Anticancer Drug Pharmacology in Very Young Children

描述（由申请人提供）：尽管抗癌药物广泛用于患有恶性脑肿瘤的婴儿和幼儿，但这些毒性药物的剂量通常基于体型（例如，BSA或体重）或任意年龄临界值。这种给药方法没有考虑到婴儿和幼儿发生的许多发育变化。这些变化，包括肝脏和肾脏的成熟，可能会影响抗癌药物的处置，导致更严重的毒性，特别是骨髓抑制，使这些儿童面临危及生命的感染风险。然而，许多抗癌药物的药代动力学和毒性尚未在婴儿和幼儿中得到充分研究。因此，我们建议对甲氨蝶呤（MTX）、环磷酰胺（CTX）和拓扑替康（TPT）进行临床药代动力学（PK）、药物遗传学和药效学（PD）研究，作为治疗患有恶性脑肿瘤的婴幼儿的临床方案的一部分。在本申请中，我们提出了三个假设指导目标：1。描述MTX、口服和静脉注射CTX以及口服和静脉注射TPT在患有恶性脑肿瘤的婴幼儿中的分布，2.）使用统计学和机制模型来确定PD和PKPD对婴幼儿抗癌药物的反应关系，以及3.）为婴幼儿制定给药方案，以使所有儿科年龄组的抗癌药物全身暴露更加均匀。总的来说，这些研究缩小了我们对用于治疗婴幼儿的抗癌药物的临床药理学理解的差距。我们的长期目标是通过更好地了解抗癌药物的发育药理学来确定婴幼儿的合理给药方案，并将这些方案应用于其他儿童恶性肿瘤和慢性疾病的治疗。 公共卫生相关性：抗肿瘤药物如甲氨蝶呤、环磷酰胺和拓扑替康对于治疗患有恶性脑肿瘤的婴幼儿是重要的。然而，还没有进行足够的研究来了解如何计算这些患者的抗癌药物剂量。除了器官中发生的许多生理变化（例如，肝脏、肾脏）与这些药物在婴儿期的分布有关，使问题进一步复杂化的是发育药物遗传学对这些药物在该患者群体中分布的潜在影响。这些研究将检查患有恶性脑肿瘤的婴儿和幼儿的药物处置，并将药物浓度与毒性和治疗反应联系起来。这些研究的结果将为设计改进的药物给药方法提供必要的数据，这些方法可以改善患有恶性脑肿瘤的婴幼儿的预后。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.