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剂， 由于其对成熟T细胞的毒性， 细胞 它可能是最常用的大剂量药物 造血干细胞移植前化疗。 其 在这种情况下的作用主要是免疫抑制，因为它是 对骨髓和淋巴前体细胞毒性极小。 我们有 建立了仔细的个体药代动力学靶向， 白消安，通常与环磷酰胺一起用于干细胞 移植准备方案的互补毒性， 造血祖细胞，将避免发病率和死亡率 与高剂量方案相关。 然而，白消安的控制 仅血浆水平不足以阻止方案相关的 毒性 CY药代动力学的变异性及其在 干细胞移植的结果尚未研究。 环磷酰胺 本身是不活跃的。 CY的细胞毒性作用是通过 细胞色素P450介导的转化为羟基环磷酰胺（HCY）。 HCY是一个分析挑战，因为它的半衰期仅为 在血液样本中。 我们开发了一种化学分析方法 适用于临床，它捕获HCY作为一对腙 稳定且适合于HPLC分析的双异构体。

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.