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1 World Health Organization
Pharmaceutical Development 6 April, 2017 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

2 Pharmaceutical Development:
World Health Organization Pharmaceutical Development: 6 April, 2017 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

3 Pharmaceutical Development
World Health Organization Pharmaceutical Development 6 April, 2017 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
World Health Organization Definitions and relevance to paediatric medicines 6 April, 2017 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 World Health Organization
F.D.A definition World Health Organization 6 April, 2017

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 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)

7 World Health Organization
F.D.A(cont..) 6 April, 2017 So this determination must be considered as a value of the performance of the drug dosage form, quite as a parameter of the dosage form.

8 World Health Organization
F.D.A(cont..) World Health Organization 6 April, 2017

9 World Health Organization
F.D.A (cont..) World Health Organization 6 April, 2017

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

11 World Health Organization
L.A.D.M.E.R. system World Health Organization 6 April, 2017

12 Technological (galenicals!) Factors of B.A
World Health Organization Technological (galenicals!) Factors of B.A 6 April, 2017 Release DDF Dissolution Absorption Free API Dissolved API Absorbed drug

13 World Health Organization
Drug Product Type of DDF 6 April, 2017 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…,

14 relevance to paediatric medicines
World Health Organization relevance to paediatric medicines 6 April, 2017 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

15 Modification of absorption phenomena
World Health Organization Modification of absorption phenomena 6 April, 2017 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.

16 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;

17 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.

18 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.

19 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 .

20 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.

21 World Health Organization
Consequences 6 April, 2017 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

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

23 Question Study of all dosage forms? yes


25 Clinical Investigation

26 Clinical Investigation

27 Clinical Investigation

28 Clinical Investigation

29 Clinical Investigation

30 Clinical Investigation

31 Clinical Investigation

32 Clinical Investigation

33 Clinical Investigation

34 Clinical Investigation

35 Pharmacokinetics

36 Pharmacokinetics

37 Pharmacokinetics

38 Dose calculation: area/weight. Normogram



41 Protocol

42 Protocol

43 Subjects

44 Ethical issues in pediatric studies

45 Ethical issues in pediatric studies

46 Ethical issues in pediatric studies

47 Ethical issues in pediatric studies

48 Ethical issues in pediatric studies

49 Ethical issues in pediatric studies

50 Ethical issues in pediatric studies

51 Ethical issues in pediatric studies

52 World Health Organization
Bioequivalence 6 April, 2017 “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

53 World Health Organization
Bioequivalence 6 April, 2017 “This definition emphasizes the use of pharmacokinetic measures in an accessible biological matrix such as blood, plasma, and/or serum to indicate release of the drug substance from the drug product into the systemic circulation. This approach rests on an understanding that measuring the active moiety or ingredient at the site of action is generally not possible and, furthermore, that some relationship exists between the efficacy/safety and concentration of active moiety and/or its important metabolite or metabolites in the systemic circulation.” Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food and Drug Administration October 2000

54 World Health Organization
Bioequivalence 6 April, 2017 Pharmacodynamic studies are not recommended for orally administered drug products when the drug is absorbed into the systemic circulation and a pharmacokinetic approach can be used to assess systemic exposure and establish BE.” Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food and Drug Administration October 2000

55 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)

56 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

57 World Health Organization
Bioequivalence : Why? 6 April, 2017 “Prescribability refers to the clinical setting in which a practitioner prescribes a drug product to a patient for the first time. In this setting, the prescriber relies on an understanding that the average performance of the drug product has been well characterized and relates in some definable way to the safety and efficacy information from clinical trials. Switchability refers to the setting in which a practitioner transfers a patient from one drug product to another. This situation arises with generic substitution, as well as with certain post approval changes by an innovator or generic firm in the formulation and/or manufacture of a drug product. Under these circumstances, the prescriber and patient should be assured that the newly administered drug product will yield comparable safety and efficacy to that of the product for which it is being substituted.” “Guidance for Industry Average, Population, and Individual Approaches to Establishing Bioequivalence” Aug 1999

58 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”

59 What is a Generic 1st definition given in France(1963) by the Trade Minister: “Copy of a drug product ,the production and marketing of which are allowed after the patent caducity”. It contains the same API, the same excipients, has the same therapeutic effects and /or secondary and is administered by the same route: TRUE COPY

60 Definitions (CPMP/EWP/QWP/1401/98, EU)
World Health Organization 6 April, 2017 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” Two pharmaceutical products will be considered essentially similar once they have demosnstrated to be bioequivalent….The problem we have to resolve is How to demosntrate bioequivalence.

61 Bioequivalence on what???
On a general point of view for all dosage forms for routes of administration!!

62 FDA / EMEA recommendations

63 FDA / EMEA recommendations

64 Bioequivalence : How?

65 World Health Organization
6 April, 2017 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 The assessment of bioequivalence has been clasically performed with pharmacokinetic studies, but it is accepted that under the right circumstances, an in vitro study can provide the same information about the two formulations under comparison.

66 Parameters

67 Parameters

68 Parameters

69 Parameters

70 Parameters

71 Parameters

72 Example: Nevirapine Nevirapine was readily absorbed (> 90 %) after oral administration in healthy volunteers and in adults with HIV-1 infection. A 3-way crossover study compared the bioavailability from three production/commercial scale batches with varying dissolution profiles. All three batches were bioequivalent with respect to systemic exposure (AUC). The significantly different values for Cmax and tmax were considered not to be clinically relevant. In studies and 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 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.

73 Example It has been later determined in a single dose study in 9 patients aged between 9 months and 14 years administered after an overnight fast (3 patients per dose level equivalent to 7.5 mg/m², 30.0 mg/m² and mg/m²). Based on adult experience, a comparable lead-in period of two weeks was suggested for paediatric population. A 4 mg/kg dose is proposed for all children regardless the age. Although no particular study has been performed to find the optimal lead-in dose, this dose was considered acceptable considering the enzyme induction to achieve initial antiretroviral activity. The final recommended doses for the different ages are therefore the following: Patients from 2 months to 8 years, 4 mg/kg once daily for 2 weeks followed by 7 mg/kg bid Patients from 8 years to 16 years are 4 mg/kg once daily followed by 4-mg/kg bids.

74 Bioequivalence: Compulsory???
Drug dependence and DF dependence

75 World Health Organization
6 April, 2017 Permeability Solubility and Dissolution rate In vivo Luminal degradation The main Hypothesis supporting BCS are represented in this slide: Two drug products presenting the same drug concentration-time profile along the gastrointestinal tract will have the same rate and extent of absorption, and necessarily will be bioequivalent. Two conditions are necessary to make true this statement. First that the two drug products have the same in vivo dissolution profile under all luminal conditions and second that none of the formulation components affect the membrane permeability or intestinal transit time. Same dissolution profile Formulation components do not alter permeability or intestinal transit Amidon GL. Lennernas H. Shah VP. Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12(3):413-20, 1995

76 World Health Organization
BCS classification 6 April, 2017 Class I: HS/HP Verapamil, Propranolol Metoprolol Class II: LS/HP Carbamazepine, Ketoprofen, Naproxen Class III: HS/LP Ranitidine, Cimetidine, Atenolol Class IV: LS/LP Furosemide, Hydrochlorothiazide Permeability As permeability and solubility are identified as the key parameters controlling drug absorption, the system classify drugs into high and low solubility drugs and High and low permeability drugs. But which are the boundaries of these classes and how do we nee to proceed in order to establish the drug classification Volume of aqueous buffer to dissolve the highest dose

77 Permeability classification
World Health Organization Permeability classification 6 April, 2017 What is a good permeability? How can we estimate intestinal permeability? Eg= gut first-pass effects Eh= liver first-pass effects First question is..what is a good intestinal permeability and how can we obtain an estimation? In the current guidances, at least in FDA guidance a substance having an oral fraction absorbed higher than 90% is considered a highly permeable substance. A substance showing an ooral bioavailability of 90% has of course at least this value of fraction absorbed. If we do not have available information from human pharmacokinetic studies, we need to estimate the drug permeability and we need to be sure that this permeability will provide an oral fraction absorbed of 90% in absence of any other formulation factors.

78 World Health Organization
6 April, 2017 These are some of the methods for estimating drug intestinal permeability, that I’m going to review very briefly

79 World Health Organization
6 April, 2017 Absorption number An The adimemsional number related to drug permeability is the absorption number. The absorption number represents the ration between the absorption time and the residence time. Those compounds with high values of permeability have short absorbing times and thus can be completely absorbed during their transit through the small intestine, in absence of any formulation or solubility factors. A high Permeability value ensures that the drug is completely absorbed during its residence time in intestine. (in absence of formulation factors)

80 World Health Organization
6 April, 2017 Solubility: How much is enough? Dissolution and solubility in what? Regarding solubility classification we need to answer the same questions. Where is the limit to consider a drug a high or low solubility substance and in which media should we obtain the solubility data.

81 Average physiological pHs in GI tract. Fasted/fed
World Health Organization 6 April, 2017 Average physiological pHs in GI tract. Fasted/fed Site fasted Stomach Duodenum Jejunum Ileum First importan point to consider is that the drug in the gastrointestinal tract has to dissolve in fluids of changing pH values that on the other hand are different in fed versus fasted states. we need to characterize the solubility profile at different pHs. The average pH value in stomach is lower than 3.00 during fasted state. Intestinal pH values are considerably higher due to the pancreatic secretions, rich in bicarbonate ions that neutralize the acid emptying from stomach. And as you can see there is a pH gradient along the small intestine. Adapted from Dressman et al. Pharm.Res 15(1) 11-22(1998)

82 Average physiological pHs in GI tract. Fasted/fed
World Health Organization 6 April, 2017 Average physiological pHs in GI tract. Fasted/fed Site fasted fed Stomach Duodenum Jejunum Ileum In fed state this picture is altered as GI secretions change in the presence of food. The gastric pH value becomes less acidic, depending on meal composition, but typical gastric values after a meal can vary from 3 to 7 and it takes 2-3 hours to return to fasted values. A reasonable range of pHs to be tested could be from 1 to 6.8 which corresponds to proximal values. The drug should be able of dissolving in the proximal part of intestine in order to ensure the access to its site of absorption during transit time. Adapted from Dressman et al. Pharm.Res 15(1) 11-22(1998)

83 World Health Organization
6 April, 2017 Exemption criteria of IN VIVO studies UE High solubility: When the active substance is highly soluble, the product could be in general exempted from in vivo BE studies. The amount contained in the highest dose strength of an IR product is dissolved in 250 mL of each of three buffers within the range of pH 1-8 at 37ºC (preferably pH 1.0, 4.6, 6.8) These conditions are clearly reflected in the europen guidance, where even if range is 1 to 8, it is indicated that preferably the solubility has ti be assured at 1, 4.6 and 6.8.

84 Solubility: Dose/solubility ratio and Do dose number
World Health Organization 6 April, 2017 Solubility: Dose/solubility ratio and Do dose number D/S Gives the volume necessary to dissolve the given dose of the active substance Do Dose The volume estimate of 250 mL comes from typical BE study protocols where the dose is administered with a glass of water, and on the other hand this constitutes a conservative estimation of the available volume of fluid for drug dissolution in the gastrointestinal tract High solubility ensures that solubility is not likely to limit the dissolution and therefore absorption. When the dose number is less than 1 than means that the dose can be dissolved in the glass of water. Drug solubility High solubility ensures that solubility is not likely to limit the dissolution and therefore absorption.

85 World Health Organization
6 April, 2017 Coming back to high solubility and high permeability drugs. For compounds showing these characteristics and besides if the drug product dissolves rapidly, releasing the drug in less than 15 minutes then gastric emptying is the rate controlling process in their absorption.

86 World Health Organization
6 April, 2017 In fasted state gastric emptying rate depends on volume and on the motility phase. Gastric emptying half –time can be from 5 to 22 minutes with an average of 22 and 12 minutes after the administration of 50 and 200 mL respectively as you can see on the slide.

87 Dissolution rate: Dn dissolution number
World Health Organization 6 April, 2017 Dissolution rate: Dn dissolution number Solubility mg/mL Residence time in small intestine ~180 min Diffusivity 5*10-6 cm2/s Rapid dissolution ensures that in vivo dissolution is not likely to be the rate limiting step. Dissolution rate depends on solubility and on the particle radius. The dissolution number represents the ratio between the resisdence time in small intestine and the time required for complete dissolution. A lower dissolution number means that in vivo dissolution will limit the absorption of the drug. Particle radius ~25m Density ~1.2mg/mL Time required for Complete dissolution Rapid dissolution ensures that in vivo dissolution is not likely to be the rate limiting step

88 World Health Organization
6 April, 2017 Exemption criteria of IN VIVO studies UE-EMEA Rapid dissolution: Demonstrate similarity of dissolution profile between test and reference in each of three buffers within the range of pH 1-8 at 37ºC (preferably pH 1.0, 4.6, 6.8). In cases where more than 85% of the active substance are dissolved within 15 minutes, the similarity of dissolution profiles may be accepted as demonstrated. 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). In section of the eu guidance it is mentioned that the criteria for requesting in vivo studies are based on the BCS concepts as high sol, high per, high dissolution rate, even if the only reference to the definition of this later factor is given here. In the FDA guidance the definition is more detailed

89 World Health Organization
6 April, 2017 Biowaiver: permission to use dissolution test as a surrogate of pharmacokinetic data: Dissolution test: In vitro Bioequivalence EMEA/CPMP and FDA/BCS High solubility, pH (6.8) High permeability (Fabs>90%) Rapid dissolution (T85<30min, pH=1.2,4.5,6.8) Excipients currently approved for IR Dosage Forms (FDA Inactive Ingredients List) Non-NTI drugs High solubility, pH 1-8 (6.8) Linear and complete absorption Rapid dissolution (T85<30min, pH=1.0,4.6,6.8) Excipients well established (not large doses) Risk of therapeutic failures The conditions for requestion biowaivers are summarised in emea and FDA guidances with slight differences.

90 Classify WHO Essential Drugs
World Health Organization Classify WHO Essential Drugs 6 April, 2017 Readily available data (solubility) Easily Implemented Estimation (permeability) Provisional Classification Now I’m going to show you the main results of a recently published survey about the who essential drugs. Our aim was to stablish a provisional classification of the drugs in inmediatly release form of that list. The classification is based on solubility data from commonly available references and permeability is estimated from a a correlation of human permeability data with partition coefficients.

91 World Health Organization
WHO and US Drugs 6 April, 2017 WHO 325 Medicines 260 Drugs 123 Oral IR US 200 Drug Products 141 Oral 43 on WHO List The who essential drug list consist of 325 medicines containing 260 different drugs, 123 of them are formulated I oral inmediate-release products. In order to compare, we also classify the 141 oral drugs from the 200 top-list of drug products in USA. 43 of these drugs are contained in the WHO lists.

92 World Health Organization
6 April, 2017 Merck Solubilities Descriptive Term Parts of solvent required for Solubility range, Solubility assigned, (Solubility Definition) 1 part of solute mg/ml Very soluble (vs) Less than 1 1000 and over 1000 Freely soluble (fs) From 1 to 10 100 to 1000 100 Soluble (s) From 10 to 30 33 to 100 33 Sparingly soluble (sps) From 30 to 100 10 to 33 10 Slightly soluble (ss) From 100 to 1000 1 to 10 1 Very slightly soluble (vss) From 1000 to 10,000 0.1 to 1 0.1 Practically insoluble (pi) 10,000 and over Less than 0.1 0.01 Drug solubilities (mg/mL) were obtained mainly from USP and Merck index. When specific values were not available the lower limit of the range defined in USP was used as a conservative estimation

93 Solubility Classification
World Health Organization 6 April, 2017 Solubility Classification High Solubility Drugs Dose numbers were calculated as I have explained previously using the max strenght indicated in the who list or in the orange book for USA drugs. Drugs with dose numbers less than 1 were classified as high solubility and thus drugs with dose numbers higher than 1 were classified as low solubility. That way 67% and 68% respectively of the who and usa list are high solubility drugs. The solubility distribution is very similar in both lists.

94 Solubility Conclusions
World Health Organization 6 April, 2017 Majority of Drugs of the WHO list are High Solubility (Do<1) Most of the drugs included in the who essential medicines list are high solubility compounds.

95 Human Jejunal Permeability Data Base
World Health Organization 6 April, 2017 Human Jejunal Permeability Data Base In order to stablish a permeability classification the first step was selecting a high permeability reference compound. Metoprolol was chosen as reference because it has a permeability value that correponds with a oral fraction absorbed around 95%.

96 World Health Organization
WHO Essential Drugs World Health Organization 6 April, 2017 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 On the bases of solubility alone 67% of the drugs were highly soluble, representing a potential number of drugs that may be eligible for in vitro bioequivalence and biowaivers. Or taking the most conservative approach at least around 30% that correponds to the class I compounds. The impact of waiving in vivo bioequivalence studies in developing countries while assuring the quality of medicines and the clinical performance with an affordable dissolution study is expected to be profoundly significant.

97 What to do for children?? Use of BCS for API
Study of the dosage form in vitro whatever the BCS of the API if there is a reference as the innovator and comparison with sharpness of the dissolution curves and results. There is a dissolution device for all the dosage form and a lot of possibility for media!! Correlation IVIVC to be developed, but no extrapolation of adult data to children, except in case of proof!!! It seems better to privilege the PD bioassays than PK with sampling in children if it possible and so to facilitate the determination of exposure /activity with M.AC. than exposure /plasmatic levels, essentially for antibiotics ,antiviral, anticancer drugs.

98 Proposed BE Dissolution
BCS Class Drug Solubility pH 1.2 Drug Solubility pH 6.8 Drug Permeability Preferred Procedure I High >85% Dissolution in 15 min., pH = 6.8. II-A Low >85% Dissolution in 15 min., pH = 1.2. II-B >15 min at pH=1.2, then 85% Dissolution in 30 min., pH = 6.8; F2>50; 5 points minimum; not more than one point > 85%. II-C >15 min at pH=1.2; then 85% Dissolution in 30 min., pH = 6.8 plus surfactant*; F2>50; 5 points minimum, not more than one point > 85%. III >85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8. IV-A IV-B >15 min. at pH = 1.2; then 85% Dissolution in 30 min., pH = 6.8,; F2>50; 5 points minimum.; not more than one point > 85%. IV-C

99 Recent Examples of BA and BIE trials
Sponsored by:National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Information provided by:National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Identifier:NCT Purpose 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.

100 Ibuprofen Effective for Acute Musculoskeletal Pain Relief in Children  CME
News Author: Laurie Barclay, MD CME Author: Charles Vega, MD, FAAFP Disclosures Release Date: March 13, 2007; Valid for credit through March 13, 2008 Credits Available Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians; Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians March 13, 2007 — In a group of children randomly assigned to ibuprofen, acetaminophen, or codeine, ibuprofen was the most effective for treating the pain of acute musculoskeletal injuries, according to the results of a study reported in the March issue of Pediatrics. "Our goal was to determine which of 3 analgesics, acetaminophen, ibuprofen, or codeine, given as a single dose, provides the most efficacious analgesia for children presenting to the emergency department with pain from acute musculoskeletal injuries," write Eric Clark, MD, from the University of Ottawa in Ontario, Canada, and colleagues. "Although there have been studies comparing the pain relief provided by different oral analgesics in children postoperatively, there are no published randomized, controlled trials examining the use of common oral pain medications for children with acute musculoskeletal injury in the ED [emergency department]." This study enrolled 336 children age 6 to 17 years with pain from a musculoskeletal injury to the extremities, neck, and back that occurred in the preceding 48 hours before presentation in the emergency department. These children were randomized to receive a single oral dose of 15 mg/kg of acetaminophen, 10 mg/kg of ibuprofen, or 1 mg/kg of codeine. Children, parents, and evaluators were blinded to group assignment, and the main endpoint was change in pain from baseline to 60 minutes after treatment with study medication, measured with a visual analog scale. Of 336 patients randomized, 300 were included in the analysis of the primary outcome (100 in the acetaminophen group, 100 in the ibuprofen group, and 100 in the codeine group). Age, sex, final diagnosis, previous analgesic given, and baseline pain score were similar in the 3 groups. At 60 minutes, improvement in pain score was significantly greater in the ibuprofen group (mean decrease, 24 mm) than in the codeine group (mean decrease, 11 mm) and acetaminophen group (mean decrease, 12 mm). More patients in the ibuprofen group achieved adequate analgesia (visual analog scale, < 30 mm) at 60 minutes than in the other 2 groups.

101 HIV Pharmacology Workshop: The dangers of breaking up tablets for paediatric dosing
printer friendly versionsend to friendglossarycomment  Yasmin Halima, Monday, May 01, 2006Further evidence that dividing adult Triomune tablets for use by children may result in under- dosing was presented last week at the HIV Pharmacology Workshop in Lisbon, and the workshop also heard the first bioequivalence data on a paediatric tablet formulation of Triomune, called Pedimune. Triomune (a fixed dose combination of stavudine (d4T), lamuvdine (3TC) and nevirapine) is the cheapest regimen available in much of sub-Saharan Africa, and is commonly prescribed to adults. Attempts have been made to estimate doses for children by halving and quartering tablets, but it is unclear if these doses are correct. A European-African study involving the Radboud University and Nijmegen University in the Netherlands, two African hospitals in Malawi and Zambia respectively and the UK Medical Research Council (MRC) was carried out. The aim of the study was to investigate whether Triomune tablets that are routinely divided for administration, deliver the same active ingredients, particularly in children who are malnourished. Tablets are difficult to split, the drugs are not equally distributed and there are no formal recommendations on how to divide them with the distinct possibility of under-dosing.

102 Bioavailability study results for new paediatric tablets for oral suspension, and caution against splitting adult doses Polly Clayden, HIV i-Base All discussion concerning obstacles to paediatric scale up - both at this conference and to date - has highlighted the lack of easily stored, low cost, age appropriate antiretroviral formulations for children. As an interim measure many programmes prescribe divided adult fixed dose combinations (FDCs) but this is not without problems, and can yield suboptimal levels of nevirapine, particularly in very young children (see below). Obviously FDCs for children will be a welcome development.

103 Paediatric FDCs At the pharmacology (PK) workshop in Lisbon earlier this year, independent investigators presented bioavailability data for Indian generic manufacturer Cipla’s Pedimune Baby and Pedimune Junior FDC tablets of NVP, 3TC and d4T, which led them to conclude that it would be acceptable to begin testing PK and dosing requirements of these formulations in African children even though the formal bioequivalence study by Cipla has not yet been completed. [1, 2] Another Indian generic company, Ranbaxy has developed two new paediatric formulations of tablets for oral suspension (TFOS) “designed to disintegrate quickly into a uniform suspension in small volume of liquid media like water”. A poster from Singla and co-workers from Ranbaxy described the formulation development of 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 company’s bioavailability study of a single dose of the Triviro-LNS kids DS formulation compared to reference propriety liquid formulations. [4] The investigators reported that the tablet has: a break line, “to enhance accuracy of dosing”; “a pleasant orange flavour” and requires no specific measuring device or refrigeration. Time to dispersion is 40 seconds in a small amount of water. The bioavailability study was an open label, single dose crossover study conducted in 36 fasting HIV negative adult males. The investigators reported that the geometric mean ratios (% Test/Reference) of log-transformed parameters of AUC, Cmax and 90% confidence intervals were within % interval, see Table 1. They wrote “Therefore the two treatments were considered to be similarly bioavailable and they concluded “Ranbaxy’s novel paediatric triple ARV TFOS could be used in place of individual liquid formulations.”

104 MedlinePlus related topics:  Thyroid Diseases Genetics Home Reference related topics:  Thyroid Diseases Study Type: Interventional Study Design: Treatment, Randomized, Open Label, Active Control, Crossover Assignment, Bio-equivalence Study Official Title: Generic vs. Name-Brand Levothyroxine: Assessment of Bioequivalence Using TSH as a Marker in Children With Permanent Hypothyroidism Further study details as provided by Children's Hospital Boston: Primary Outcomes: Thyroid Stimulating Hormone Measure Expected Total Enrollment:  40 Study start: June 2006;  Expected completion: January Last follow-up: January 2008;  Data entry closure: January 2008 This study is an unblinded, randomized controlled cross-over study, which involves taking 2 different forms of levothyroxine sequentially over a 16 week period. Subjects will have a total of 3 visits over this time period. At the first visit, subjects are randomized to rec


106 Purpose This is a randomized, double-blind, multi-centered study to compare 6 months of medical treatment with digoxin or propranolol in infants with SVT Background: SVT is the most common sustained arrhythmia of infancy. Neither digoxin nor propranolol has been evaluated for pediatric use in a controlled trial in the context of SVT, yet both medications are used frequently. Specific aims of the study: To determine whether propranolol and digoxin differ in the: Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin Time to first recurrence of SVT in infants treated with propranolol or digoxin. Incidence of adverse outcomes in infants treated with propranolol or digoxin. Condition InterventionPhaseSupraventricular Tachycardia in Infants Drug: digoxin and propranololPhase IIIMedlinePlus consumer health information  Study Type: Interventional Study Design: Treatment, Randomized, Double-Blind, Active Control, Single Group Assignment, Bio-equivalence Study Official Title: Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia

107 The purpose of this research study is to:
Asthma and gastroesophageal reflux disease (GERD) are common disorders, which although are not usually lethal, both have high morbidity, and high healthcare costs. Recent studies have demonstrated that asthma and GERD often co-exists, and that this 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 to treatment with a PPI( Proton Pump Inhibitor), have fewer asthma episodes than similar participants assigned to placebo for a similar duration of time Determine whether children treated with Lansoprazole ( i.e., proton pump inhibitor) : have a longer time to first exacerbation, have improved lung function, improved asthma symptom scores, improved quality of life, decreased rescue inhaler use, or other asthma medications, reduced emergency room/urgent care/ physician office visits that are asthma related. Determine whether a subgroup of symptomatic asthmatics, who show a greater benefit from PPI’s, can be identified.

108 Ranbaxy presents bioequivalence data on two paediatric fixed dose triple combination tablets
printer friendly versionsend to friendglossarycomment  Edwin J. Bernard, Thursday, August 17, 2006Two fixed dose triple combination water- dispersible tablets produced by generic manufacturer Ranbaxy providing half- and quarter-doses of nevirapine, lamivudine and stavudine for paediatric use are bioequivalent to their proprietrary liquid formulations in adults, according to a study presented to the Sixteenth International AIDS Conference in Toronto on August 16th. The two formulations have already been approved by the Indian government, and have been submitted to the World Health Organisation (WHO) for inclusion on their pre-qualification list. Several recent initiatives have begun to address the issue of lack of paediatric formulations in low-income countries, first highlighted two years ago at the Fifteenth International AIDS Conference in Bangkok by Médecins Sans Frontières (MSF) director Daniel Berman.


110 Conclusion A new way for the future and a long way to solve all the issues….

111 Further references Yu LX et al. Biopharmaceutics Classification System: The scientific basis for biowaiver extensions. Pharm Res (7). Polli J.E et al. Summary Workshop Report: Biopharmaceutics Classification System- Implementation Challenges and Extension Opportunities. J Pharm Sci (6) Vogelpoel H. et al. Biowaiver monographs for IR solid oral dosage forms based on BCS literature data: Verapamil HCl, Propranolon HCL and Atenolol J Pharm. Sci. 93(8) Lindenberg et al.: Classification of orally administered drugs on the WHO model list of essential medicines according to the biopharmaceutics classification system. Eur. J. Pharm. Biopharm. 58: , 2004

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