Pharmacokinetics in pediatric population

Transcription

1 Pharmacokinetics in pediatric population Children cannot be considered to be small adults. The physiologic processes that determine drug disposition undergo radical changes during biological maturation. These changes may be due to: 1. A large inter patient variability in drug disposition is observed for many drugs in pediatric patient population. 2. A little data is available concerning the disposition of drugs in infants before the general release of new drugs. 3. Studies in infants and young children are difficult to perform because of the limited amount of sample which can be collected. 4. In the pediatric population, growth and developmental changes in factors influencing ADME also lead to changes in pharmacokinetic measures and/or parameters Possible causes of pharmacokinetic and pharmacodynamic changes: 1. basic physiologic properties such as lipid and water composition ( neonates, infants, children, adolescents, and adults have different percentages of body water and fat) 2. organ weights (neonates, infants, children, adolescents, and adults have their body organs in different stages of development). Liver mass per body weight is higher in infants than in adults, and tissues such as liver, kidney, and lung undergo rapid growth during the first 2 years. The brain is disproportionately large in young children 3. blood flows 4. Functional deficits as a result of the immaturity of hepatic and renal systems. 5. The pediatric population needs to be categorized into various age groups,each age group has differences with respect to their growth and development characteristics for which same medication may have different doses, dosage forms and administration techniques Drug Dosages in pediatric population: The administration of medications to pediatric patients is difficult because less information is available about the use of most medications for pediatric patients (In fact only about 20% of drugs marketed in the United States have labeling for pediatric use)

2 Many drugs that are used for some pediatric patients are not in appropriate dosage forms for use by children. This includes even some medications approved for use in pediatric patients. Because the majority of drug dosages are based on the patient's weight on a mg per kg body weight per day, it is important to know the current patient weight. Medication intervals may vary depending on the child s age. e.g. a medication which is renally eliminated in the very young has an extended interval compared to an older child. Body surface area (BSA) is a calculation based on the patients height and weight. It is mainly used to calculate chemotherapy dosages. Dosing recommendations 1. Dosing based on weight, e.g. per mg doses or Clark's rule 2. Dosing based on surface area SA, e.g. per m 2 Dose = SA of patient(m2). adult dose Dosing based on age, e.g. Young's rule for children older than 2 years Pharmacokinetic changes Absorption Infants after the newborn period have a relative achlorhydria; with gastric acid secretions increasing to reach adult levels at age 3. e.g. The bioavailability of acid labile penicillins is increased in newborns. Delayed gastric emptying and irregular intestinal peristalsis leads to slower absorption of some drugs in infants and young children. Other factors can affect absorption in pediatric include Surface area of the absorption site Gastrointestinal enzyme systems for drugs that are actively transported across the Gastrointestinal mucosa Gastrointestinal permeability Biliary function. Developmental changes in skin, muscle, and fat, including changes in water content and degree of vascularization, can affect absorption patterns of drugs delivered via intramuscular, subcutaneous, or percutaneous absorption Inhalation exposure can also be greatest in early life, which in this case is attributable to the greater respiratory volume per lung surface area.

3 Distribution Neonates and infants have different percentages of body content of water and lipid than older children and adults. At birth, there is a greater percentage of body water and less body lipid. This can increase the volume of distribution of water-soluble drugs because of expanded water volume but may also decrease the partitioning and thus retention of lipidsoluble drugs. Total body water as a fraction of body weight decreases throughout the first year of life. Plasma protein binding and tissue binding changes arising from changes in body composition with growth and development may also influence distribution e.g. decreased protein binding in infant Neonates have low protein-binding levels, with regard to both albumin and [alpha]- 1-glycoprotein. This combined with the fact that neonates have immature capability to conjugate and excrete bilirubin, an important endogenous molecule that binds extensively to plasma proteins, may lead to a considerably smaller number of available proteinbinding sites in plasma. Other Factor cause increasing Vd and change t1/2: The immaturity of the blood-brain barrier Liver mass per body weight is high in infants Rapid growth of tissues such as liver, kidney, and lung undergo during the first 2 years. Metabolism The various pathways of drug metabolism mature at different rates, and therefore the ability of the newborn to metabolize drugs differs both quantitatively and qualitatively from that of older subjects. The overall elimination is much slower in newborns compared with adults. Drug metabolism usually occurs in the liver, but may also occur in the blood, gastrointestinal wall, kidney, lung, and skin. Developmental changes in metabolizing capacity can affect both absorption and elimination, depending on the degree to which intestinal and hepatic metabolic processes are involved.although developmental changes are recognized, information on drug metabolism of specific drugs in newborns, infants, and children is limited. In general, it can be assumed that children will form the same metabolites as adults via pathways such as oxidation, reduction, hydrolysis, and conjugation, but rates of metabolite formation can be different, increased enzyme capacity in young children and decreased enzyme capacity in neonate & Infant. e.g. chloramphenicol toxicity (anemia) as a result of immature glucuronidation capacity in neonates. This deficiency is critical for chloramphenicol as its primary route of elimination is via conjugation with glucuronide e.g. Sulfate conjugation is well developed at birth thus newborn paracetamol elimination, predominantly sulfation, is not greatly different from that of adult elimination. e.g. phenytoin, Km is not changed with age, but the maximum metabolism rate, Vm falls progressively with younger patients. e.g Valproic acid,this antiepileptic drug induces hepatotoxicity most frequently in young children (<2 years of age) who are on multidrug therapy. Although this reaction can occur in older children and adults, the generally higher activity of CYP metabolism per body weight in the 6-month to 2-year age group suggests

4 that PK factors can contribute to this sensitivity. Excretion Drug excretion by the kidney is controlled by glomerular filtration, tubular secretion, and tubular reabsorption. Because these processes mature at different rates in the pediatric population, age can affect systemic exposure for drugs where renal excretion is a dominant pathway of elimination. The pediatric populations have: Decreased GFR in neonate Decreased tubular reabsorption in infants. transporter (secretory) systems in the proximal convoluted tubule are deficient at birth Renal clearance is impeded by the relatively low percentage of cardiac output reaching this organ in the first weeks to months of life. That lead to relatively slow clearance of a wide array of antibiotics and other renally cleared Renal tubular capacity, measured by renal clearance of p -aminohippurate, achieve adult values 1 to 2 months later. GFR, normalized for body surface area, increases gradually reaching adult values at about 6 months. The immaturity of hepatic enzymes in neonates has been evidenced as prolonged drug half-life, reduced hepatic clearance. Consideration should also be given to the maturation of other excretory pathways, including biliary and pulmonary routes of excretion. Clinical studies Intravenous and oral propafenone for treatment of tachycardia in infants and children :pharmacokinetics and clinical response To elucidate contribution of an active metabolite to overall clinical responses to propafenone, steady-state disposition of propafenone and its active metabolite and the clinical responses to treatment were examined in pediatric patients receiving intravenous or oral propafenone. There were more than tenfold interindividual differences in apparent clearance, resulting in a wide range of the steady-state trough plasma concentrations of propafenone. The active metabolite, 5-hydroxypropafenone, was detected in four of the six patients receiving oral propafenone; however, two neonates receiving oral propafenone and all eight receiving intravenous propafenone had no detectable levels of 5-hydroxypropafenone in plasma. In nine patients for whom electrocardiographic (ECG) data were available, the PQ interval was significantly increased, whereas the QRS duration and the QTc interval were not. There was no close relationship between plasma concentrations of propafenone or 5- hydroxypropafenone and ECG parameters. Lack of good correlation between serum concentrations and clinical response precludes using a serum-concentration targeting strategy with propafenone therapy. Pharmacokinetics and pharmacodynamics of Saquinvir in pediatric patients with human immunodeficiency virus infection The Objectiveof this study was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in

5 combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection. The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weightadjusted dosing (50 mg/kg) was also investigated. The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism. Pharmacokinetics and pharmacodynamics of bumetanide on critically ill pediatric patients This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 ml/min/kg and / L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics. Pharmacokinetic Properties and Tolerability of Single-Dose Terbutaline in Patients with Severe Asthma Treated in the Pediatric Intensive Care Unit This study was to determine the pharmacokinetic (PK) properties and tolerability of single-dose terbutaline in pediatric patients across a broad age range who were admitted to the PICU and were receiving maximal conventional asthma drug therapy. This study was conducted at the PICU at Rainbow Babies and Children s Hospital (Cleveland, Ohio). Patients aged 6 months to 16 years with severe exacerbation of reactive airways disease and who were undergoing maximal conventional therapy and had an arterial catheter were enrolled. Patients were arbitrarily assigned to receive a single IV infusion of 1 of 3 doses of terbutaline (10,

6 20, or 30 pg/kg), infused over 5 minutes. Blood samples were obtained for the determination of plasma terbutaline concentrations just before terbutaline was administered (baseline), immediately on completion of the IV infusion, and at 10, 20, and 40 minutes and 1,2,4,8, 16, 32, 48, and 72 hours after the 5-minute infusion. PK properties (elimination halflife [t1,,2], mean residence time [MRT], apparent steady-state volume of distribution [Vd5], and total body clearance [Cl]) were determined and adverse effects were recorded. The determination of terbutaline PK properties was possible in 50 of 56 enrolled patients (31 boys, 19 girls; mean [SD] age, 6.5 f 4.5] years). The PK properties of terbutaline were linear over the dose range studied and, with the exception of the expected dose-dependent increases in peak terbutaline plasma concentration and area under the terbutaline plasma concentration time curve, no statisticafly significant differences were observed in PK relative to dose. Therefore, we pooled the data for all subsequent analyses. Statistically significant correlations with patient age were observed with t112 (r = 0.4, P 0.005), MRT (r = Q4, p < 0.002), and Vd (r = 0.33, P < 0.02), but not Cl (r = 0.03, < P = NS). Single-dose terbutaline administration was generally well tolerated. A rational dosing algorithm for Basiliximab in pediatric renal transplantation based on pharmacokinetic-dynamic evaluation The phannacokinetics and immunodynamica of basilixitnab were assessed in 39 pediatric de novo kidney allograft recipients to rationally chose a dose regimen for this age group. To achieve similar basilixirnab exposure as Is efficacious In adults, pediatric patients <35 kg should receive two 10-mg doses and those >36 kg should receive two 20-mg doses of basiliximab by intravenous infusion or holus injection. The first dose is given before surgery and the second on day 4 after transplantatioct Several inulticonter clinical trials have established the capacity of monoclonal antibodies directed to the interlcukin-2 receptor (hl-2r) on activated T lymphocytes (IL-2R or CD25) to prevent acute cellular rejection after kidney allografting in adults. Bosiliximab is a high-affinity clii- merit (human/mouse) monoclonal antibody in this therapeutic clas, of inimunosuppressants. It is applied in adult renal transplantation in a convenient, two-dose regimen in the perkransplant days and provides CD25 saturation for an average of 4 to 6 weeks after transplantation. It is a reasonable premise that pediatric kidney allograft recipients would also benefit from this agent.

7 APPINDIX Terms Definition Time from the mother's last menstrual period to the time the baby is born;at birth, a Dubowitz score in Gestational age weeks gestational age is assigned, based onthe physical examination of the newborn Postnatal age Age since birth Postconceptional Age since conception, i.e., gestational plus postnatal age age Neonate First 4 weeks or first month of life Premature neonates Born at less than 37-weeks gestation Fullterm neonates Born between 37- and 42-weeks gestation Postterm neonates Born after 42-weeks gestation Infant 1 month to 1 year of age Child 1 12 years of age Adolescent years Glomerular Filtration Rate at Various Ages Age GFR (ml/min/m2) First four days 1 14 days 22 One year 70 Adult 70

8 Physiologic Differences between Neonates and Adults of Pharmacokinetic Importance Neonate Adult Gastric acid output (meq/10kg/hr) Gastric emptying time (min) Total body water (% of body weight) Extracellular water (% of b.wt.) Intracellular water (% of b.wt.) Adipose tissue (% of b.wt.) Serum albumin (gm/dl) Glomerular filtration rate (ml/min/m2) Pharmacokinetic Parameter Values for Infants and Children compared with Adult values Theophylline Age group Volume term (L/kg) Premature neonates 0.62 ( ) Infants 0.44 ( ) Children 0.44 ( ) Adults 0.47 ( ) Half-life (hr) 26.9 ( ) 4.6 ( ) 3.4 ( ) 5.7 ( ) Total body clearance (ml/min/kg) 19 ( ) 76 (28-156) 95 (60-221) 65 (32-131) Gentamicin Vc TBC (ml/min/1.73 m2) Preterm infants and full-term infants

9 Infants and children Adults Chloramphenicol Vd TBC (ml/hr/kg) Infants (11-56 d) 10 Infants (1-12 mo) Children (1-11 yr) Adults

10 Refrences: Marshall jd; wells t g; letzig l; kearns gl; pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients.j clin pharmacol1998,38(11): Encyclopedia of pharmaceutical technology technology. Second edition (pediatric dosing and dosage forms) Ito s;gow r; verjee z; giesbre cht e;et al intravenous and oral propafenous for treatment of tachycardia in infants and children: pharmacokinetics and Clinical response.j clin pharmacol 1998;38(6): Lebovitz d j; smith p g ; o riobordan m;reed md. Pharmacokinetic properties and tolerability of singledose terbutaline in patient with severe asthma treated in the pediatric intensive care unit. Curr ther res may 2004,65(1): Daniel j. Lebovitz, MD, Paul C. Smith, DO, MaryAnn O Riordan, MS. and Michael D. Reed, PharmD. Pharmacokinetic Properties and Tolerability of Single-Dose Terbutaline in Patients with Severe Asthma Treated in the Pediatric Intensive Care Unit. January/february2004,65,(1) PNF37.march 1999 (page 10) Applied biopharmaceutics and pharmacokinetics fourth edition (pages ) Food and Drug Administration Center for Drug Evaluation and Research (CDER) General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products..November 1998 Pediatric considerations PDF John m kovarik Gisela offner michel 13royer Patrick niaudkt chan ml loirat mark nentser Jacques lemire john f. s.crocker Pierre cochat 1 godfrey clark 1. Algorithm for basiliximab (simulect) in pediatric renal transplantation based on pharmacokinetic-dynamic evaluation, october ,64(7):

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