic and / or appropriate alternative assessment. Local tolerability studies may be needed. It may be important to determine blood levels and systemic effects to assess safety.

34. Pharmacokinetics • Pharmacokinetic studies should be performed to support formulation development and determine pharmacokinetic parameters in different age group to support dosing recommendations. • Relative bioavailability comparisons of paediatric formulation with the adults oral formulation typically should be done in adults. • 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.

35. Pharmacokinetics • 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.

36. Pharmacokinetics: 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

37. Pharmacokinetics: 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.

38. Ethical issues 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.

39. Ethical issues in pediatric studies • It is important to minimize the distress and discomfort : • use of topical anesthesia to place IV catheters, which have to be indwelling catheters. • Personnel knowledgeable and skilled in dealing with the paediatric population. • A physical setting with furniture, play equipment, activity, and food appropriate to the age of population. • A familiar environment such as the hospital or clinic where participants is normally receive their care.

40. 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

41. 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. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food and Drug Administration October 2000

42. 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)

43. 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

44. 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 transfers a 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

45. 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”

46. What 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 same therapeutic effects and /or secondary and is administered by the same route: TRUE COPY

47. 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”

48. Bioequivalence on what??? • On a general point of view for all dosage forms for routes of 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.

49. Bioequivalence : How?

50. Methods for assessing BE1 USA 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 or in vitro studies as long as they are appropriately justified and/or validated • 1.Note for guidance on the investigation of BA and BE (CPMP/EWP/QWP/1401/98, EU) • 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