Although anti-cancer drugs are widely used in infants and young children with malignant brain tumors, the dosing of these toxic drugs is often scaled based on body size (e.g., BSA or body weight) or arbitrary age cut-offs. This dosing approach does not take into account the many developmental changes that occur in infants and young children. These changes, which include hepatic and renal maturation, may affect the disposition of anticancer drugs, leading to more severe toxicity, particularly myelosuppression, which puts these children at risk of life-threatening infections. Yet the pharmacokinetics and toxicity of many anticancer drugs have not been adequately studied in infants and young children. Thus, we propose to perform clinical pharmacokinetic (PK), pharmacogenetic, and pharmacodynamic (PD) studies of methotrexate (MTX), cyclophosphamide (CTX), and topotecan (TPT) as part of a clinical protocol that treats infants and young children with malignant brain tumors. In this grant application, we propose three hypothesis directed aims: 1.) To characterize the disposition of MTX, oral and intravenous CTX, and oral and intravenous TPT in infants and young children with malignant brain tumors, 2.) To use statistical and mechanistic models to identify PD and PKPD response relationships for anti-cancer drugs in infants and young children, and 3.) To develop dosing regimens for infants and young children to achieve more uniform systemic exposure to anticancer drugs across all pediatric age groups. Collectively, these studies narrow the gap in our understanding of the clinical pharmacology of anti-cancer drugs used to treat infants and young children. Our long-term goal is to determine rational dosing regimens for infants and young children by better understanding the developmental pharmacology of anti-cancer drugs and to apply these regimens to therapy for other childhood malignancies and chronic medical conditions.
Anti-cancer drugs such as methotrexate, cyclophosphamide, and topotecan are important for the treatment of infants and young children with malignant brain tumors. However, inadequate studies have been performed to know how to calculate anti-cancer drug dosages for these patients. In addition to the many physiological changes occurring in the organs (e.g., liver, kidney) associated with disposition of these drugs during infancy, further complicating the matter is the potential effect of developmental pharmacogenetics on the disposition of these drugs in this patient population. The studies proposed will examine drug disposition in infants and young children with malignant brain tumors, and relate drug concentrations to toxicity and response to therapy. Results of these studies will provide the data necessary to design improved drug dosing approaches, which can improve the outcome of infants and young children with malignant brain tumors.