Rational Therapeutics for Infants and Children Workshop Summary (2000) / Chapter Skim
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2 Similarities and Dissimilarities in Physiology, Metabolism, and Disease States and Responses to Therapy in Children and Adults
2 Similarities and Dissimilarities in Physiology, Metabolism, and Disease States and Responses to Therapy in Children and Adults
Pages 14-33
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From page 14... ...
The ontogeny of drug-metabolizing enzymes in humans, for instance, may explain several differences in the responses to drugs by adult and pediatric populations. Understanding the relative role of absorption in drug biotransformation may also lead to better understanding of the drug 14
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From page 15... ...
The results of studies with adults thus cannot typically be extrapolated to children because growth and development issues add a range of complicated variables to the already intricate realm of drug metabolism and pharmacodynamics. Studies of drugs for use in children must be designed to account for the complex developmental changes that can affect drug biodisposition and pharmacodynamics.
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From page 16... ...
By 5 months of age, however, total body water accounts for only 60 percent of body weight and then remains relatively constant. However, there is a progressive decrease in extracellular water throughout childhood and into young adulthood.
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From page 17... ...
However, relative hypochlorhydria persists during the first 1 to 2 months of life. Premature infants have impaired gastric acid production until after 32 weeks of gestational age.
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From page 18... ...
large growth spurts mediated by surges in human growth hormone and other growth factors, (2) increase in luteinizing hormone and follicle-stimulating hormone concentrations with secondary sexual maturation associated with the effects of estrogen or progesterone and testosterone, and (3)
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From page 19... ...
This possibility must always be considered when designing a drug trial or developing a new drug for pediatric use. There have been numerous examples of greater or unpredictable vulnerability of children to adverse effects, including the following: · An entire generation of children suffered enamel dysplasia from exposure to tetracycline antibiotics during critical periods of formation of dentition, an adverse effect that could never have been anticipated on the basis of data from clinical trials conducted with adult populations.
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From page 20... ...
This frequently requires age-appropriate modification of approaches typically used in studies with adult subjects, particularly when obtaining informed consent and conducting risk-benefit analyses. In terms of informed consent, children cannot independently consent to participate in research, thus, surrogate consent or permission must be provided by a parent or guardian.
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From page 21... ...
Professor and Chief of Clinical Pharmacology, Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport Past negative experiences with the differential responses of children to drugs such as the deaths that occurred with elixir of sulfanilamide, tooth staining after tetracycline treatment, kernicterus after sulfisoxazole treatment, and cardiovascular collapse after chloramphenicol treatment highlight the long-standing and sometimes severe effects that can occur when drugs are not properly studied before their use in children. Insufficient information about pediatric dosing prompted investigations of the pharmacokinetics and pharmacodynamics of drugs in children.
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From page 22... ...
Applications of the classification system to known differential drug responses in children illustrate its utility. Questions about differential efficacy are qualified according to intensity and confounded as they apply to antipyretics as a drug class.
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From page 23... ...
Paradoxical reactions to diazepam, aggression with clonazepam, and disinhibition with midazolam are examples. In sum, efficacy and safety components of study design should be strengthened by a structured classification system that yields data for analysis of differential drug responses in children.
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From page 24... ...
Further exposure can occur through breast-feeding. The knowledge of the biotransformation pathways that a drug undergoes in the human liver and the capacity of the fetal and neonatal liver to catalyze these reactions will allow one to predict the metabolic fate and the potential risk of drug toxicity at every stage of development.
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From page 25... ...
In fetuses of 11 to 24 weeks of gestational age, no RNA coding for CYP1A, CYP2A, CYP2B, or CYP2E has been detected, whereas RNA encoding CYP3A was the major isoform found in the liver (Hakkola et al., 1994~. Exploration of Neonatal Period To understand the ontogeny of P450 isoforms, the liver content of individual P450 proteins and RNA and the capacities of these proteins to metabolize endobiotic and xenobiotic compounds were investigated by using postmortem liver samples from newborns and children between the ages of 1 hour and 10 years who had died from various pathologies, such as infection, hypotrophy, malformation, respiratory distress, or sudden death.
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From page 26... ...
The major P450 subfamily expressed in the human liver is the CYP3A subfamily, which comprises three isoforms: CYP3A4, CYP3A5, and CYP3A7. A1though highly homologous in terms of protein sequence (CYP3A5 is 87 percent homologous to CYP3A7 and 84 percent homologous to CYP3A4)
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From page 27... ...
For instance, caffeine could be demethylated by CYP1A2 and hydroxylated by 3A: when caffeine was incubated in vitro with liver microsomes, the C8 hydroxylation was active in fetal preparations, whereas the demethylation by CYP1A2 remained negligible before a rise in its level during the first trimester (Cazenave et al., 1994~. Other CYP proteins are expressed during the perinatal period.
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From page 28... ...
The capacity of the human liver to eliminate xenobiotic compounds during the neonatal period is effective and the intensity of biotransformation depends primarily on the level of maturation of phase I enzymes.
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From page 29... ...
For example, an antiprotease molecule is extensively metabolized in vitro by adult human liver microsomes into four derivatives. As shown with recombinant human P450 the metabolism seems to be mostly dependent on CYP3A4 and, to a lesser extent, on CYP2C9 and CYP3A5, whereas CYP3A7 has no or little activity.
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From page 30... ...
Significant positive correlations were observed between the 60-hydroxycortisol-to-free cortisol ratio and gestational age as well as, to a lesser extent, between the ratio and birth weight, suggesting that the level of CYP3A activity is higher in more mature infants. However, the ratio in term infants declined over the first 3 to 5 days after birth to levels comparable to those in premature infants and to levels similar to those observed in adults (Nakamura et al., 1998a)
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From page 31... ...
, and thus, developmental changes in renal CYP3A5 activity could conceivably account for the observed maturational profile of cortisol 60-hydroxylation, a possibility that has not been addressed directly either in vitro or in vivo. On the other hand, pharmacokinetic studies of other drugs that can serve as markers of CYP3A activity, such as midazolam, indicate that CYP3A activity in newborns is indeed reduced compared with that in older infants.
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From page 32... ...
Although changes in phenytoin bioavailability may also contribute to the latter finding, the investigators cite data indicating that the fractional excretion of HPPH in urine does not vary over the age range studied, thus implying that the observed decrease in Vmax is a function of decreased CYP2C9 activity during childhood (Chiba et al., 1980~. This fact would then account for the higher phenytoin dosage requirements (on the basis of body weight)
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From page 33... ...
Concurrent data for metabolites would be extremely valuable since the ability to characterize individual drug biotransformation pathways becomes more likely. Longitudinal phenotyping studies with healthy children and specific disease populations may help bridge the gap between preclinical in vitro drug biotransformation studies.
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