BAYESIAN STRATEGY TO ASSESS ERROR FROM MEASURED MODEL PARAMETERS: TOXICOKINETICS

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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.