Anticancer Drug Pharmacology in Very Young Children

说明(申请人提供)：虽然抗癌药物被广泛用于患有恶性脑瘤的婴幼儿，但这些有毒药物的剂量通常是根据身体尺寸(例如，BSA或体重)或任意的年龄界限来衡量的。这种剂量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，这将使这些儿童面临威胁生命的感染风险。然而，许多抗癌药物在婴幼儿中的药代动力学和毒性还没有得到充分的研究。因此，我们建议进行甲氨蝶呤(MTX)、环磷酰胺(CTX)和拓扑替康(TPT)的临床药代动力学(PK)、药物遗传学和药效学(PD)研究，作为治疗婴幼儿恶性脑瘤的临床方案的一部分。在本次拨款申请中，我们提出了三个假设导向的目标：1)目的：了解甲氨蝶呤、口服和静脉注射环磷酰胺、口服和静脉注射甲氨蝶呤在婴幼儿恶性脑肿瘤中的分布特点。使用统计和机械模型来确定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，以实现在所有儿科年龄组中更均匀地全身接触抗癌药物。总而言之，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的理解差距。我们的长期目标是通过更好地了解抗癌药物的发展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。

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.