CLINICAL PHARMACOKINETICS IN CHILDREN Need of Study:

New drugs are untried in children Poor patient compliance Possible under dosing or over dosing Developmental Changes In Body Water Compartments: TBW 1. 70- 75 % of body weight 2. 50- 55 % in adults ECW 1. 40 % of body weight 2. 20 % in adults 3. Varied through out child hood 4. Important for the ultimate drug concentration of non tissue binding drug Developmental Changes In The Kidneys Drug Elimination Process: Low GFR and long half life of penicillin GFR attains normal value at 2.5- 5 months

 Renal tubular secretary capacity (PAH secretion) attains normal value at 7 months 50% of t1/2 due to GFR Three times longer t1/2 due to tubular secretion Other Developmental Changes: Age dependent changes in size of liver Changes in hepatic metabolizing enzymes Possible exposure of the new born to the drug in utero More sleep during 24 hr period Biphasic and more acidic pH in children at night Possible presence of bilirubin and free fatty acids Qualitative and quantitative changes in plasma proteins Drug Absorption: Gastrointestinal absorption 1. Gastric emptying time Prolonged and approaches to normal values after 6 months Function of gestational maturity, post natal age, nature of feeding Very irregular and unpredictable peristalsis 2. Gastric pH Dropped to 1.5-3 with in few hours and attain neutral within 24 hrs Normal pH is attained after 2 years in premature new borns High bioavailability for penicillins Lower absorption of acidic compounds 3.Other factors 1.Variable colonisation rate 2.Higher glucuronidase activity

3.Presence of disease (cardiac insufficiency) 4.Alteration of biliary function (steatorrhoea) 5.Presence of antibiotic therapy Intramuscular absorption 1. Ease of penetration through endothelial capillary walls 2. Surface area 3. Blood flow 4. Changes in relative blood flow of various muscles 5. Reduced skeletal muscle mass and subcutaneous fat 6. High percentage of water 7. Complicated by circulatory in sufficiency 8. Rapid absorption of phenobarbitone, delayed absorption of gentamicin and reduced absorption of digoxin. Percutaneous absorption 1. Inversely related to thickness of stratum corneum 2. Directly related to skin hydration 3. Aggravated by the use of abrasive tapes 4. Toxic effects with boric acid powder Drug Distribution And Drug Protein Binding: Different absolute and relative size of body compartments Higher extra cellular: intracellular water Low fat tissue (15% body weight) Reduced skeletal muscle mass (25%) Low myelin content and higher cerebral flow in brain tissue Larger brain and liver in relation to body weight Variations of blood pH, acid base balance, cardiac out put and regional blood flow Reduced plasma protein binding due to Reduced total plasma protein concentration

 Hypoxaemia associated with low blood pH High plasma concentration of FFA and un conjugated bilirubin Possible presence of competitive binding substances of maternal origin Drug Biotransformation: Esterase activity 1. Reduced esterase activity in plasma and various tissues 2. Increased volume of distribution with low level of esterase 3. Prolonged effect and cardio respiratory depression with local anesthetics containing ester bonds Hepatic microsomal activity 1. Reduced cytochrome P-450 and NADPH cytochrome C-reductase 2. Reduced enzymatic catalysing activity in phase 1 biotransformation reactions 3. Possible exposure in utero to microsomal enzyme inducing enzymes 4. Reduced hepatic up take of organic anions and bilirubin due to deficiency of hepatic cytoplasmatic anion binding protein ligandin. 5.More significant for drugs with low hepatic extraction ratio 6.Reduced hydroxylation rates 7.No change in sulphate and glycine conjugation 8.Reduced conjugation with glucuronic acid and attains normal after 3 years of age 9.Reduced metabolic activity further decreased by pathological conditions 10.Possible risk of over dosing to under dosing Drug Excretion: Anatomically and functionally immature kidney More advanced glomerular function than tubular function Effect of gestational age and hemo dynamic changes on renal function Low tubular function capacity for transport of glucose, phosphate, bicarbonate and PAH

 Reduced passive resorption Lack of diurnal rhythm of renal function. Low urinary pH Low clearance rate and high half life values of aminoglycoside antobiotics (dependent on GFR) Low clearance rate and high half life values of penicillins (depends on tubular secretion)

Reduced renal secretion may modify the kinetics of drugs Pathological conditions may cause a delay in maturation of kidney Pre and post natal drug administration may alter renal function.