A Phase I trial: dose escalation of melphalan in the "BEAM" regimen using amifostine cytoprotection.

With the eventual goal of reducing relapse and thus improving overall survival in selected lymphoma patients, a Phase I study was performed using the cytoprotectant amifostine to permit safe dose-augmentation of melphalan in the carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen before autologous hematopoietic stem cell transplantation. Between 30 July 2003 and 25 November 2008, a total of 32 lymphoma patients were entered, of which 28 were evaluable. We found the melphalan dose in BEAM could be safely escalated to at least 260 mg/m², a substantial increase from the usual dose of 140 mg/m² in BEAM while the trial was terminated early due to poor accrual, no maximal tolerated dose or dose-limiting toxicity was found. A Phase II trial is planned.

Development of a pharmacokinetic and Bayesian optimal sampling model for individualization of oral busulfan in hematopoietic stem cell transplantation.

Therapeutic drug monitoring is used to minimize toxicity and maximize the therapeutic efficacy of busulfan, which shows high intra- and interpatient pharmacokinetic variability and erratic oral absorption. This study was designed to develop a pharmacokinetic model that could accommodate the erratic oral absorption of busulfan and to use this model to develop an optimal sparse pharmacokinetic sampling strategy to improve the precision and efficiency of therapeutic drug monitoring. Twenty-one pharmacokinetic profiles were collected from 12 patients receiving oral busulfan before hematopoietic stem cell transplantation. Each pharmacokinetic profile was defined by 5 to 9 plasma concentrations. Candidate pharmacokinetic models were initially fit to the data by maximum likelihood, with model discrimination by Akaike's Information Criterion. Maximum likelihood results were used to derive Bayesian previous parameter estimates, and D-optimal design was used to determine optimal sparse sampling strategies. Each candidate sampling strategy was tested in each patient by comparing the resultant Css obtained from the sparse strategy to the actual Css derived from each patient's full pharmacokinetic dataset. The final model was a 1-compartment model, with oral busulfan absorbed in 1 to 3 phases, and fit the data well. All limited sampling models tested were unbiased in their results, and a 4-sample scheme proved to adequately characterize busulfan pharmacokinetics, and should allow for a reduced sampling frequency for therapeutic drug monitoring.

Experience with computerized chemotherapy order entry.

PURPOSE: The elimination of errors related to chemotherapy administration remains an elusive goal. Computerized order entry has been shown to reduce errors. We assessed a chemotherapy computer order entry system for errors related to dosing and for the time required to prepare chemotherapy orders. METHODS: A prospective study of all patients treated with chemotherapy over a 12-month period was performed. Chemotherapy order sets done via computerized order entry were reviewed for errors related to drug selection, dose calculations, decimal-point errors, and for exceeding a warning level set within the system. We also measured the time required to produce three order sets by hand versus by computer. RESULTS: There were no errors in dose calculations, decimal points, or drug selection for 2,558 drug administrations in 235 patients treated with 26 different chemotherapy regimens. The dose warning level was exceeded in 152 (6%) of drug administrations, but never without user permission to override the warning. The average time saved per order set using computer order entry was 10 minutes (P < .05). CONCLUSION: By using computer order entry with error-checking algorithms, it may be possible to eliminate a number of types of errors associated with chemotherapy administration without sacrificing efficiency.