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There are several equations designed for pediatric use; the National Kidney Disease

Education Program (NKDEP) and the National Kidney Foundation recommend the

bedside isotope dilution mass spectroscopy (IDMS) Schwartz equation

53,54

:

where CLCr

is creatinine clearance (mL/minute/1.73 m2

), Ht is height (cm), and SCr

is

serum creatinine (mg/dL).

Using this method, H.G. has a calculated creatinine clearance of 116

mL/minute/1.73 m2

, indicating normal renal function. As with patients of any age, this

equation should be used only as an estimate of renal function. It should be interpreted

with caution in patients with little muscle mass or those who are dehydrated.

Pharmacokinetic Changes During Puberty

CASE 102-7

QUESTION 1: A.M. is a 16-year-old, 67-kg boy with osteosarcoma. He has received morphine for pain

throughout his numerous hospitalizations for surgery and chemotherapy during the past 2 years, requiring an

infusion rate as high as 0.5 mg/kg/hour. During this period, he has also progressed through puberty and is now a

mature adult male. During his last admission, it was noted that his pain was well controlled on an adult morphine

infusion rate of 10 mg/hour, equivalent to 0.15 mg/kg/hour. It was noted by the medical team that A.M.’s

morphine infusion requirements were actually lower than in earlier admissions, although his pain scores have

been unchanged. What might explain the change in A.M.’s response to morphine?

Although developmental pharmacology has traditionally focused on the differences

in neonatal pharmacokinetics, there is growing interest in the influence of puberty on

drug disposition.

55–57 Adolescence is not simply a link between childhood and

adulthood, but is a distinct period of significant physiologic change. Hormonal

fluctuations and sexual maturation can alter the efficacy or toxicity of many drugs

administered during this period. Drug distribution can be altered as a result of an

increase in body fat. Rapid increases in serum protein concentrations that occur

during puberty alter drug binding characteristics.

56 Renal function, as measured by

GFR, may exceed average adult values, resulting in rapid clearance of renally

eliminated drugs such as aminoglycosides and vancomycin. Metabolic activity

changes as well.

57 A study conducted in adolescents receiving morphine during a

sickle cell crisis revealed a reduction in drug clearance with advancing sexual

maturation.

58 Postpubertal adolescents, such as A.M., had weight-normalized

clearance values 30% lower than younger patients during early puberty, suggesting a

possible reduction in UGT2B7 activity. The titration of A.M.’s morphine must

encompass not only the changes in drug clearance resulting from growth and

development but also the progression of his

p. 2134

p. 2135

disease and his need for pain control. Assessment of pain, using frequent selfreport or a standardized pain scale, as well as heart rate, blood pressure, and

respiratory rate, is essential for appropriate adjustment of A.M.’s morphine infusion.

A second example comes from a recent study of lopinavir pharmacokinetics in

children who exhibited identified age- and sex-related differences in drug

clearance.

59 When normalized for weight, there was no significant difference in

clearance between prepubertal boys and girls. After the age of 12, boys had a mean

rate of lopinavir clearance 39% greater than girls. The area under the concentration–

time curve in boys was only half that of the girls. The authors suggest that this

difference may reflect a reduction in CYP3A4 in girls that becomes apparent only

with sexual maturation. Similar sex-related results have been reported in lopinavir

studies conducted in adults. Caffeine metabolism via CYP1A2 has also been found to

differ by sex in adolescents.

60 The rate of N-demethylation slows in both sexes after

puberty, but appears to decrease earlier in puberty for girls than for boys. Other

investigators have identified pharmacokinetic changes during adolescence with

acetaminophen, alprazolam, carbamazepine, digoxin, isoniazid, lamotrigine,

lorazepam, and theophylline.

56

PEDIATRIC PHARMACODYNAMIC

DIFFERENCES

Although not as well studied as pharmacokinetics, developmental changes in

pharmacodynamics during growth may have equally significant effects on response to

drug therapy in children.

CASE 102-8

QUESTION 1: S.L. is a 0.725-kg infant boy with an estimated gestational age of 24 weeks. He was brought

to the neonatal intensive care unit immediately after birth with severe hypotension. A dopamine infusion was

started at a rate of 10 mcg/kg/minute and quickly titrated to 20 mcg/kg/minute without significant benefit. What

might explain S.L.’s lack of response, and how should his hypotension be managed?

Maturational changes in receptor conformation, density, and affinity, as well as

signal transduction, can result in clinically significant differences in response to

common therapies.

61 Although a dopamine infusion of 20 mcg/kg/minute will produce

an adequate increase in myocardial contractility and elevate systemic vascular

resistance in most children and adults, infants may not have a significant change in

cardiovascular response. Infants have long been suspected to be relatively resistant

to the effects of β-adrenergic agonists, including dopamine, dobutamine, and

epinephrine. Recent research suggests the lack of response is related to a relative

reduction in adrenergic receptor density or a downregulation of receptors within the

myocardium of premature and critically ill neonates.

62 A higher dopamine infusion

rate, up to 40 mcg/kg/minute, may be necessary to achieve an adequate blood

pressure for S.L. If the dopamine is increased, S.L.’s extremities must be closely

monitored for any signs of excessive peripheral vasoconstriction. Supplemental

therapy with hydrocortisone, at a dose of 0.7 mg (1 mg/kg) IV every 8 hours, may

also be used to manage his hypotension.

CASE 102-9

QUESTION 1: You will be counseling the parents of E.S., a 7-year-old girl with refractory seizures as a result

of Lennox-Gastaut syndrome, on the use of lamotrigine. While preparing for your discussion, you notice in the

manufacturer’s prescribing information a black box warning regarding the risk for serious skin rashes. The

incidence is listed as 0.8% in children 2 to 16 years of age, but only 0.3% in adults.

63 What might explain the

difference in the incidence of an adverse effect by age?

Differences in pharmacodynamics resulting from growth and development can

alter more than just therapeutic response. A drug’s adverse effect profile may be

distinctly different during childhood. A classic example of this phenomenon is the

higher incidence of serious dermatologic reactions, including toxic epidermal

necrolysis, in children taking lamotrigine compared with that of adults.

64–66 This was

first suspected during initial pediatric clinical trials and appeared to be associated

with rapid dose titration during the first several months of treatment, which had been

based on previous studies in adults.

65 The slower dose escalation, now recommended

for pediatric patients, is starting E.S.’s lamotrigine dose at 0.15 mg/kg/day and

increasing by 0.15- to 0.3-mg/kg/day increments every 2 weeks, and may reduce the

likelihood for these reactions.

CASE 102-9, QUESTION 2: What is the possible mechanism(s) for the increased risk for toxicity with

lamotrigine in children such as E.S.?

Research has led to several theories for the greater incidence of serious

dermatologic reactions in children. Some investigators have suggested that this is a

dose-related toxicity more evident in children who have a limited capacity to

metabolize lamotrigine through glucuronidation to its inactive metabolites.

65 This

theory, however, does not explain why other patient groups known to have higher

serum lamotrigine concentrations during treatment, such as the elderly, are not at

increased risk. Others have speculated that this represents an immune-mediated

hypersensitivity response, because many of the affected patients reported have had

previous reactions with other antiepileptic drugs.

66 Children with refractory seizures,

such as those with Lennox-Gastaut syndrome, who are often treated with multiple

agents beginning in the first years of life may be more likely to develop

hypersensitivity. Although the mechanism underlying the age-related difference in the

incidence of lamotrigine-associated rashes is not yet well understood, the importance

of patient counseling is clear. The caregivers of all children receiving lamotrigine

should be made aware of the risk and the need to seek medical care as soon as any

signs of rash or erythema are noted.

MEDICATION DOSING IN CHILDREN

CASE 102-10

QUESTION 1: A.K. is a 7-year-old, 20-kg boy recently diagnosed with ADHD. After developing insomnia

when treated with methylphenidate, he was switched to clonidine by his pediatrician. The recommended starting

dose for clonidine in children is 5 mcg/kg/day divided and given in two to four doses.

67 His prescription is for

clonidine 0.05 mg by mouth twice daily. Because A.K. does not yet swallow tablets easily, he will need a

solution made from the tablets. It will be prepared from a published extemporaneous formulation with a final

concentration of 0.1 mg/mL. What steps are necessary to ensure the accuracy of this prescription?

p. 2135

p. 2136

The differences in pharmacokinetics and pharmacodynamics observed in children

influence the choice of dose and dosing interval.

68 Because incorporating all of these

variables would result in dosing calculations too difficult for practical use, weight

has traditionally been chosen as the single best estimate of growth. Pediatric drug

references provide most doses in units per weight, such as mg/kg/day or

mcg/kg/dose. Among the exceptions to this are chemotherapeutic agents, which are

dosed by body surface area, incorporating height as an additional variable. Because

of the difficulty in accurately determining height (or length) in young children, it is

not commonly used for other drugs.

Age can be an important variable, especially for premature infants, in whom it can

be used to account for differences in volume of distribution and elimination half-life.

For example, neonatal gentamicin dosing is often based on a rubric of gestational or

postconceptional age, postnatal age, and weight.

17 A recent study of clonidine

clearance in the early postnatal period suggests that both age and weight should be

used to optimize clonidine doses in newborns being treated for neonatal abstinence

syndrome.

69

In the future, pediatric dosing recommendations for many drugs may be

based on more than just weight to incorporate new pharmacokinetic data.

70

Medication orders or prescriptions with doses outside of the dosing range listed in

a pediatric drug reference should always be questioned for appropriateness. Older

children and adolescents should transition to adult dosing whenever the calculated

weight-based dose exceeds the usual adult dose. When evaluating a pediatric

prescription or medication order, determining whether the dose is appropriate for the

patient’s weight is not the only step undertaken by the pharmacist. As with all

patients, allergies, underlying diseases, and concomitant therapy must be taken into

account as well.

A.K.’s clonidine dose of 0.05 mg twice daily is equivalent to 5 mcg/kg/day, the

appropriate starting dose for a child. Using a 0.1-mg/mL extemporaneous solution,

his dose will be 0.5 mL twice daily. The label on A.K.’s clonidine bottle should

include the concentration of the formulation, as well as the dose in both mg and mL.

Before the start of treatment, A.K.’s parents should be counseled about the drug, the

dose, and potential adverse effects. They should be given or have access to an oral

dosing syringe or spoon to accurately measure the dose.

PREVENTING MEDICATION ERRORS IN

CHILDREN

CASE 102-10, QUESTION 2: After 2 days of therapy, A.K. returns to his pediatrician’s office with his

parents. He is lethargic and feels dizzy when getting out of bed. His blood pressure is 90/54 mm Hg (normal for

age and weight is 99/59 mm Hg), suggesting a possible clonidine overdose. As you begin to investigate the

potential cause of A.K.’s symptoms, what factors may have led to an error in A.K.’s case?

Medication errors pose a significant risk for infants and children.

71–75 Whereas the

rate of medication errors reported in studies of adults is approximately 5%, rates in

many pediatric studies have ranged from 10% to 15%.

71–73 The need to calculate

weight-based doses can lead to mathematic errors. In A.K.’s case, the dose must be

multiplied by the patient’s weight, divided into individual doses, and converted from

micrograms to milligrams. Unit conversions and decimal point errors are particularly

dangerous in pediatrics, because a 10-fold overdose of a drug with a narrow dosing

range such as clonidine, digoxin, morphine, or fentanyl can be fatal.

76

In addition to

prescribing errors, dosage formulation manipulation, such as the preparation of an

extemporaneous liquid in this case, increases the risk for drug preparation errors.

Oral liquid medications also present a risk for administration errors. Healthcare

providers and caregivers in the home must be aware of the potential for errors and

the need for precise dose measurement. A.K.’s medical history must include

information on how the clonidine had been prepared by the pharmacy as well as how

his parents were preparing and administering his doses.

CASE 102-10, QUESTION 3: What steps could have been taken to prevent the medication error that

occurred with A.K.?

There are a number of methods to reduce the potential for medication errors,

including recommendations from the Joint Commission, the American Academy of

Pediatrics, and a recent Cochrane review (Table 102-3).

74,75,77–82 Use of standard

concentrations for IV products and oral liquids, smart-pump technology, bar coding,

and electronic prescribing with clinical decision support tools have been found to

significantly reduce errors in pediatric hospitals. In the outpatient setting, medication

errors can be reduced by the inclusion of patient-specific information on

prescriptions, including diagnosis and patient weight.

83 The product label, whether it

is a prescription or over-the-counter medication, should include all the information

needed to correctly prepare and administer the dose. Caregivers should have access

to the appropriate tools for measuring liquid medications, such as oral dosing spoons

or syringes, and the opportunity to practice preparing a dose under the supervision of

a healthcare provider to ensure that they are able to prepare the dose correctly.

84

Table 102-3

Methods for Reducing Pediatric Medication Errors

Improve Ordering and Preparation

Perform careful medication histories, including assessment of oral liquid concentrations

Provide access to current pediatric medication information

Include patient weight (in kg) on all medication orders and prescriptions

Include dosage calculations on orders and prescriptions

Limit the number of concentrations available for high-risk medications

Use accurate measuring devices, in both the hospital and home settings

Implement Appropriate Technology

Adopt weight-based electronic prescribing or dose-checking software

Employ barcode technology to reduce patient identification and medication administration errors

Use smart-pump technology (programmable IV pumps with weight-based dosing limits)

Use Staff Expertise

Provide pediatric-specific continuing education for allstaff on a routine basis

Develop pediatric-specific medication orders and protocols to guide care

Assign staff with pediatric expertise to all committees involved in medication management

Involve Families and Other Caregivers

Encourage all caregivers to ask questions about their child’s medications

Recommend that all caregivers know the names and doses of their children’s medications or carry information

about their medications

Remind caregivers to include nutritionalsupplements, herbal or complementary therapies, and over-the-counter

medications when giving a medication history

Ensure that caregivers can accurately prepare the medication dose

IV, intravenous.

p. 2136

p. 2137

One of the most effective methods to prevent medication errors has been to include

pharmacists in the medication ordering and review process.

83,85 The value of

pharmacists in reducing pediatric medication errors was demonstrated by Folli et

al.

85

In this landmark study, clinical pharmacists performed prospective evaluations

of medication orders at two children’s hospitals for a 6-month period. The overall

rate of medication errors detected by the pharmacists averaged 4.7 per 1,000

medication orders. Of these, 5.6% were considered potentially lethal. The majority

of the errors (64.3%) occurred in children younger than 2 years of age. The most

common type of error identified by the pharmacists was incorrect dosage. The

authors concluded that pharmacy intervention had a significant effect on medication

error prevention, a finding that resulted in the expansion of pediatric clinical

pharmacy services in many institutions. Pharmacists in the community provide the

same benefit when reviewing pediatric prescriptions and play a significant role in

caregiver medication education.

INCREASING AVAILABILITY OF PEDIATRIC

MEDICATION INFORMATION

CASE 102-10, QUESTION 4: Although the dose of clonidine for the treatment of ADHD is available in

most pediatric dosing references, it is not found in the manufacturer’s prescribing information (package insert)

for the drug because the treatment of ADHD is not currently an FDA-approved indication. What is being done

to increase the availability of pediatric drug information?

Although the availability of pediatric drug information has been limited in the past,

several recent initiatives from the FDA are increasing the number of clinical trials

being conducted in infants and children. The Pediatric Exclusivity Program, part of

the FDA Modernization Act of 1997, was developed to address the lack of pediatric

study data, including medication prescribing information.

8,86–88 The Exclusivity

Program provides pharmaceutical manufacturers with incentives to study their

products in children, including a 6-month extension at the end of a drug’s patent life if

a pediatric study is conducted. The 1998 Pediatric Rule and the Research Equity Act

of 2003 authorized the FDA to require that manufacturers conduct clinical trials of

drugs that would be used in a significant number of patients. The Best

Pharmaceuticals for Children Act supplements the previous incentives by the creation

of a mechanism for funding studies of older, off-patent medications that are often

used in children.

These programs have been successful in adding pediatric dosing and adverse

effect information to the prescribing information of many drugs routinely used in

children. As of June 2017, the FDA had issued 430 written requests for pediatric

studies, and 241 drugs had been granted a patent extension under the Exclusivity

Program.

86 An assessment of the first 7 years of the program found that 50% of the

studies conducted resulted in the new information supporting the use of the drug in

children.

87

In spite of this success, much work remains to be done. Modifications in

clinical trial design to incorporate pharmacogenomic studies and the use of combined

pharmacokinetic–pharmacodynamic analyses have been recommended to further

refine our knowledge of drug disposition in children.

87,88 The emphasis on the needs

of pediatric patients has not been limited to just the United States; similar programs

are in place in the European Union and throughout Asia. With the growing interest in

developmental pharmacology and pharmacogenomics, as well as the increased

funding and support for pediatric clinical trials worldwide, our understanding of the

unique differences in how children respond to drug therapy continues to improve.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

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(86)

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