Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota.
Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota.
Transplant Cell Ther. 2022 Dec;28(12):845.e1-845.e8. doi: 10.1016/j.jtct.2022.09.011. Epub 2022 Sep 24.
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/m" 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 AUC and PM AUC, 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 AUC between patients with versus without obesity, whereas dosing by BSA and TBW-ABW50 attained equivalent PM AUC (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 AUC). The data suggest though that CY dosing based on "mg/m" by BSA or "mg/kg" by TBW-ABW50 would result in similar total exposure (i.e., PM AUC) and may minimize exposure differences in obese and nonobese patients.
环磷酰胺（CY）是一种广泛应用于肿瘤学和造血细胞移植（HCT）领域的烷化剂。对于接受 HCT 的肥胖患者，建议使用调整后的体重（ABW25）乘以 0.25 的调整系数来调整 CY 的剂量。然而，支持这一建议的基于 CY 药代动力学（PK）的证据不足。我们旨在确定一种 CY 给药策略，使肥胖患者和非肥胖患者的暴露水平相当。本研究是对先前进行的磷酰胺氮芥（PM）观察性 PK 研究的二次分析，PM 是 CY 的最终细胞毒性代谢物。数据来自 85 名患有血液恶性肿瘤的成年人，他们接受了单次输注 50mg/kg CY、氟达拉滨、±抗胸腺细胞球蛋白和单次全身照射作为 HCT 预处理。在这些患者中，先前开发的群体 PK 模型用于模拟。使用该分析的个体化 PK 参数，模拟了 8 种不同剂量策略的 PM 累积暴露（即 AUC），这些策略根据不同的身体大小测量方法：（1）总体重（TBW）的“mg/kg”；（2）理想体重（IBW）的“mg/kg”；（3）去脂体重的“mg/kg”；（4）体表面积（BSA）的“mg/m”；（5）TBW 与 ABW25 的“mg/kg”（TBW-ABW25）；（6）IBW 与 ABW25 的“mg/kg”（IBW-ABW25）；（7）TBW 与 ABW 的调整系数为 0.50 的“mg/kg”（TBW-ABW50）；和（8）固定剂量的“mg”。我们将等效暴露定义为肥胖对 PM AUC 的影响，使其在非肥胖组 PM AUC 的±20%范围内，其中肥胖是根据 TBW/IBW 比值（即非肥胖，<1.2；轻度肥胖，1.2-1.5；中度/重度肥胖，>1.5）来定义的。主要和次要结局分别为 PM AUC 和 PM AUC。在 85 名患者中，中位年龄为 63 岁（范围 21-75），根据 TBW/IBW 比值，46%的患者被归类为轻度肥胖，25%的患者被归类为中度/重度肥胖。当基于 IBW、TBW-ABW25 和固定剂量进行给药模拟时，PM AUC 呈负相关（即肥胖程度越高，PM AUC 越低）（P<0.05）。当基于 TBW 进行剂量模拟时，显示出正相关（P<0.05）。在 8 种给药策略中，没有一种能使肥胖患者和非肥胖患者的 PM AUC 达到等效，而 BSA 和 TBW-ABW50 给药策略则能使 PM AUC 达到等效（P<0.05）。我们的研究预测，建议的 ABW25 剂量调整可能会导致肥胖患者接受 CY 治疗的暴露水平低于非肥胖患者。对于早期暴露（即 PM AUC），尚未确定使肥胖患者和非肥胖患者 PM 浓度相当的 CY 给药策略。尽管如此，数据表明，基于“mg/m”的 BSA 或“mg/kg”的 TBW-ABW50 的 CY 给药策略可能会导致相似的总暴露（即 PM AUC），并可能最大限度地减少肥胖和非肥胖患者之间的暴露差异。
