Paediatric Drug Development

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Seminar on Paediatric Drug Development By Ashok Velpula M Pharm(1st Sem) Industrial Pharmacy St Peter’s Institute of Pharmaceutical Sciences Vidyanagar Hanamkonda ,Warangal.506 001

Contents : 

Contents Introduction Current issues Regulatory pathways Development challenges Pharmacokinetics in paediatrics Drug product development Calculations Conclusion References

Introduction : 

Introduction paediatrics is a branch of medicine dealing with the development, disease and disorders of children. The paediatric population comprises 20-25% of total world population, and numerous acute and chronic diseases can affect this subpopulation. AGE DEFINITIONS: The childhood is divided into the following age ranges for the purposes of clinical trials and licensing of medicines Preterm new born infants Term new born infants(neonates)(0-27 days) Infants and toddlers(28 days-23 months) Children(2-11 years) Adolescents(12-16-18 years)

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paediatrics is the fastest growing prescription segment paediatric patients should be given medicines properly evaluated in appropriate subjects paediatric Drugs are new formulations – not tweaking existing formulations Significant risk due to lack of adequate paediatric use information – almost ¾ medications lack paediatric use data Need for the establishment of Bioavailability data in paediatric population needs to be amplified.

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Children are not just “little adults,” and lack of data on important pharmacokinetic and pharmacodynamic differences has led to several disastrous situations in paediatric care. Variations in absorption of medications from the gastrointestinal tract, intramuscular injection sites, and skin are important in paediatric patients, especially in premature and other newborn infants. The rate and extent of organ function development and the distribution, metabolism, and elimination of drugs differ not only between paediatric versus adult patients but also among paediatric age groups. The effectiveness and safety of drugs may vary among various age groups and from one drug to another in paediatric versus adult patients.

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Special methods of drug administration are needed for infants and young children. Many medicines needed for paediatric patients are not available in appropriate dosage forms, and thus the dosage forms of drugs marketed for adults may have to be modified for infants and children, requiring assurance of potency and safety of drug use. The paediatric medication-use process is complex and errorprone owing to multiple steps required in calculating, verifying, preparing, and administering doses The myth that neonates and younger children do not experience pain has led to inadequate pain management in this population

Current Issues : 

Current Issues Many adult dosage forms not suitable for infants / children – ONE SIZE DOES NOT FIT ALL Non compliance rates in 50-70% , worse in chronic cases Limited drugs currently labeled for paediatric use. paediatric drug development internationally is an issue. Lack of appropriate formulations- denied access , extemporaneous preparation risk , non reproducibility, adverse events , overdose or under treatment

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Regulatory Pathway Regulatory Strategy would be inline with the NDA / ANDA guidelines depending on the product. Desired Development Pharmaceutics details covered in the Module 3 of the Common Technical Document ( CTD ) for Registration of Pharmaceuticals Paediatric Exclusivity – Additional market for exclusivity for approved drugs for studies in paediatric population

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Benchmarks in the regulation of paediatric drugs 1902 Biologics control Act 1906 Pure Food and Drug Act 1938 Food Drug and Cosmetic Act 1962 Kefauver – Harris Amendment 1979 Labeling Requirement 1994 paediatric Labeling Rule 1997 Food and Drug Administration Modernization Act 1998 paediatric Rule 2002 Best Pharmaceuticals for Children Act(BPCA) 2003 paediatric Research Equity Act(PREA)

BENCHMARKSpaediatric Drug Development (cont.) : 

BENCHMARKSpaediatric Drug Development (cont.) 2002 – Congress passes Best Pharmaceuticals for Children Act (BPCA) renewed Exclusivity provides process for drug development public health benefit 2003 – Congress passes paediatric Research Equity Act (PREA) Requires the study of drugs and biologics for paediatric population except in defined situations Creates paediatric Advisory Committee

Development Challenges : 

Development Challenges Scientifically challenging – measurable dose based on body weight , taste masking Availability of limited ingredients for paediatric design – functional , taste Drug taste an issue – Adults have a better tolerance to bad taste Taste / Sweetness preference – differ significantly Alcohol not desirable, Toxicity of excipients vary across age groups Compliance – Taste , smell, texture , shape , mouth feel etc .Acceptable palatability Convenience for administration Clinical evaluation difficult – new sampling methods, new analytical techniques, limited patient population

Pharmacokinetics in paediatrics : 

Pharmacokinetics in paediatrics Children’s pharmacokinetic parameters changes during maturation from neonates to adolescents Each aspect of drug disposition is affected including absorption ,distribution ,metabolism , and elimination. None of these process is fully mature at birth , and they develop at different rates over the first year of life. The study of these changes is known as development pharmacology. (A) Gastrointestinal absorption :- Oral drug absorption is most greatly altered during the first year of life. Several aspects of absorption are age dependent including gastric PH ,Gastric emptying time , intestinal motility , bile salt production and pancreatic enzyme function.

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(i)Elevated gastric :- Gastric elevated ( > 4). This results from a elevative decrease in gastric acid production and an overall decrease in the volume of gastric secretions. Acid production rises steadily after birth, Reaching adult levels with in two months. (ii)Prolonged gastric emptying intestinal motility:- The rate of passage of drugs through the gastro intestinal tract is also important in determining the rate and extent of their absorption. Coordination of contractions within the stomach begins to improve shortly after birth, while intestinal peristalsis increases more slowly , over the first four months of life. As a result of this prolonged transit time, absorption of drugs may be significantly slowed.

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(iii) Bile salt production pancreatic enzyme function. The rate of bile salt synthesis in preterm and term infants is reduced to approximately 50% of adult values. Decreased fat absorption from enteral feeding , as well as decreased drug absorption, Can occur. Percutaneous absorption : Absorption of drugs through skin is enhanced in infants and young children owing to better hydration of the epidermis , greater perfusion of the subcutaneous layer, and the larger area of total body surface area to body mass compared to adults. Intra muscular absorption : Intra muscular administration of drugs is generally discouraged in the paediatric population because of the pain associated with the injection and the risk of nerve damage from inadvertent injection into nerve tissue.

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Pulmonary administration: Inhalation of medications is increasingly being used in infants and older children to avoid systemic exposure. Drug distribution : Growth and maturation effect many of the factors that determine drug distribution. Body water content , fat stores, plasma protein concentrations Body water and fat content ; Total body water content decreases with increase in age. This is primarily the result of a larger extra cellular body water content in neonates and young infants which decreases with age. Approximately 80% of a new born weight is body water. By one year of age, this value declines to 60%,similar to that of an adult.

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Protein binding : Binding of drugs to plasma proteins is also decreased in new born infants because of the decreased plasma protein concentration , lower binding capacity of protein, decreased affinity of proteins for drug binding, and competition for certain binding sites by endogenous compounds such as bilirubin . Metabolism : The most significant research in developmental pharmacology during the fast decade has come in the area of metabolism. Developmental changes have been identified for many phase 1 and phase 2 reactions. Glucuronidity is generally decreased in neonates, compared with older children and adults. The rate of metabolism increases with increase in age Unlike glucuronidation, sulphation develops in utero and is well developed in the neonate.

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Elimination : Development of renal function is a complex and dynamic process. Nephrons begin forming as early as the 9th week of gestation and are complete by 36 week. Filtration capacity is significantly low at the birth .Glomerular filtration rate in neonates is approximately half that of adults. Glomerular filtration rate increases rapidly during the first two weeks of life and typically reaches adult values by 8 to 12 months of age. Tubular secretion rate is also reduced at birth to approximately 20% of adult capacity but matures by 12months of age To account for the reduced ability of a neonate to eliminate these drugs, longer dose in intervals are often required failure to account for the reduction in renal function may result in drug accumulation and toxicity.

Drug Product Development- Aim : 

Drug Product Development- Aim paediatric Product should be designed to meet – Patient Need (Clinical Benefit , accurate dosing , compliance ) & Intended Product Performance ( product quality , stability , drug release ) Must address general Drug Development Processes and PK profile for population age and side effect profile Cover the evolution of the formulation design from initial concept to final design

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Stage Specific Tasks During Product Development Define Product identified Bulk supplier identified & committed Literature research strategy & submission strategy firmed up Packaging development initiated Research Development strategy firmed up Tentative method development started Design Prototype developed and put on stability A R&D Methods developed Formulation / process finalized Develop Prototype scaled up to Lab scale A R&D methods firmed up and validated Exhibit batch replica executed Pilot bio studies conducted on PE Batch Implement Exhibit batch Stability test Pivotal bio studies ANDA compilation ANDA filing/Product launch

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Drug Product Development- Factors Drug Substance : Physicochemical & Biological Characteristics : Performance ( dissolution , stability , BA ) Manufacturability Compatibility : With excipients Between drugs Excipients : Type , Concentration, Characteristics Performance ( dissolution , stability ) Manufacturability Compatibility Within excipients / Between Excipients Functionability - taste maskers, disintegrant

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Drug Product Development- Factors Manufacturing Process : Type of Process Robustness , Critical process attributes Drug Product Characteristics : Active Stability Preservative system effectiveness Palatability considerations , pH , Viscosity etc Container Closure System: Intended Use , Suitability for Storage/Transportation , CCS Integrity , Non Interaction , Adequate Protection , Safety of construction material

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Drug Product Development- Factors Microbiological Attributes : May / May not be require – Dosage Form specific Type / Concentration – Product Concentration – Efficacy & Safety , Shelf-life , Chemical content , Least concentration

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Drug Product Development - Options Ready To Use (Oral ) : Solution, Syrup, Suspension, Tablet, Scored Tablet, Chewable Tablet, Orally Disintegrating Tablet, Sublingual Strip, Flavored Medicated Lozenges, Lolli-pop formats , Wafers , Sublingual , Easy to Swallow Dosages etc .

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Drug Product Development - Options Modification Before Use ( Oral ) : Sachets, Powder for Constitution to Suspension/Solution , Tablet for Constitution to Suspension / Solution, Drops for Reconstitution to Suspension/Solution, Concentrated Solution for Dilution , Effervescent Tablet, Sprinkles for Dispersion in drink/food. Alternate Delivery Route : Suppository dosages , Painless injections , Transdermal

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Calculations Bastedo’s rule: paediatric dose= Formulas based on age of the paediatric patient: Formula based on body surface area of the paediatric patient(Clarke’s formula): paediatric dose= Formula based on body weight of the paediatric patient(Clark’s formula): paediatric dose=

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Calculations Fried’s rule for infants: Infant dose= Young’s rule: paediatric dose= Dilling’s rule: paediatric dose=

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CHALLENGES AND OPPORTUNITIES FOR THE FUTURE:- Suggestions include Improving the post market safety surveillance system; Combining incentives and requirements for the conduct of paediatric research into one process; Increasing transparency throughout the clinical research enterprise; Increasing training for the next generation of clinical pharmacologists and paediatric researchers; Providing additional funding and incentives for paediatric drug development;

Reflection : 

“ paediatric Drug Development ” “ It is like turning over rocks and discovering how much you did not know about what was under the rock. The next problem is how to communicate what is under the rock and how to answer questions that arise from looking.” Reflection

conclusion : 

conclusion Development of paediatric drug product is challenging and very complex. Product Quality with respect to stability, safety, efficacy, acceptability, compliance are very critical. paediatric drug development inspired by increased regulatory initiative. Patient compliance can be radically improved by creative dosage delivery. Conducting the necessary bridging studies in early development stages is inexpensive compared to rerunning the studies after approval Shared responsibility – PharmaCompanies, RegulatoryAgencies, Health Professionals and Society .

References : 

References Gilbert S. Banker, Christopher T. Rhodes. Modern Pharmaceutics,Fourth Edition. (2002), chapter 21. The McGraw-Hill Companies, Pharmacotherapy. 6th edition. (2005). Page no : 91 – 102.

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Thank You