DRUG DOSING IN PEDIATRIC PATIENTS

1. DRUG DOSING IN PEDIATRIC PATIENTS Dr S Sirisha DEPARTMENT OF PHARMACY PRACTICE

2. INTRODUCTION • Better understanding of various physiological variables that are regulating the fate of the drug is important to improve both safety and efficacy of drug therapy • Pediatric patients show such physiological variability and so it is important to select an appropriate dose for a pediatric patient • Here, the organs are not matured • The development of organs continue until at least to the age of 12 years • Pediatric patients were always considered in the past for treatment as MINI ADULTS

3. INTRODUCTION… • Classification of pediatric patients: • Preterm Neonate (Preterm Newborn Infant) (<37 weeks gestation) • Neonate (Newborn Infant ) (Birth To 27 Days) • Infant & Toddlers (28 Days To 23 Months) • Young Child (2 To 5 Years) • Older Child (6 To 11 Years) • Adolescent (12 To 18 Years) • The Adult (>18 Years)

4. INTRODUCTION… • The practice of scaling adult drug doses to infants and children based on BW or BSA does not account for the developmental changes that affect drug pharmacokinetics or target tissue and organ sensitivity to the drug • In fact, this dosing practice has resulted in therapeutic tragedies that illustrate the importance of understanding the effects of ontogeny on drug pharmacokinetics and drug effect and the need for separate clinical trials and pharmacological studies of drugs in pediatric patient populations • The chloramphenicol-induced gray baby syndrome is an example of the potential dangers inherent in treating newborns based on dosing recommendations in adults

5. INTRODUCTION… • In late 1950s case reports of unexplained deaths in newborns who were receiving chloramphenicol appeared • These deaths led to a controlled clinical trial of chloramphenicol therapy in premature newborns • High concentrations of chloramphenicol and its metabolites accumulated in newborns presumably accounted for the severe toxicity • This accumulation of drug on a dosing regimen that is tolerable in adults resulted from the reduced capacity of newborns to metabolize chloramphenicol by glucuronide conjugation • The rate of chloramphenicol metabolism was found to be highly age dependent and the half-life was 26 hours in the newborns, 10 hours in the infants, and 4 hours in the older children

6. INTRODUCTION… • Therapeutic tragedies such as this could be avoided by performing pediatric pharmacological studies during the drug development process • Zidovudine is eliminated in adults primarily by glucuronide conjugation, suggesting that newborns may have a reduced capacity to eliminate the drug • Unlike chloramphenicol, prior to widespread administration of zidovudine to newborns and infants born to HIV infected mothers, the pharmacology and safety of the drug were carefully studied in this population and age-specific dosing guidelines were developed

7. GENERAL CONSIDERATIONS • Infancy and childhood is a period of rapid growth and development of organ systems and so careful administration of drugs should be ensured • Term infants undergo rapid physiologic changes in total body water and in renal and hepatic function during the first few days of life • CNS maturation with completion of myelination occurs in the infant and toddler age group • During the age of 1-12 years almost 60% drop in extra cellular volume • Dosage is adjusted based on pharmacokinetic data of a given age group for the desired response, but considering each individual’s drug handling capacity is often the most rational approach

8. ABSORPTION • Gastric pH is6-8 at birth, but drops to pH 1–3 within 24hours of birth • Gastric acid secretion then declines (Achlorhydria) during 8–30 days, and does not approach adult values until approximately 3 years of age • This lower level of gastric acid secretion contributes to the increased bioavailability of acid-labile drugs in neonates compared to older children and adults (E.g.: Penicillin G, Ampicillin)

9. ABSORPTION… • Gastric emptying is delayed (upto 6 – 8 hours) and irregular in the neonate and infant, but approaches adult values by 6–8 months of age • Intestinal motility (peristalsis) is also irregular, unpredictable and only partially dependent on feeding patterns in newborn until 1 year • In newborns, decreased GI motility can delay drug absorption and result in lower peak plasma drug concentrations, but does not alter the fraction of drug absorbed for most drugs • In older infants and children, GI transit time may be increased

10. ABSORPTION… • Premature infants and neonates have diminished bile acid pool and biliary function develops during the first month of life • This may have influence on drugs undergo enterohepatic circulation after conjugation with glucuronic acid • Enzymatic activity in the GI tract, specifically, a 7 fold increase in the capacity of β - glucuronidase andUDP – glucuronyl transferase in the neonatal gut • The ratio of absorptive surface area to BSA is greater in infants and children than in adults • Although pancreatic enzymeexcretion is low in neonates, malabsorption does not occur and no effect on drug absorption has been observed

11. ABSORPTION… • The newborn intestine is colonized with bacteria within days of birth, but the spectrum of bacterial flora may change over the first few years of life • The patterns and extent of colonization depend on age, type of delivery, type of feeding, and concurrent drug therapy • Compared to adults, the capacity of intestinal bacterial flora to inactivate orally administered drug is less and thereby bioavailability is increased in infants less than 2 years old • Drug absorbed by the oral route is erratic in the newborn baby of any gestation • Thus it is usual to give many drugs by the iv/im route to ensure maximum BA

12. AGE DEPENDENT PHYSIOLOGIC VARIABLES INFLUENCING ORAL DRUG ABSORPTION AS COMPARED TO ADULTS

13. ABSORPTION… • Absorption following i.m. administration depends mainly on the regional blood flow which may differ among specific muscles • In neonates, the i.m. absorption pattern may considerably change during the first 2 weeks of life • Reduction in absorption rate of intramuscularly administered Digoxin and Gentamycin have been reported in neonates • Increased skin permeation found in neonates and infants results in increased systemic absorption

14. SUMMARY OF DRUG ABSORPTION IN PEDIATRIC PATIENTS

15. POSSIBLE PHARMACOKINETIC CONSEQUENCES

16. RELATIVE GASTROINTESTINAL ABSORPTIONOF SELECTED DRUGS IN INFANTS AND ADULTS

17. DISTRIBUTION • Total body water accounts for a larger fraction of body weight in newborns than in older children and adults • There is also a larger fraction of extracellular water at birth

18. DISTRIBUTION • As a result of this, the apparent distribution volume of the water-soluble drug is greater in newborns and infants than in adults when normalized to body weight or surface area (E.g.: Sulfisoxazole) • Total body water decrease throughout the first year and shift predominantly from extra cellular to intracellular fluid • Dosage adjustment has to be done to drugs that are highly water soluble like Gentamycin to avoid ADR • Few lipophilic drugs have comparatively a large Vd despite of lower adipose tissue (because of higher proportion of body fat than adults and high affinity of these lipid sites) e.g.: Diazepam • Large interpatient variability in Vd due to varied nature of maturation

19. DISTRIBUTION • Serum albumin, α-1 acid glycoprotein, and total protein concentrations are lower at birth and during early infancy • Total proteins and plasma protein binding reach adult values at about 1 year of age • The reduced plasma protein binding in newborns is due to the concurrence of several factors such as • Reduced total plasma protein concentrations associated with a qualitative difference in plasma protein content • Fetal albumin has lower affinity for drugs and a lower level of γ-globulin and lipoproteins • A condition of relative hypoxaemia associated with a lower blood pH • A high plasma concentration of free fatty acids and unconjugated bilirubin which may compete with acidic drugs at albumin binding sites • The possible presence of ‘competitive binding’ substances of maternal origin

20. DISTRIBUTION • The ratio of bound drug concentration (B) to free drug concentration (F) can be written in terms of the number of binding sites (n), the molar protein concentration (P), and the affinity constant (KA), as shown in Equation • For most drugs in their therapeutic range, the product of F and KA is much less than 1; therefore, the fraction unbound is drug concentration independent (ie, linear binding) • Hence, the above equation could be written as follows for the infant and adult, respectively

21. DISTRIBUTION • If the intrinsic properties of the protein (n and KA) are assumed to remain constant with age, adult equation may be rearranged to solve for a common KA and subsequently substituted into infant equation results in • From a pharmacokinetics perspective, the fraction unbound is more valuable and more frequently reported than is B/F ratios • Fraction unbound drug in the plasma ƒu is defined as the ratio of F to total drug concentration is the sum of F and B

22. DISTRIBUTION • Based on the above two equations, a relationship can be derived that predicts the fraction unbound for infants in terms of the ratio of the binding protein concentration (infant to adult) and the adult fraction unbound • As the ratio of abundance of binding proteins approaches unity, the fraction unbound in infants approaches adult values • The use of adult intrinsic clearance values may need to be adjusted for differences in binding for highly bound drugs in cases where the plasma protein concentration is significantly lower in infants

23. PLASMA PROTEIN BINDING AND DRUG DISTRIBUTION (SUMMARY)

24. POSSIBLE PHARMACOKINETIC CONSEQUENCES

25. METABOLISM • At birth, majority of the metabolic enzyme systems are either absent or present in considerably reduced amounts (20 % - 70 %) compared to adults (Exemptions: Sulphate conjugation is more) • Glucuronitation is very less. Therefore, chloramphenicol is not bound extensively and so no / poor elimination (metabolism) results accumulation of chloramphenicol that leads to Gray baby syndrome • Caffeine in children may have half life of even 5 days but, in adults it is 4 hours • So, drugs that are extensively metabolized by liver should be administered cautiously(caffeine, lidocaine, chloramphenicol) • A reduced capacity to dispose of drugs is constantly observed during the first 156 days of life

26. METABOLISM… • In most cases such a stage of reduced metabolic degradation is then followed by a dramatic increase in the metabolic rate of mainly phase I reactions • The increased metabolic disposition rate is usually very evident from 2-3months up to 2-3 years of age • Then values tend to decline gradually to reach those of adults after puberty • Hormonal changes occurring during puberty can also affect drug disposition • Another important aspect of drug metabolism is dose – dependent or enzyme capacity limited drug elimination that is important for all age groups

27. DRUG METABOLISM IN NEONATE, INFANT AND CHILD (SUMMARY)

28. POSSIBLE PHARMACOKINETIC CONSEQUENCES

29. EXCRETION • Renal function is significantly lower in infants and small children when compared to adults, because of variation in • Renal plasma blood flow • GFR • Secretion • Reabsorption • At birth, kidney blood flow is characterized by increased vascular resistance and a preferential intrarenal flow away from the outer kidney cortex • After 2-3 days of extra uterine life the GFR may be 8 -20 ml/min • GFR is approximately 40 ml/min/1.73 Sq. m in the term neonate and gradually increases to adult values by three years of age

30. EXCRETION… • Passive tubular reabsorption may be reduced in the infant and neonate • Therefore , dosage must be individualized with a careful assessment of therapeutic effect • Renal drug elimination is the primary route for antimicrobial agents which are the most commonly used drugs in children(β- lactam antibodies, amino glycosides)

31. RENAL FUNCTION IN NEONATE, INFANT AND CHILD (SUMMARY)

32. POSSIBLE PHARMACOKINETIC CONSEQUENCES

33. ISSUES IN THERAPEUTICS • Sampling blood is both difficult & questionable • Alternative source to be considered (saliva, urine) • Estimation from urinary samples involve either • Sigma Minus Method log (Xuα– Xut) = log Xuα-Kt / 2.303 Or • Excretionrate plot log (∆Xu/ ∆t) = log Ke X0/ 2.303 • Many drugs are often estimated by this method (paracetamol, gentamycin) • For drugs that achieve saturation kinetics rate of drug administration can be calculated using “Michaelis – Menton equation D/t = Vmax * C/Km + C

34. DOSAGE • In selecting a method of dosage calculation therapeutic index of the drug should be considered • For narrow therapeutic index drugs, dosing must be based on the calculated body surface area (recommendations are quoted in per square meter area) • Dosage adjustments based on TDM and nomograms in single and drug combination situations are possible • However, wide variations in Vd and CL exist

35. FACTORS TO BE CONSIDERED WHEN SELECTING A DRUG DOSAGE REGIMEN OR ROUTE OF ADMINISTRATION FOR A CHILD PATIENT • Age / Weight / Body surface area • Dose / Dose interval • ROA • Formulation / Preparation • PK • Interactions • ADR • Counseling and compliance aids • Legal considerations

36. SOME USEFUL FORMULAS TO CALCULATE CHILD DOSE • Clark’s rule: Infant dose = (BW infant / BW adult) * Adult dose • Based on BSA: Infant dose (if Vd < 0.3 L/Kg) = (BSA/1.73) * A.D Infant dose (if Vd≥ 0.3 L/Kg) = (BSA/70) * A.D BSA neonate = 0.224265 * BW0.5378 *Ht0.3964 BSA infant = 0.007184 * BW0.425 *Ht0.725

37. MONITORING • Monitoring drug concentration from serum or the biological fluids is useful if desired effect is not obtained • Monitoring also helps to avoid ADR which may sometimes be fatal to the children