Neonates pharmacokinetics

A. Neonatal pharmacokinetics. The newborn (birth to 1 month) and infants... 

Children s Susceptibility. No studies were located in which comparisons were made between the sensitivity of children and adults to the toxicity of americium. Animal studies indicate that juvenile dogs are less susceptible than adults to americium-induced bone cancer (Lloyd et al. 1999). No direct evidence was located to indicate that the pharmacokinetics of americium in children may be different from that in adults. Based on dosimetric considerations related to differences in the parameters of available models, as well as studies in animals, it seems likely that children may be more susceptible to americium toxicity than are adults by virtue of age-related differences in pharmacokinetics. Absorption of ingested americium may be as much as 200 times greater in neonatal animals than in adults. (Bomford and Harrison 1986 David and Harrison 1984 Sullivan et al. 1985). 

L. Notarianni, Plasma protein binding of drugs in pregnancy and in neonates, Clin. Pharmacokinet, 18, 20 (1990). 

I. Gauntlett, D. Fisher, R. Hertzka, E. Kuhls, M. Spellman, and C. Rudolph, Pharmacokinetics of fen-tanyl in neonatal humans and lambs Effects of age, Anesthesiology, 69, 683 (1988). 

Although there is no reason to suspect that the pharmacokinetics of 1,4-dichlorobenzene differs in children and adults, scant data are available to support or disprove this statement. Studies of absorption, distribution, metabolism, and excretion in children would aid in determining if children are at an increased risk, particularly if conducted in an area where a high-dose acute or low-dose chronic exposure to an environmental source were to occur. With regard to exposure during development, additional research on maternal and fetal/neonatal toxicokinetics, placental biotransformation, the mechanism of... 

Clewell et al. (2002b) have reviewed and evaluated the potential impact of age-specific pharmacokinetic differences on tissue dosimetry. A large number of age-specific quantitative differences in pharmacokinetic parameters were identified. The majority of these differences were identified between neonates/children and adults, with fewer differences being identified between young adults and the elderly. 

Children-The safety and effectiveness of ranitidine have been established in children from 1 month to 16 years of age. There is insufficient information about the pharmacokinetics of ranitidine in neonatal patients under 1 month of age to make dosing recommendations. Do not give OTC ranitidine to children under 12 years of age unless directed by physician. 

Fig. 4. Ontogeny of glomerular filtration in the neonate (from Ritschel WA and Kearns GL, 1999, reproduced by permission, from the Handbook of Basic Pharmacokinetics, 5th edn. 1999 by the American Pharmaceutical Association).

Gilman JT, Gal P. Pharmacokinetic and pharmacodynamic data collection in children and neonates. Chn Pharmacokinet 1992 23(l) l-9. 

Kearns GL, Bradley JS, Abdel-Rahman S, Jacobs RF and the PPRU Network. Pharmacokinetics of pleconaril in neonates. Chn Pharmacol Ther 1999 65(2) 140. 

Pharmacokinetics Rapidly, completely absorbed from G1 tract rectal absorption variable. Widely distributed to most body tissues. Acetaminophen is metabolized in liver excreted in urine. Dichloralphenazone is hydrolyzed to active compounds chloral hydrate and antipyrine. Chloral hydrate is metabolized in the liver and erythrocytes to the active metabolite trichloroethanol, which maybe further metabolized to inactive metabolite. It is also metabolized in the liver and kidneys to inactive metabolites. The pharmacokinetics of isometheptene is not reported. Removed by hemodialysis. Half-life Acetaminophen 1-4 hr (half-life is increased in those with liver disease, elderly, neonates decreased in children). 

Pharmacokinetics Highly plasma protein-bound and distributed to all body tissues. Excreted in the urine (80%), Half-life 40 9 seconds in adults, 84 30 seconds in neonates. 

Pharmacokinetics Rapid, complete absorption after IM administration. Protein binding less than 30%. Widely distributed (doesn t cross the blood-brain barrier low concentrations in cerebrospinal fluid (CSF). Excreted unchanged in urine. Removed by hemodialysis. Half-life 2-4 hr (increased in impaired renal function and neonates decreased in cystic fibrosis and febrile or burn patients). 

In neonates, and especially in premature infants, the mechanism for glucuronide conjugation is poorly developed. Renal function is also very inefficient. The pharmacokinetics of morphine in neonates is thus markedly different from that in older children and adults. This, together with age-related differences in the development of opioid receptors, may explain their increased sensitivity to morphine. 

Besunder JB, Reed MD, Blumer JL Principles of drug biodisposition in the neonate A critical evaluation of the pharmacokinetic-pharmacodynamic interface. (Two parts.) Clin Pharmacokinet 1988 14 189, 261. 

Paap CM, Nahata MC Clinical pharmacokinetics of antibacterial drugs in neonates. Clin Pharmacokinet 1990 19 280. [PMID 2208898]... 

PG, similar to glycerin, is a multifunctional excipient that can be an effective preservative when used at concentrations of 15% to 30% in oral solutions. However, formulations containing 35% PG can cause hemolysis in humans. PG exhibits nonlinear pharmacokinetics and when elimination pathways are saturated, serum levels dramatically increase. Pyruvic and lactic acid are produced from the metabolic degradation of PG and can lead to acidosis. Neonates have a longer PG half-life (16.9 hours) compared with adults (5 hours) and seizures, and respiratory depression has occurred in children who have ingested oral liquid medications containing PG (9). Therefore, special consideration should be placed on the amount of PG in formulations that are intended for infants and children. 

The 1996 Food Quality Protection Act (FQPA) now requires that an additional safety factor of 10 be used in the risk assessment of pesticides to ensure the safety of infants and children, unless the EPA can show that an adequate margin of safety is assured with out it (Scheuplein, 2000). The rational behind this additional safety factor is that infants and children have different dietary consumption patterns than adults and infants, and children are more susceptible to toxicants than adults. We do know from pharmacokinetics studies with various human pharmaceuticals that drug elimination is slower in infants up to 6 months of age than in adults, and therefore the potential exists for greater tissue concentrations and vulnerability for neonatal and postnatal effects. Based on these observations, the US EPA supports a default safety factor greater or less than 10, which may be used on the basis of reliable data. However, there are few scientific data from humans or animals that permit comparisons of sensitivities of children and adults, but there are some examples, such as lead, where children are the more sensitive population. It some cases qualitative differences in age-related susceptibility are small beyond 6 months of age, and quantitative differences in toxicity between children and adults can sometimes be less than a factor of 2 or 3. 

Chlorpyrifos provides an example of the utility of human pharmacokinetic models to estimate daily dose from biomonitoring data for a rapidly cleared pesticide. The urinary metabolite trichloro-2-pyridinol (TCP) is used in the NHANES study to monitor population exposure to chlorpyrifos (CDC 2005). Several epidemiologic studies have linked chlorpyrifos exposure to adverse birth outcomes through associations between urinary and blood biomarkers and have demonstrated maternal exposure and physiologic measurements in the neonate (Berkowitz et al. 2003, 2004 Whyatt et al. 2004 Needham 2005). 

---