Rational Therapeutics for Infants and Children Workshop Summary (2000) / Chapter Skim
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3 Pharmacokinetics and Pharmacodynamics in Children Versus Adults
3 Pharmacokinetics and Pharmacodynamics in Children Versus Adults
Pages 34-60
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From page 34... ...
Studies with adolescents reveal even more complexity in drug metabolism and differences in drug metabolism between the sexes. The therapeutic value of understanding differences in pharmacokinetics because of developmental factors thus relies on an ability to understand better the dose versus concentration versus effect profile for a specific drug in patients of various ages (Kearns, 1998~.
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From page 35... ...
were evident. For many compounds, developmental differences in drug clearance have, for drugs where the primary biotransformation pathways are known, produced partial developmental "road maps" that have provided information on the patterns of ontogeny for important drug-metabolizing enzymes.
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From page 36... ...
and, thus, implicate sexual maturation and disease as potentially important co-variates for the expression of this particular cytochrome P450 during development. Another example where pharmacokinetic data have shed important insights on the impact of development on drug metabolism resides with CYP3A4, the most abundant cytochrome P450 isoform in the human body which is responsible for catalyzing the biotransformation of well over 20 drugs commonly used in pediatric practice (Leeder and Kearns, 1997~.
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From page 37... ...
These changes were not associated with age-associated differences in the urinary excretion of HPPH. As well, recent pharmacokinetic data for the CYP2C9 substrate ibuprofen collected from 26 patients with cystic fibrosis ranging in age from 5.5 to 29.6 years demonstrated an inverse linear correlation between age and the apparent oral clearance of the drug (Kearns et al.
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From page 38... ...
activity using caffeine as a pharmacologic probe demonstrated attainment of adult activity by approximately 4 to 6 months of postnatal age (Pariente-Khayat et al., 1991~. In contrast, the activity of thiopurine methyltransferase (TPMT)
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From page 39... ...
Despite a relative wealth of pharmacokinetic data and emerging information on isoform-specific differences in the activities of several important drugmetabolizing enzymes across the pediatric age range, there is little to no evidence that clearly describes the regulatory events at a cellular or molecular level that are responsible for producing developmental differences in drug metabolizing enzyme activity. Although it was commonly believed that age-dependent differences in hepatic size (relative to total body size)
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From page 40... ...
Support for this assertion was drawn from evidence that human growth hormone can modulate the effect of many general transcription factors, the demonstrated regulatory role for growth hormone in the expression of CYP2A2 and CYP3A2 in rats, the documented effects of human growth hormone treatment on the alteration of the pharmacokinetics for pharmacologic substrates of selected P450 cytochromes, and also from evidence of altered CYP1A2 activity that appears to correlate with the pubertal height spurt (Lambert et al., 1986~. In conclusion, pharmacologic and pharmacokinetic evidence supports the presence of isoform-specific developmental differences in the activities of a host of phase I and phase II drug-metabolizing enzymes.
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From page 41... ...
Evidence suggests that bilirubin is an endogenously generated substrate for P-glycoprotein. The expression of P-glycoprotein in brain capillary endothelial cells may play a protective role in limiting the uptake of bilirubin into the central nervous system and thus plays a role in the pathogenesis of protecting against the genesis of kernicterus (hyperbilirubinemic encephalopathy)
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From page 42... ...
This has been demonstrated in tumor cells: approximately 60 percent of all tumors solid or hematogenous express Pglycoprotein. This has also been demonstrated in cell lines transfected with Pglycoprotein complementary deoxyribonucleic acids (cDNAs)
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From page 43... ...
Watchko and colleagues are testing the hypothesis that the brain capillary endothelial cell P-glycoprotein may provide an important protective effect against bilirubin toxicity by reducing brain bilirubin influx. Additional evidence that bilirubin is a P-glycoprotein substrate includes work on brain bilirubin content in wild-type versus transgenic mdrlA null mutant P-glycoprotein deficient mice (Watchko et al., 1998~.
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From page 44... ...
Thus, an intrauterine milieu induced by uteroplacental insufficiency and characterized by hypoxia acidosis and altered metabolic fuel availability is associated with a significant reduction in brain microvessel Pglycoprotein expression. These findings are of interest in relation to understanding hyperbilirubinemic encephalopathy because alleged risk factors for kernicterus include hypoxia and acidosis, and the understanding that Pglycoprotein may limit the next influx of various lipophilic compounds, including bilirubin into the central nervous system.
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From page 45... ...
. The glucose transporter Glut-1 is responsible for basal glucose transport.
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From page 46... ...
In the fetus and the newborn it appears that there is no change from that in adults in the skeletal muscle Glut-4 level, and there is no effect on translocation of Glut4. So, in comparison with published reports in which it has been described that adults on glucocorticoid therapy have developed insulin resistance (with a decline in skeletal muscle Glut-4 levels and a diminished translocation of Glut-4)
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From page 47... ...
which includes acceptable chemistry manufacturing and control (CMC) data, as well as comparative clinical trials to demonstrate efficacy.
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From page 48... ...
. These parameters are useful in understanding differences in microbiologic and clinical cure between drugs, not only in terms of the extent of cure but also in terms of the cure rate.
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From page 49... ...
Moreover, as concentrations in middle ear fluid increased relative to the MIC, there was a nearly 100 percent likelihood of eradication. Most of the studies of the pharmacokinetics of drugs in pediatric populations have used conventional dosing strategies, which presents a challenge because of the need to obtain multiple blood samples.
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From page 50... ...
Information is now developing regarding patients at risk for asthma, such as parental asthma, maternal smoking, atopic features and the presence of relevant allergens in the environment, and small lungs (National Heart, Lung, and Blood Institute, 1995, 1997~. One of the consequences of undertreatment may be a loss over time of pulmonary function tFEV1]
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From page 51... ...
. Moreover, insufficient information is available on the long-term effects of asthma medications, especially inhaled glucocorticoids and leukotriene modifiers, administered to children at an early age and for prolonged periods of time.
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From page 52... ...
Mild persistent: characterized by frequent episodes of bronchospasm, for example, more than twice per week but less than once per day, with marginal compromise in pulmonary function. First-line therapy may begin with an inhaled glucocorticoid (low dose)
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From page 53... ...
The response to inhaled glucocorticoids is parameter specific, for example, a low dose may be effective in improving pulmonary function whereas a higher dose may be necessary to improve airway hyperresponsiveness (Pedersen and Hansen, 1995~. A high-dose, high-potency inhaled glucocorticoid (fluticasone propionate)
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From page 54... ...
relieve and even prevent symptoms and also improve pulmonary function, however, their effect on long-term control of airway inflammation and disease progression is not clear. It is therefore difficult to adjust the inhaled glucocorticoid dose when indirect measures of inflammation, such as pulmonary function, can be ablated by nonsteroid long-term controllers.
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From page 55... ...
they may be used as an alternative to inhaled glucocorticoid therapy in patients with mild persistent asthma who are unable to take inhaled medication, (2) they may be used as a supplement to inhaled controller medications to reduce the need for-high dose inhaled glucocorticoid therapy, (3)
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From page 56... ...
One unique property of inhaled glucocorticoids is the relatively slow offset of the effect in pulmonary function control and airway hyperesponsiveness, especially after long-term therapy. This observation suggests that inhaled glucocorticoids have provided some long-term effects on the airways.
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From page 57... ...
Leukotriene modifiers improve many measures of asthma control, however, except for pranlukast, there is limited information on their effect on resolving persistent airway inflammation. Studies are needed to determine whether the use of leukotriene modifiers alters the course of persistent asthma in a way that is comparable to that demonstrated with inhaled glucocorticoids.
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From page 58... ...
A number of treatment concepts that are routinely applied in the treatment of adult malignancies actually evolved from developments in the treatment of pediatric malignancies. In addition, numerous drugs currently used to treat adult cancer were initially developed for the treatment of pediatric cancer.
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From page 59... ...
With increasing frequency in the future, clinicians are likely to be using agents developed to target molecular targets unique for a particular pediatric cancer but not necessarily relevant to adult cancers. Phase 3 trials for pediatric cancer have also been influenced by the improvement in overall prognosis.
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From page 60... ...
Currently, Phase 1 trials are done at approximately 50 centers throughout the United States. Only a handful of these centers have active pediatric cancer clinical pharmacology laboratories, even a smaller number are actually training individuals in cancer clinical pharmacology.
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