{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:06:20Z","timestamp":1784034380241,"version":"3.55.0"},"reference-count":19,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T00:00:00Z","timestamp":1697760000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Melphalan flufenamide (melflufen) is a novel lipophilic peptide\u2013drug 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\u2010compartment model. Following a 30\u2010minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half\u2010life in the \u03b1 phase of the curve was 1.24 minutes, half\u2010life in the \u03b2 phase of the curve 26.7 minutes, and clearance 13.4 L\/min. Desethyl\u2010melflufen 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\u2010compartment 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.<\/jats:p>","DOI":"10.1002\/jcph.2355","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T03:45:41Z","timestamp":1695786341000},"page":"240-252","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide\u2013Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8114-1486","authenticated-orcid":false,"given":"Gunilla","family":"Huledal","sequence":"first","affiliation":[{"name":"Oncopeptides AB (publ)  Stockholm 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