BAYESIAN STRATEGY TO ASSESS ERROR FROM MEASURED MODEL PARAMETERS: TOXICOKINETICS

环磷酰胺(CY)是一种非常有用的化疗药物 也用于免疫抑制，因为它对成熟的T细胞有毒性 细胞。它可能是大剂量中最常用的药物 在造血干细胞移植前进行化疗。它的 此设置中的角色主要是免疫抑制，因为它是 对髓系和淋巴系前体细胞毒性最小。我们有 确定了谨慎的个体药动学靶向 白花丹，通常与环磷酰胺一起用于干细胞 移植准备方案对患者的补充毒性 造血祖细胞，将避免发病率和死亡率 与高剂量的治疗方案有关。然而，白花丹的防治 仅有血浆水平不足以阻止与药物有关的 毒性。环磷酰胺药代动力学的变异性及其在体内的作用 干细胞移植的结果还没有研究。环磷酰胺 它本身是不活跃的。环磷酰胺的细胞毒作用是通过 细胞色素P450介导的羟基环磷酰胺(HCY)的转化。 HCY是一个分析挑战，因为它的半衰期仅为 在血样中只有几分钟。我们已经开发出一种化学分析方法 适用于临床，可将HCY作为一对肼类药物进行诱捕 非对映异构体是稳定的，易于进行高效液相色谱分析。

Cyclophospharnide (CY) is a very useful chemotherapy agent that also is used for immunosuppression due to its toxicity to mature T cells. It is perhaps the most commonly used agent in high dose chemotherapy prior to hematopoietic stem cell transplantation. Its role in this setting is primarily immune suppression, since it is minimally toxic to myeloid and lymphoid precursors. We have established that careful individual pharmacokinetic targeting of busulfan, commonly used with cyclophsophamide in the stem cell transplantation preparative regimen for its complimentary toxicity to hematopoietic progenitor cells, will avoid morbidity and mortality associated with the high dose regimen. However, control of busulfan plasma levels alone is not sufficient to prohibit regimen-related toxicity. Variability in CY pharmacokinetics and its role in the outcome of stem cell transplantation is unstudied. Cyclophsophamide itself is inactive. The cytotoxic effects of CY are mediated through cytochrome P 450-mediated conversion to hydroxycyclophosphamide (HCY). HCY is an analytical challenge since it has a half-life of only minutes in a blood sample. We have developed a chemical analysis applicable in the clinic, which traps HCY as a pair of hydrazone diasteriomers that are stable and amenable to HPLC analysis.