Comparison of Dose Adjustment Strategies for Obesity in High-dose Cyclophosphamide Among Adult Hematopoietic Cell Transplantation Recipients: Pharmacokinetic Analysis

Abstract

Cyclophosphamide (CY) is an alkylating agent widely used in the field of oncology and hematopoietic cell transplantation (HCT). It is recommended to use an adjusted body weight with an adjustment factor of 0.25 (ABW25) for dosing of CY in obese patients undergoing HCT. However, evidence based on the pharmacokinetics (PK) of CY to support this recommendation is lacking. We aimed to identify a dosing strategy of CY that achieves equivalent exposures among obese and nonobese patients. The present study is a secondary analysis of a previously conducted observational PK study of phosphoramide mustard (PM), the final cytotoxic metabolite of CY. Data were collected from 85 adults with hematologic malignancy who received a single infusion of CY 50 mg/kg, fludarabine, ± anti-thymocyte globulin, and a single fraction of total body irradiation as HCT conditioning therapy. A previously developed population PK model in these patients was used for simulations. Using individualized PK parameters from that analysis, simulations were performed to assess cumulative exposures of PM (i.e., area-under-the-curve [AUC]) resulting from 8 different dosing strategies according to various measures of body size: (1) “mg/kg” by total body weight (TBW); (2) “mg/kg” by ideal body weight (IBW); (3) “mg/kg” by fat free mass; (4) “mg/m2” by body surface area (BSA); (5) “mg/kg” by TBW combined with ABW25 (TBW-ABW25); (6) “mg/kg” by IBW combined with ABW25 (IBW-ABW25); (7) “mg/kg” by TBW combined with ABW by adjustment factor of 0.50 (TBW-ABW50); and (8) “mg” by fixed-dose. We defined equivalent exposure as the effect of obesity on PM AUC within ±20% from the PM AUC in the nonobese group, where obesity is defined based on TBW/IBW ratio (i.e., nonobese, <1.2; mildly obese, 1.2-1.5; and moderately/severely obese, >1.5). Primary and secondary outcomes were PM AUC0-8hours and PM AUC0-infinity, respectively. In the 85 patients, with the median age of 63 years (range 21-75), 46% were classified as mildly and 25% were moderately/severely obese based on the TBW/IBW ratio. Negative correlations (i.e., higher the extent of obesity, lower the PM AUC) were shown when dosing simulations were based on IBW, TBW-ABW25, and fixed dosing (P < .05). Positive correlations were shown when dosing was simulated by TBW (P < .05). None of the 8 dosing strategies attained equivalent PM AUC0-8hours between patients with versus without obesity, whereas dosing by BSA and TBW-ABW50 attained equivalent PM AUC0-infinity (P < .05). Our study predicted that the recommended ABW25 dose adjustment may result in lower exposure of CY therapy in obese patients than in nonobese. A CY dosing strategy that would result in similar PM concentrations between obese and nonobese was not identified for early exposure (i.e., PM AUC0-8hours). The data suggest though that CY dosing based on “mg/m2” by BSA or “mg/kg” by TBW-ABW50 would result in similar total exposure (i.e., PM AUC0-infinity) and may minimize exposure differences in obese and nonobese patients.