Purpose: Dose-related toxicity of cyclophosphamide may be reduced and therapeutic efficacy may be improved by pharmacokinetic sampling and dose adjustment to achieve a target area under the curve (AUC) for two of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM). To facilitate real-time dose adjustment, we developed open-source code within the statistical software R that incorporates individual data into a population pharmacokinetic model. Experimental Design: Dosage prediction performance was compared to that obtained with nonlinear mixed-effects modeling using NONMEM in 20 cancer patients receiving cyclophosphamide. Bayesian estimation of individual pharmacokinetic parameters was accomplished from limited (i.e., five samples over 0-16 hours) sampling of plasma HCY and CEPM after the initial cyclophosphamide dose. Conditional on individual pharmacokinetics, simulations of the AUC of both HCY and CEPM were provided for a range of second doses (i.e., 0-100 mg/kg cyclophosphamide). Results:The results compared favorably with NONMEM and returned accurate predictions for AUCs of HCYand CEPM with comparable mean absolute prediction error and root mean square prediction error. With our method, the mean absolute prediction error and root mean square prediction error of AUC CEPM were 11.0% and 12.8% and AUC HCY were 31.7% and 44.8%, respectively. Conclusions: We developed dose adjustment software that potentially can be used to adjust cyclophosphamide dosing in a clinical setting, thus expanding the opportunity for pharmacokinetic individualization of cyclophosphamide. The software is simple to use (requiring no programming experience), reads individual patient data directly from an Excel spreadsheet, and runs in less than 5 minutes on a desktop PC.The alkylating agent cyclophosphamide is used for treating a wide range of malignancies in both pediatric and adult patients and as part of myeloablative conditioning regimens before hematopoietic cell transplant. Cyclophosphamide dosing based on body weight (mg/kg) or body surface area (mg/m 2 ) results in highly variable area under the concentration-time curve (AUC) of the parent drug between patients and an even greater variability in the AUC of its metabolites (1, 2).Cyclophosphamide is a prodrug with complex metabolic features that include autoinduction and inhibition of its metabolism. Approximately 10% to 30% of a cyclophosphamide dose is excreted unchanged in the urine, whereas 5% of a dose is inactivated to dechloroethylcyclophosphamide. The remaining 65% to 85% of a dose is activated by several cytochrome P450 enzymes to hydroxycyclophosphamide (HCY); this oxidative pathway is autoinducible. HCY or its tautomer aldophosphamide is metabolized via at least five separate pathways, the most relevant of which to this work is its conversion to carboxyethylphosphoramide mustard (CEPM) by aldehyde dehydrogenase 1A1 (3 -5). Increased CEPM systemic exposure, as measured by its AUC, has been associated with an increased risk o...
When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUC(CEPM)) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUC(CEPM), 325 +/- 25 micromol/L.h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUC(CEPM) from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUC(CEPM) for 0 to 48 hours was estimated, and the second cyclophosphamide dose was determined. The mean second cyclophosphamide dose was 42 mg/kg, and the mean total cyclophosphamide dose was 86 mg/kg (range, 54-120 mg/kg). The mean AUC(CEPM) for the time from 0 to 48 hours was 296 micromol/L.h (95% confidence interval, 275-317 micromol/L.h). A retrospective analysis indicated that AUC(CEPM) could be more accurately predicted by use of a population pharmacokinetic model. We conclude that metabolism-based dosing of cyclophosphamide is feasible and that a lower cyclophosphamide dose does not affect engraftment.
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