Dosing Considerations in Pediatric Oncology

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.

PK Considerations

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 pediatric population.⁷

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 toxicities.²⁰

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 formulation.²³

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 forms.

Conclusion

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.

REFERENCES

1. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology—drug disposition, action, and therapy in infants in children. N Engl J Med. 2003;349:1157-1167.
2. Stewart CF, Hampton EM. Effect of maturation on drug disposition in pediatric patients. Clin Pharm. 1987;6:548-564.
3. Rodriguez W, Selen A, Avant D, et al. Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics. 2008;121:530-539.
4. Paolucci P, Jones KP, del Carmen Cano Garcinuno M, et al. Challenges in prescribing drugs for children with cancer. Lancet Oncol. 2008;9:176-183.
5. CDC. Trends in childhood cancer mortality—United States, 1990-2004. MMWR Morb Mortal Wkly Rep. 2007;56:1257-1261.
6. Bleyer WA, Danielson MG. Oral cancer chemotherapy in paediatric patients: obstacles and potential for development and utilisation. Drugs. 1999;58(suppl 3):133-140.
7. Adamson PC, Balis FM, Berg S, et al. General principles of chemotherapy. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:291-366.
8. Gurney H. Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. J Clin Oncol. 1996;14:2590-2611.
9. Leahey A. A cautionary tale: dosing chemotherapy in infants with retinoblastoma. J Clin Oncol. 2012;30:1023-1024.
10. Veal GJ, Boddy AV. Chemotherapy in newborns and preterm babies. Semin Fetal Neonatal Med. 2012;17:243-248.
11. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748-1756.
12. Madden T, Sunderland M, Santana VM, Rodman JH. The pharmacokinetics of high-dose carboplatin in pediatric patients with cancer. Clin Pharmacol Ther. 1992;51:701-707.
13. Marina NM, Rodman J, Shema SJ, et al. Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumors. J Clin Oncol. 1993;11:554-560.
14. Newell DR, Pearson AD, Balmanno K, et al. Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. J Clin Oncol. 1993;11:2314-2323.
15. Pinkerton CR, Broadbent V, Horwich A, et al. ‘JEB’—a carboplatin based regimen for malignant germ cell tumours in children. Br J Cancer. 1990;62:257-262.
16. Mann JR, Raafat F, Robinson K, et al. UKCCSG’s germ cell tumor (GCT) studies: improving outcome for children with malignant extracranial non-gonadal tumours—carboplatin, etoposide, and bleomycin are effective and less toxic than previous regimens. Med Pediatr Oncol. 1998;30:217-227.
17. Ciurea SO, Andersson BS. Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:523-536.
18. Sandler ES, Hagg R, Coppes MJ, et al. Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium. Med Pediatr Oncol. 2000;35:403-409.
19. Bolinger AM, Zangwill AB, Slattery JT, et al. Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation. Bone Marrow Transplant. 2001;28:1013-1018.
20. Bhagwatwar HP, Phadungpojna S, Chow DS, Andersson BS. Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy. Cancer Chemother Pharmacol. 1996;37:401-408.
21. Vassal G, Deroussent A, Challine D, et al. Is 600 mg/m² the appropriate dosage of busulfan in children undergoing bone marrow transplantation? Blood. 1992;79:2475-2479.
22. Vassal G, Michel G, Espérou H, et al. Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring. Cancer Chemother Pharmacol. 2008;61:113-123.
23. Halfdanarson TR, Jatoi A. Oral cancer chemotherapy: the critical interplay between patient education and patient safety. Curr Oncol Rep. 2010;12:247-252.
24. Nahata MC, Allen LV Jr. Extemporaneous drug formulations. Clin Ther. 2008;30:2112-2119.
25. Traynor K. Pediatric cancer chemotherapy formulations remain elusive. Am J Health Syst Pharm. 2010;67:170-171.
26. Christiansen N, Taylor KM, Duggan C. Oral chemotherapy in paediatric oncology in the UK: problems, perceptions and information needs of parents. Pharm World Sci. 2008;30:550-555.
27. Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31:164-192.
28. Griffin E. Safety considerations and safe handling of oral chemotherapy agents. Clin J Oncol Nurs. 2003;7(suppl 6):25-29.
29. Birner A. Safe administration of oral chemotherapy. Clin J Oncol Nurs. 2003;7:158-162.

To comment on this article, contact rdavidson@uspharmacist.com.