US Pharm. 2013;(38)(Oncology suppl):8-11.
ABSTRACT: The formulation of chemotherapy regimens for pediatric
patients is a challenge for multiple reasons. Because of developing
physiological processes, children differ from adults in each of the four
pharmacokinetic stages. These differences lead to varying levels of
medication exposure and clearance. The toxicity profiles of these drugs
and the unpredictable efficacy in pediatric patients can have
potentially devastating consequences in the treatment of pediatric
cancers. Whether dosing should be based on body surface area (as is the
practice in adult patients) or on body weight is another complicating
factor, as is the availability of age-appropriate dosage forms.
As current wisdom acknowledges, children are not “small adults.” The
effects of chemotherapeutic agents on infants and young children are
much different from those occurring in adolescents and adults. This
article will discuss clinical factors that influence the complexity of
chemotherapy regimens in pediatric patients, including differences in
pharmacokinetic (PK) parameters, dosing (body surface area [BSA] vs.
body weight [BW]), and age-appropriate dosage forms.
The four PK stages are absorption, distribution, metabolism, and
excretion. The developmental physiological changes that occur throughout
childhood, termed ontogeny, can affect these stages. As infants
age, they undergo significant maturational alterations in gastric and
intestinal pH and in gastrointestinal motility, flora, and enzyme
activity, all of which can affect the absorption of orally administered
medications.1,2 Age-dependent changes in body composition,
including total body water and adipose tissue and alterations in
circulating plasma proteins, can alter the physiological spaces in which
a medication distributes. As the infantile liver matures, changes in
expression of phase I and II metabolizing enzymes—including CYP450—alter
the biotransformation of toxic medications to nontoxic metabolites and
the biotransformation of prodrugs to active moieties.1 Because of poor renal arterial blood flow at birth, the glomerular filtration rate (GFR) is virtually nil (2-4 mL/min/1.73 m2)
in newborns, increases rapidly in the first 2 weeks of life, and then
(around age 8-12 months) begins a steady rise to adult values.1
Combined, these differences in each PK stage alter overall
chemotherapy exposure and clearance in infants and young children
compared with adults. The resulting efficacy and toxicity profile may be
unpredictable, which makes the designing of chemotherapy regimens
difficult in this vulnerable population.3
Pediatric Chemotherapy Dosing
Cancer is the second leading cause of death in children in developed
countries, despite improvements in multimodal treatment strategies that
have increased the probability of cure.4,5 Approximately 80% of newly diagnosed cancer patients aged less than 15 years will be cured.6
Although pediatric cancer treatment has advanced remarkably in the last
several decades, the determination of optimal chemotherapy dosing for
infants has lagged behind that for older children and adults, since
infants frequently are excluded from clinical trials. The scarcity of
published PK data on chemotherapeutic agents commonly used in infants
and young children often necessitates that doses be estimated by
extrapolating from data on older children and adults. Such estimation
leads to significant interpatient variability in systemic drug exposure.
This variability, together with the drugs’ toxicity and the importance
of dose intensity in cancer chemotherapy, points to the need for more
precise, individualized dosing methods for anticancer drugs in the
It is standard practice to individualize chemotherapy doses in patients of all ages.8
In adults, dosing is usually based on BSA, a practice that is more
historical than scientific. Because of differences in PK properties, the
chemotherapy dosage derived from adult studies may not accurately
predict similar drug exposure in pediatric patients. In phase I
dose-finding studies, when the chemotherapy was administered to adults
and children on similar schedules, pediatric patients often required
higher chemotherapy doses based on BSA. For example, in patients with
similar organ function, the recommended phase II mitoxantrone doses for
pediatric patients and adults, respectively, were 18 mg/m2 and 12 mg/m2; those for carboplatin were 560 mg/m2 and 400 mg/m2.8
The inaccuracies of chemotherapy dosing based on BSA in pediatric
patients have raised the question of when to use BW instead. It is
important to note that the ratio of BSA to BW is significantly higher in
infants and drastically lessens as a child grows. Thus, for infants and
young children, BSA can greatly overestimate the dose needed to achieve
a desired AUC, whereas BW may be a more accurate predictor of drug
exposure.9,10 The “rule of 30” may be used to adjust a dose from mg/m2 to mg/kg according to the assumption that a patient with a BSA of 1 m2 weighs approximately 30 kg. By this rule, a 1,500-mg/m2
dose of cyclophosphamide in an older child could be converted to a dose
of 50 mg/kg in a younger child. The dose for an average-sized infant
aged 3 months (BSA 0.3 m2, BW 5.3 kg) would be approximately 450 mg if calculated according to BSA (1,500 mg/m2)
and 265 mg if calculated according to BW (50 mg/kg)—a 40% difference.
Thus, this conversion can be problematic, since it sometimes leads to a
large variability in calculated chemotherapy dose. Although it is known
that BSA-based dosing can be overestimated, there is significant
inconsistency across protocols and tumor types as to which developmental
milestone is endorsed as a scaling method for the use of BW versus BSA.
Different studies evaluating the same drug and tumor type may determine
to use BW-based dosing in pediatric patients based on age (<12
months or <3 years) or weight (<10, 12, or 30 kg).
To further complicate the design of chemotherapy regimens for
pediatric patients, dose adjustments may be applied after scaling to BSA
or BW. In neonates, dose reductions of up to 50% are commonly made to
offset the immaturity of elimination pathways, even though the process
of scaling the dosage to BW already significantly reduces the dose
administered compared with BSA.9,10 As with the determination
of dose-scaling parameters, dose reductions are applied inconsistently
across treatment regimens and protocols and often are based on toxicity
observed in previous studies, rather than on true PK data.
Carboplatin: Carboplatin is a prime example of how PK
data can be applied to derive successful, innovative dosing strategies
for a chemotherapeutic agent with large interpatient PK variability.
Since carboplatin is excreted almost entirely unchanged in the urine,
GFR alone can predict carboplatin drug exposure more accurately than
body size can.8 This was established by Calvert et al, who
developed a dose-calculation method based on GFR that was intended to
achieve a target carboplatin AUC in adults.11 The use of this
formula to individualize carboplatin dosing lessens the variability in
systemic drug exposure and reduces the incidence of severe
thrombocytopenia.7 Pediatric patients also can benefit from
the application of adaptive dosing formulas based on findings that
carboplatin doses normalized to BSA in children resulted in two- to
threefold variability in AUC.12 Since the development of the
Calvert equation, many alternatives have been utilized that are based on
PK data from pediatric patients (TABLE 1).13-16 The selection of a formula for clinical practice often varies among protocols and treatment centers.
Busulfan: Busulfan is another chemotherapeutic agent
for which clinicians utilize PK data to maximize efficacy and minimize
toxicities. Busulfan is an alkylating agent commonly used in
conditioning regimens for patients with hematologic malignancies or
nonmalignant disorders who are undergoing hematopoietic stem cell
transplantation. Initially, busulfan was available only as a 2-mg tablet
dosed (for this indication) at 1 mg/kg every 6 hours for 16 doses.17-19 Patients were required to take a large number of tablets to achieve the desired systemic exposure.17
The high doses of oral busulfan required for transplantation were
commonly associated with hepatic sinusoidal obstruction syndrome since
the drug’s extensive first-pass metabolism caused increased
concentrations in the portal hepatic venous system. Oral busulfan also
demonstrated high interpatient and intrapatient variability and
unpredictable drug bioavailability. An IV busulfan formulation was
developed to improve bioavailability and reduce the incidence of
Extensive experience with busulfan in adult patients found that a
therapeutic window of 900 to 1,500 µmol/min improved stem-cell
engraftment and reduced toxicities.18 However, the PK profile of busulfan differs in children aged less than 4 years.18,19
Increased plasma clearance leads to reduced systemic exposure, making
it difficult to attain adequate levels with standard mg/kg dosing in
this age group.19
Several studies recommend dosing busulfan based on BSA, rather than BW, to increase the AUC in younger patients.17,18 A dose of 600 mg/m2
was proposed to achieve concentrations similar to those in adult
patients; however, this dose also produced wide interpatient
variability, with concentrations ranging from 850 to 3,300 µmol/min.21
Many institutions cannot perform busulfan PK monitoring, so a
decreasing BW-dosing strategy was developed based on the premise that
busulfan clearance decreases with increasing weight and age. Five
busulfan dose levels were defined: 1 mg/kg for <9 kg; 1.2 mg/kg for
9–<16 kg; 1.1 mg/kg for 16–23 kg; 0.95 mg/kg for >23–34 kg; and
0.8 mg/kg for >34 kg.22 With so many different options,
the busulfan dosing regimen and target systemic exposure will vary
according to the protocol and the treatment center.
Oral Chemotherapy in Pediatric Patients
Most agents used to treat pediatric cancers are administered IV, but
the number of orally administered chemotherapies continues to increase,
broadening the range of potential treatment options.6,23 The
FDA approved at least 12 new oral antineoplastic agents between 2005 and
2007. The National Comprehensive Cancer Network predicted that, by
2013, 25% of chemotherapy agents administered to patients would be an
Oral chemotherapy used to treat adult cancers may be beneficial in
the treatment of pediatric cancers, but pediatric-specific formulations
may not be available.24 Children aged less than 5 years generally have difficulty swallowing tablets or capsules.25
Cutting, crushing, or manipulating tablets or capsules to achieve
pediatric doses may result in inaccurate dosing, potentially leading to
increased adverse effects or decreased effectiveness.6,26,27
The same problems can result from rounding each dose to the nearest
tablet or capsule. In the case of oral mercaptopurine, which is used to
treat pediatric acute lymphoblastic leukemia, the Children’s Oncology
Group recommends using half tablets and alternating doses to attain the
weekly cumulative dose.6,26
As of 2011, data on extemporaneous solutions were available for only
46% of oral chemotherapy agents. Information on dose uniformity,
stability, bioequivalence, and safety of extemporaneously prepared
liquid formulations is limited. A review identified 46 oral
antineoplastic agents, none of which had an FDA-approved liquid dosage
form. Of these agents, only 21 had an extemporaneous formula, and even
fewer had stability and bioavailability data.27
Prior to compounding an extemporaneous solution from oral
chemotherapy agents, one should have a basic understanding of the PK
characteristics of the drug, the active drug’s chemical compatibility
with excipients, the final solution’s stability and palatability, and
ease of administration.25,27 Another consideration is safety
during the preparation process. The Occupational Safety and Health
Administration provides guidelines for the safe handling of hazardous
drugs. Manipulation of oral chemotherapy should be performed by a
trained professional in a biological safety cabinet to reduce the risk
of skin and inhalation exposure; this is in contrast to nonhazardous
liquid medications, which frequently are compounded in the inpatient
hospital, in the outpatient setting, or at home.28
Medication errors involving extemporaneous oral chemotherapy
preparations compounded by caregivers may cause harmful events, and even
death.29 Education and standards of practice are important
components in the proper and safe handling of oral chemotherapy in the
inpatient setting, the outpatient setting, and at home to prevent dosing
errors and chemotherapy exposure.27,29 Pharmacists play a
vital role in providing education regarding the proper handling and
preparation of extemporaneous solutions from solid chemotherapy dosage
Multiple factors complicate the treatment of cancer in pediatric
patients. Clinicians must take these many factors into account when
designing chemotherapy regimens for pediatric patients. Ultimately,
these considerations will enable better care and monitoring of pediatric
patients with cancer.
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