A limited sampling strategy for pharmacokinetic directed therapy with intravenous busulfan.
A limited sampling strategy for pharmacokinetic directed therapy with intravenous busulfan.
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DOI：
10.1053/bbmt.2002.v8.abbmt080619
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发表时间：
2002-11
期刊：
影响因子：
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通讯作者：
W. Vaughan;D. Carey;S. Perry;A. Westfall;D. Salzman
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作者：
W. Vaughan;D. Carey;S. Perry;A. Westfall;D. Salzman
大剂量白消安广泛用于同种异体和自体骨髓移植准备方案中。口服白消安浓度/时间曲线下面积（AUC）的变化会导致治疗过度或治疗不足的巨大风险，并导致毒性或复发风险过高。使用静脉注射制剂可以消除吸收的变异性，从而减少这种变异性。药物代谢引起的变异仍然存在，但可以采用简化的药代动力学研究来实现特定的目标 AUC。在口服给药后确定 AUC 的传统采样策略中，需要在 6 小时内使用 12 个样本，以确保准确跟踪不稳定的吸收。对于静脉注射白消安，无需在输注过程中测量血浆水平，因为白消安的药代动力学已通过单室一级消除模型得到了很好的描述。理论上，只需要峰值和谷值水平，但为了保证临床决策的可靠性，必须能够识别异常值。这个过程至少需要4个样品。我们研究了总共 59 名接受 2 小时静脉输注白消安的成年患者，以制定有限抽样策略 (LSS)。在 2 小时输注结束时，我们收集了 18 名患者的 11 个样本，并将使用所有样本时获得的 AUC 与仅每小时收集样本时获得的 AUC 进行了比较。当仅使用输注后样本时，平均 AUC 计算值高出 5%（1002 与 956 microM-min），变异系数 (CV) 明显更好（4.6% 与 8.2%）。对 41 名连续患者进行的后续研究表明，所有患者都可以轻松评估，AUC 的变异系数 (CV) 为 2.6%。为了验证这种方法，我们分析了 Anderson 等人描述的 IV 制剂 II 期临床试验中 60 名患者的药代动力学数据。还分析了一项配套研究中另外 36 名患者的数据。将基于每位患者的所有 11 个样本的 AUC 与基于 5 个输注后样本的 AUC 进行比较。该分析结果证实了阿拉巴马大学伯明翰分校 5 样本 LSS 的可靠性相当，并且可能具有更高的精度。这些结果证实，IV 白消安的 LSS 将使白消安与基于 TBI 的准备方案进行有意义且准确的比较，以及在清髓性移植试验中比较含白消安的准备方案的剂量强度成为可能。
High-dose busulfan is widely used in allogeneic and autologous marrow transplantation preparative regimens. Variation in the area under the concentration/time curve (AUC) for oral busulfan results in substantial risk of over or under treatment with excess risk of toxicity or relapse. Use of the IV formulation reduces this variability by eliminating variability in absorption. Variability due to drug metabolism remains, but simplified pharmacokinetic study may be employed to achieve a specific target AUC. In conventional sampling strategies for determining AUC after oral administration, 12 samples are used over 6 hours to assure accurate tracking of erratic absorption. With IV busulfan there is no necessity for measuring plasma levels during the infusion because busulfan pharmacokinetics are well described with a single-compartment, first-order elimination model. In theory, only peak and trough levels should be necessary, but for assurance of reliability in clinical decision making, it must be possible to identify outlier values. This process requires at least 4 samples. We studied a total of 59 adult patients receiving a 2-hour IV busulfan infusion to develop a limited sampling strategy (LSS). At the end of a 2-hour infusion, we collected 11 samples from 18 patients and compared the AUC obtained when all samples were used with the AUC obtained when samples were collected only hourly. The mean AUC calculation was 5% higher (1002 versus 956 microM-min) and the coefficient of variation (CV) was substantially better (4.6% versus 8.2%) when only the postinfusion samples were used. A follow-up study of 41 consecutive patients demonstrated that all patients were easily evaluable with a coefficient of variation (CV) for the AUC of 2.6%. To validate this approach, we analyzed pharmacokinetic data on 60 patients in the phase II clinical trial of the IV formulation described by Anderson et al. Data on an additional 36 patients from a companion study also were analyzed. The AUC based on all 11 samples from each patient were compared with the AUC based on the 5 postinfusion samples. The results of this analysis confirmed comparable reliability and possibly superior precision of the University of Alabama at Birmingham 5-sample LSS. These results validated that LSS for IV busulfan will make possible meaningful and accurate comparisons of busulfan versus TBI-based preparative regimens and comparison of dose intensity of busulfan-containing preparative regimens in trials of submyeloablative transplantation.