Preclinical comparison of intravenous melphalan pharmacokinetics administered in formulations containing either (SBE)_7 m‐β‐cyclodextrin or a co‐solvent system

Abstract

The aim of this work was to evaluate the impact of sulfobutyl ether β-cyclodextrin ((SBE)(7 m)-β-CD; Captisol(®)) on the in vivo pharmacokinetics of melphalan in rats. Melphalan is a chemically unstable antineoplastic drug which in the current commercial formulation (Alkeran(®) for Injection) has some limitations with regard to solubility, stability and biocompatibility. Melphalan formulations containing (SBE)(7 m)-β-CD have previously been evaluated in vitro and shown to significantly reduce the rate of degradation and to simplify the reconstitution procedure for lyophilised melphalan. In this study, melphalan was administered intravenously in rats in formulations that either contain (SBE)(7 m)-β-CD or a co-solvent system (i.e. the commercial formulation). Pharmacokinetic parameters, including half-life, volume of distribution, clearance and extent of renal elimination of melphalan were essentially unchanged between the two formulations. These findings indicate that the pharmacokinetics of melphalan are not altered in the presence of (SBE)(7 m)-β-CD consistent with a rapid shift in the equilibrium to the fully dissociated drug from the fraction associated with the cyclodextrin host molecule upon intravenous administration.

Rapid and simple flow injection analysis tandem mass spectrometric method for the quantification of melphalan in a lipid‐based drug delivery system

“…Nanotechnology is being applied to develop novel therapies that can improve the solubility of poorly soluble drugs . For example, cyclodextrin‐based drug delivery systems have been widely investigated to improve the delivery of melphalan as well as other chemotherapeutics . β‐Cyclodextrin (β‐CD) is a natural product with low toxicity .…”

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation

“…Propylene glycol-free melphalan hydrochloride (EVOMELA; Spectrum Pharmaceuticals, Inc., Irvine, CA, USA) is a new formulation of melphalan that incorporates Captisol (Ligand Pharmaceuticals, Inc., La Jolla, CA, USA), a specially modified cyclodextrin that improves the solubility and stability of melphalan [13,14]. This new formulation eliminates the risk of propylene glycol toxicities by using the Captisol technology used in the formulation of 6 other US Food and Drug Administrationeapproved human parenteral drugs (Vfend, Nexterone, Geodon, Abilify, Kyprolis, and Noxafil) [15][16][17][18][19][20].…”

A Phase 1c Trial Comparing the Efficacy and Safety of a New Aqueous Formulation of Alphaxalone With Propofol

“…This difference occurred even though the same depth and duration of cortical depression was present in both treatment groups evidenced by the same BIS values shown in Figure 3. The maximum decreases in systolic blood pressure, median (IQR), were 12 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) mm Hg for PHAX and 25 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) mm Hg for propofol and diastolic blood pressure were 14 (9-16) mm Hg for PHAX and 26 (22)(23)(24)(25)(26)(27)(28)(29)(30) mm Hg for propofol. Further, these differences in pressure occurred when the heart rate increases after administration of anesthetic injection, median (IQR) were: 21 (16-24) beats/minute for PHAX and 15 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)…”

“…[23][24][25][26][27] It has not been previously investigated as an excipient for alphaxalone. Such a preparation, alphaxalone in aqueous solution with SBECD, Phaxan™ (PHAX), has been made and tested in preclinical studies.…”