Pharmacokinetic study of sulfobutylether beta-cyclodextrin as an excipient of remdesivir

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SBECD (Captisol®) with an average degree of substitution of 6.5 sulfobutylether functional groups (SBE = 6.5), is a solubility enhancer for remdesivir (RDV) and a major component in Veklury, which was approved by FDA for the treatment of patients with COVID-19 over 12 years old and weighing over 40 kg who require hospitalization. SBECD is cleared mainly by renal filtration, thus, potential accumulation of SBECD in the human body is a concern for patients dosed with Veklury with compromised renal function. An LC-MS/MS method was developed and validated for specific, accurate, and precise determination of SBECD concentrations in human plasma. In this method, the hexa-substituted species, SBE6, was selected for SBECD quantification, and the mass transition from its dicharged molecular ion [(M–2H)/2]2-, Molecular (parent) Ion (Q1)/Molecular (parent) Ion (Q3) of m/z 974.7/974.7, was selected for quantitative analysis of SBECD. Captisol-G (SBE-γ-CD, SBE = 3) was chosen as the internal standard.

Due to the limited sample volume that can be collected from pediatric patients (50 μL plasma per time point and limited timepoints), the plasma time point samples collected in the studies needed to be used for both drug/metabolite and SBECD determinations. With 25 μL of formic-acid-treated sample and with a calibration range of 10.0–1000 μg/mL, the method was validated with respect to pre-established criteria based on regulatory guidelines and was applied to determine SBECD levels in plasma samples collected from pediatric patients during RDV clinical studies.

No accumulation of SBECD was found after 6 h of infusion.

SBECD plasma concentration-time curves of 2 subjects (Subjects were pediatric patients > 12 years to < 18 years and weight ≥ 40 kg.) SBECD plasma concentrations were measured at pre-infusion, middle of infusion, end of infusion, 2 h, 4 h, and 6 h after infusion, determined by the validated LC-MS/MS method.

Yang Z, Xiao D, Ling KHJ, Tarnowski T, Humeniuk R, Parmentier B, Fu YA, Johnson E, Luna ML, Goudarzi H, Cheng Q. The determination of Sulfobutylether β-Cyclodextrin Sodium (SBECD) by LC-MS/MS and its application in remdesivir pharmacokinetics study for pediatric patients. J Pharm Biomed Anal. 2022, 212:114646. doi: 10.1016/j.jpba.2022.114646.

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