Oncopeptides AB (publ), Stockholm, Sweden.
Metrum, Tariffville, CT, USA.
J Clin Pharmacol. 2024 Feb;64(2):240-252. doi: 10.1002/jcph.2355. Epub 2023 Oct 20.
Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the α phase of the curve was 1.24 minutes, half-life in the β phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.
美法仑氟苯酰胺（melflufen）是一种新型亲脂性肽-药物偶联物，最近在欧盟和英国获批用于治疗复发/难治性多发性骨髓瘤。美法仑快速穿过细胞膜，在肿瘤细胞内，美法仑利用肽酶和酯酶释放具有烷化活性的亲水性代谢物。在体外，在全血中，美法仑迅速分布到血细胞中，并迅速转化为其主要代谢物美法仑，分别在 1 分钟和 6 分钟时达到非共价结合的美法仑和美法仑的最大细胞浓度。美法仑从血细胞中的流出缓慢，在 25 分钟时达到血浆中的峰值浓度。美法仑的药代动力学最好通过两室模型来描述。在 27 例复发/难治性多发性骨髓瘤患者中静脉输注 30 分钟 40mg 后，曲线的α相半衰期为 1.24 分钟，β相半衰期为 26.7 分钟，清除率为 13.4L/min。与美法仑相比，去乙基美法仑的暴露量低于 20%。基于群体分析（298 例复发/难治性多发性骨髓瘤患者），美法仑药代动力学特征良好，美法仑通过外周室给药，假设美法仑瞬时分布到细胞中，随后迅速代谢为美法仑。平均清除率和中央及深部外周分布容积分别为 22.4L/h、2.70L 和 51.3L。清除率随体重和估计肾小球滤过率的增加而增加，最大浓度降低。总之，美法仑的给药方式与美法仑不同，美法仑更快地分布到细胞中，与快速的细胞内代谢相结合，允许更高的烷化剂最大浓度，并允许美法仑更广泛地分布到外周组织。
