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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
Application of general PK principles, equations, and models is essential to
determining appropriate pediatric dosages. Because the ontogeny of various
elimination pathways can differ, detailed knowledge of a drug’s PK behavior
is important in determining when to expect significant age-specific PK.
Significant variability in PK parameters exists and can result in variable drug
exposure with similar doses. Defining the determinants of between-participant
variability by developmental, genetic, and other clinical characteristics
allows optimization of treatment for individual patients. Linking dosing
information to population PK/PD (pop PK/PD) and disease models can
facilitate informed and improved therapeutic decision making.
SUGGESTED READINGS
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Anaesth 2002;12:205–219.
Barrett JS, Della Casa Alberighi O, Läer S, et al. Physiologically based pharmacokinetic (PBPK)
modeling in children. Clin Pharmacol Ther 2012;92(1):40–49.
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Pharm Sci 1979;68:1071–1074.
Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol
Ther 2002;71:115–121.
Capparelli EV, Lane JR, Romanowski GL, et al. The influences of renal function and maturation on
vancomycin elimination in newborns and infants. J Clin Pharmacol 2001;41(9):927–934.
Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in
preterm infants. J Pediatr 2003;142(1):47–52.
Chiba K, Ishizaki T, Miura H, et al. Michaelis–Menten pharmacokinetics of diphenylhydantoin and
application in the pediatric age patient. J Pediatr 1980;96:479–484.
Edginton AN, Schmitt W, Voith B, et al. A mechanistic approach for the scaling of clearance in children.
Clin Pharmacok inet 2006;45:683–704.
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translational pharmacology. Drug Discov Today Technol 2016;21–22:57–65.
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J Pharm Sci 1971;60:1338–1340.
Gibaldi M, Perrier D. Pharmacok inetics, 2nd ed. New York, NY: Marcel Dekker, 1982.
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parameters and applications to the population pharmacokinetic-pharmacodynamic modeling of
biologics. Expert Opin Drug Metab Toxicol 2009;5(7):803–812.
Haddad S, Restieri C, Krishnan K. Characterization of age-related changes in body weight and organ
weights from birth to adolescence in humans. J Toxicol Environ Health 2001;64:453–464.
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intravenous, oral and buccal administration in healthy volunteers. Br J Clin Pharmacol 1989;27:499–
505.
Johnson TN, Tucker GT, Tanner MS, et al. Changes in liver volume from birth to adulthood: a meta-
analysis. Liver Transpl 2005;11(12):1481–1493.
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Pharmacok inet 1989;17(suppl 1):29–67.
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Lundeberg S, Beck O, Olsson GL, et al. Rectal administration of morphine in children. Pharmacokinetic
evaluation after a single-dose. Acta Anaesthesiol Scand 1996;40:445–451.
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plasma-derived products. Am J Ther 2016;23(4):e1043–e1056.
Malik P, Edginton A. Pediatric physiology in relation to the pharmacokinetics of monoclonal antibodies.
Expert Opin Drug Metab Toxicol 2018;14(6):585–599.
Murray DJ, Crom WR, Reddick WE, et al. Liver volume as a determinant of drug clearance in children
and adolescents. Drug Metab Dispos 1995;23:1110–1116.
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developmental changes and current tools for predictions. Biopharm Drug Dispos 2017;38(3):209–
230.
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research and forensic applications. Clin Pharmacok inet 2003;42:1–31.
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pharmacokinetic intraspecies uncertainty factors for volatile organic compounds. Regul Toxicol
Pharmacol 2001;33:12–20.
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filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987;34(3):571–590.
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1992;32:185–209.
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parameters from routine clinical data. J Pharmacokinet Biopharm 1977;5:445–479.
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2′,3′-dideoxyinosine distribution in brain tissue and cerebrospinal fluid. J Pharmacol Exp Ther
1997;282:1509–1517.
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basis of drug therapy. Philadelphia, PA: Lippincott Williams & Wilkins, 2006.
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Hussain Mulla
C H A P T E R
3
Developmental Pharmacodynamics, Receptor Function, and Drug Action in Newborns and Children
ONTOGENY OF DRUG ACTION
(PHARMACODYNAMICS)
A rational use of drugs is based on knowledge of their pharmacokinetic (PK)
and pharmacodynamic (PD) properties.1 Key to understanding drug response
and, therefore, optimizing drug therapy both in populations and individuals is
defining the relationship between PK and PD. This relationship is affected by
many factors, including age, genotype, comorbidities, and comedications. It is
only from a thorough understanding of the age-dependent PK–PD relationship
that optimal doses for the pediatric population can be defined.
Although most basic cellular and physiologic processes and receptors are
common to all mammals, irrespective of age or stage of development,
2
structural and functional characteristics of biologic systems constantly evolve
from birth to adulthood. Alongside developmental changes in drug metabolism
and other physiologic processes affecting PK, developmental changes also
affect the therapeutic targets and receptors that mediate drug action and
response.
Developmental PD is the study of age-related maturation of the structure
and function of biologic systems and how this affects response to drug
therapy. Age-dependent changes in potency and efficacy may be a
consequence of maturational changes in receptor affinity, density, or signal
transduction, and so even if the nature of the pharmacologic response is
predicted to be the same in children, the magnitude of the response may not be
(Fig. 3.1). In some cases, receptors or mediators may be absent altogether so
that no response is observed. In others, altered response is a consequence of
changes further downstream in the biochemical pathway.
Figure 3.1 Hypothetical age-dependent changes in (A) drug potency and (B) efficacy.
STUDIES OF DEVELOPMENTAL
PHARMACODYNAMICS
Unfortunately, to date, there is a dearth of studies reported in the literature on
developmental PD. Whereas developmental PK has been and continues to be
studied extensively, preclinical and clinical studies of developmental PD are
relatively rare.
ANIMAL MODELS
Juvenile animal models can potentially help in the understanding of the
maturation of human biologic systems and how this maturation affects both the
disease process and drug response in neonates through to adolescence and
adulthood. A limited number of juvenile animal studies (mostly in rodents)
have been conducted, but these are quite rare, largely because of a lack of
suitable models.
3,4
But even with juvenile animal models, extrapolating
findings to children is hampered because correlating the postnatal age of the
TABLE 3.1
experimental animals with the corresponding stages of human development is
not straightforward. The maturational rate of each developmental process
varies across species; hence, cross-species extrapolation may not be very
accurate. For example, it is assumed that the 7th to 13th postnatal days in
rodents approximately correlate with the human full-term newborn, based on
gross measures of brain growth, whereas the birth of the macaque coincides
approximately with the 172nd to 217th postconceptual days of human
development, depending on the brain region.
3
STUDIES IN CHILDREN
There is a large evidence gap in the pediatric population, a consequence of a
general insufficiency of studies in children but also lower quality clinical
research relative to adults.5 Special ethical considerations in children, for
example, relating to consent and number of biologic samples, increase the
complexity and reduce the feasibility of research studies. Direct comparison
between control groups and severely diseased children is also limited
because of ethical constraints regarding the inclusion of healthy children in
clinical trials. In addition, the lack of age-appropriate, disease-specific, and
validated PD endpoints makes assessing efficacy and safety in infants and
young children particularly challenging (Table 3.1).
Examples of Age-Dependent Pharmacodynamic Responses by Therapeutic
Class
To increase the efficiency of clinical studies and limit unnecessary
evaluations in children, regulatory authorities have issued guidelines to aid
the pharmaceutical industry on the nature of clinical data required from
pediatric drug development programs for marketing authorization.6 These
guidelines address the circumstances under which data from adult studies can
be extrapolated to children, given a similar disease process and PK–PD
response to intervention. But few example drugs exist where pediatric use
could be completely extrapolated from adult data, because in the vast majority
of cases, there is a lack of a validated, pediatric-specific biomarker. The
paucity of validated biomarkers in neonates and children for use as endpoints
in clinical trial settings and clinical practice has made it difficult to establish
the PK–PD response in children and contributed to the knowledge gap.
The ideal PD endpoint should be “relevant, responsive, reproducible, and
reliable.”7 The PD endpoint must be able to consistently quantify the clinical
response to a specific intervention, at a given stage of development. The PD
endpoint must also be acceptable and not burdensome to children and
caregivers and ideally combined with routine tests. The development of
dedicated age-specific PD measures is challenging, however, with the
absence of established normal ranges/values in healthy children and the target
population. Diligently compiled PD data from literature could be used as
supportive reference for pediatric clinical trials.
The following sections provide strong evidence for changes in drug
response during development with examples from animal reports on receptor
ontogeny and clinical studies of age-related changes in PD (Table 3.1).
DRUGS ACTING ON THE CENTRAL NERVOUS
SYSTEM
PSYCHOTROPIC DRUGS
Although psychological treatments are considered the first-line treatment of a
major depressive episode in children, and despite the U.S. Food and
Development Administration (FDA) cautions of increased suicide risk in
children and adolescents, antidepressants are widely used in the treatment of
childhood depression, and the rate of prescription has increased over time.
However, according to current evidence comparing antidepressants
(tricyclics, selective serotonin reuptake inhibitors [SSRIs], serotonin and
norepinephrine reuptake inhibitors [SNRIs], atypical agents) with placebo or
another active antidepressant as oral monotherapy in the acute treatment of
major depressive disorder in children and adolescents (mean age 9 to 18
years), only fluoxetine is significantly more efficacious than placebo and
some other active drugs at reducing depressive symptoms or the number of
discontinuations owing to adverse events over 8 weeks.
8
A common view is that delayed maturation of the norepinephrine
neurotransmitter system relative to serotonin is one factor as to why tricyclics
and SNRIs are not effective in children and adolescents.9 Several indicators
of maturation including the extent of innervation, the levels of serotonin and
norepinephrine and their biosynthetic enzymes, receptor density, and the
levels of reuptake transporters suggest that serotonergic system reaches adult
stages of development more rapidly than the norepinephrine system. For
example, in the rat, the serotonin system reaches maturity at about 3 weeks of
age, whereas the norepinephrine system is not fully developed until sexual
maturity is reached, at about 5 weeks of age. Although studies in humans are
relatively scant, those that exist, together with studies in nonhuman primates,
suggest that the serotonin system matures faster than the noradrenergic
system.
10
Even so, it is clear that the antidepressant response of children and
adolescents is less than that of adults.11 The complexity of the neural systems
means that the reasons for the age dependency of antidepressant response
remain poorly understood, and therefore, safety and efficacy of
psychopharmacologic medicines cannot be readily extrapolated from adults.
The developing brain is a highly malleable structure that is susceptible to
environmental influences.12 The adolescent brain development is
characterized by synaptic regression and pruning, increases in myelination,
strengthening of connections between limbic and cortical regions, and
maturation of monoaminergic systems. Given the malleability of the
adolescent brain to environmental stimuli, exposure to psychotropic drugs
during the adolescent period can have lasting consequences on brain
development, as well as having unexpected behavioral and neural outcomes in
the short term. Antidepressant administration during adolescence may also
modify normal developmental neurotrophic processes, thus having lasting
effects on the maturation of the brain regions involved in emotional regulation.
In the absence of more certain conclusions on the short term and enduring
behavioral and neural consequences of antidepressant exposure during
adolescence, the treatment of young persons with these agents should be
approached with caution.
Dopamine is an important catecholamine with wide-ranging effects
peripherally as well as in the central nervous system (CNS). It acts through a
family of receptors that includes at least five subtypes: D1, D2, D3, D4, and D5.
Studies of D1 and D2 ontogeny in the CNS are inconclusive. Most studies have
been done in rats, with some studies of D1 receptors showing an increasing
number of receptors during maturation and others showing an increase to 35 to
40 days of age followed by a decline. Studies of D2 receptors in the CNS are
also inconsistent, but more recent studies have shown peak expression in the
rat at 28 days with subsequent decline to adult levels.12 In correspondence
with a higher density of dopamine receptors in childhood, clinical
observations of increased extrapyramidal effects from antipsychotic
medication in children and adolescents can be traced back to an imbalance of
dopaminergic and cholinergic innervation of the basal ganglia regions.
Extrapyramidal effects are believed to be related to postsynaptic D2 receptor
antagonism in the nigrostriatal pathway. Thus, a heightened D2 receptor
density may lead to a greater vulnerability in children.
12
OPIOID ANALGESICS
For a long time, pain management in neonates and infants was suboptimal,
often justified by the belief that infants do not feel pain because of immaturity
of the CNS and because there were no long-term outcomes to infant
suffering.13 Perhaps, previous underappreciation of the impact of noxious
stimulation and neonatal pain was because, in part, of the variable and
sometimes conflicting data reported, not least, the inadequacy and limited
sensitivity of pain assessment tools. In fact, preterm infants demonstrate an
exaggerated acute response to pain and worse behavioral and sensory longterm outcomes when compared to term neonates.
14
It is now known that the neurotransmitters and structures required for pain
sensation as well as structures needed for long-term memory are developed
adequately in the neonate. Though the absence of inhibitory descending
spinothalamic fibers and an underdeveloped cortical pain memory system
point to differences in pain thresholds and perception in the newborn infant,
there is consensus that pain assessment and treatment should be part of current
standard medical care.
13,15
There is growing evidence to show that controlling
pain in the newborn period is beneficial, improving physiologic, behavioral,
and hormonal outcomes.
Pain conduction and modulation at the synapse are mediated through
opioid receptors located in both the CNS (reticular formation, hypothalamus,
thalamus, globus pallidus, and cortex) and the peripheral nervous system.
16
Studies in animals show that opioid receptor expression and binding
undergoes considerable postnatal reorganization. The three main opioid
receptors are mu (MOR), κ, and δ. All three receptors exhibit rapid
developmental changes over the first 3 postnatal weeks. In general, MOR is
the predominant opioid receptor during development as in adulthood, but it is
exuberantly expressed at birth decreasing to adult levels by postnatal day 21.
Both the MOR and κ receptor present similar patterns of ontogeny, whereas
the δ receptor is first observed on day 7 postnatally. Moreover, the ontogeny
of opioid receptors and their ligands is not uniform. The endogenous opioid
ligands (endorphins, enkephalins, and dynorphins) appear before receptors
are present.
17
The developmental changes in opioid receptor pharmacology studied in
rats provide a possible explanation for the age-related differences in opioid
sensitivity and selectivity. Spinal MOR activation produces profound
analgesia in neonatal rats, and analgesic efficacy decreases as the animals
age.18 Morphine induced a 75% depression of respiration in immature rats
with no analgesia, whereas adult rats given the same weight-adjusted dose
exhibited complete analgesia with only a 33% decrease in respiratory rate. In
contrast, supraspinal MOR activation results in pronociceptive effects in
younger rats; a switch in function occurs at around postnatal day 21, and in
matured rats, only inhibitory effects can be observed.
18
The increased expression of functional MOR is also likely to be a
significant factor in the increased responsiveness of human neonates to
opioids, although receptor expression may not necessarily correlate with
receptor activation.
17,19
Receptor density varies by brain region, with earlier
development of caudal and later development in rostral parts of the CNS.
Earlier development of opioid receptors in the medulla and pons, where
respiratory and cardiovascular centers are located, is consistent, with
clinically observed higher incidence of opioid-related respiratory depression
and bradycardia in the neonate who receives opioids.
These observations have important implications for response to opioid
analgesics in the infant and the young child, independent of age-dependent PK.
But they also suggest that changes in the normal pattern of maturation could
result in long-term alterations in nociceptive processing that may be
irreversible. The quality of pain treatment and management in the neonatal
units can be improved by clinicians being aware of the changes that occur
during this sensitive period and not disrupt the normal endogenous activity
where possible.
18
ANTICONVULSANTS