Intravenous Hydroxypropyl β‐Cyclodextrin Formulation of Letermovir: A Phase I, Randomized, Single‐Ascending, and Multiple‐Dose Trial

• Published in: Clinical and translational science 2017-11, Vol.10 (6), p.487-495
• Main Authors: Erb‐Zohar, K, Kropeit, D, Scheuenpflug, J, Stobernack, H‐P, Hulskotte, EGJ, Schanke, A, Zimmermann, H, Rübsamen‐Schaeff, H
• Format: Article
• Language: English
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin - chemistry; Acetates - administration & dosage; Acetates - adverse effects; Acetates - blood; Acetates - pharmacokinetics; Administration, Intravenous; Adult; Antiviral drugs; Area Under Curve; Demography; Deoxyribonucleic acid; DNA; DNA polymerase; Dosage; Dose-Response Relationship, Drug; Drug dosages; Drug resistance; Electrocardiography; Family medical history; Female; Humans; Intravenous administration; Laboratories; Middle Aged; Pharmacokinetics; Pneumonia; Population; Prophylaxis; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - blood; Quinazolines - pharmacokinetics; Randomization; Studies; Time Factors; Transplants & implants; Ultrasonic imaging; Visual Analog Scale; Young Adult; β-Cyclodextrin
• ISSN: 1752-8054; 1752-8062; 1752-8062
• DOI: 10.1111/cts.12483

Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two‐part, single‐center, randomized, double‐blind, placebo‐controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β‐cyclodextrin (HPβCD)‐based intravenous formulation of letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 letermovir, 2 placebo per cohort) or multiple, once‐daily doses (240 mg; 8 letermovir, 4 placebo) of HPβCD‐formulated letermovir and the associated pharmacokinetic profiles and adverse events were investigated. Single‐dose and multiple‐dose regimens were generally well tolerated. Single‐dose escalation resulted in a slightly more‐than‐dose‐proportional increase in the area under the letermovir plasma concentration–time curve (AUC), whereas increase in the maximal observed letermovir plasma concentration (Cmax) was dose proportional. After once‐daily dosing, accumulation ratios in AUC and Cmax were 1.22 and 1.03, respectively. The terminal half‐life was 28.3 h, supporting once‐daily dosing (EudraCT Number: 2012‐001603‐20).