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

Abstract

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, oncedaily 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 concentrationtime curve (AUC), whereas increase in the maximal observed letermovir plasma concentration (C max ) was dose proportional. Human cytomegalovirus (HCMV) disease is commonly reported in immunocompromised individuals, notably in transplant recipients. In the absence of appropriate prophylactic treatment during allogeneic hematopoietic stem-cell transplant (HSCT), 80% of patients with HCMV-positive disease develop symptoms of HCMV disease.1 The most serious clinical manifestation of this infection is HCMV pneumonia, with an associated mortality rate >50%.1 In addition to pneumonia, other clinical manifestations of HCMV disease include gastrointestinal complications that render the ingestion and absorption of oral drugs difficult, further complicating treatment. clovir, which act as DNA polymerase inhibitors and are associated with significant toxicity and the potential of drug resistance development.2 Therefore, there is a need to develop new antivirals with a novel mode of action to nucleosides and a lower toxicity, while maintaining activity against resistant strains. This need was compounded by recent findings regarding two candidate anti-HCMV agents, maribavir and brincidofovir (CMX001), that failed to demonstrate efficacy in clinical phase III trials. 3,4 Letermovir (AIC246) is a novel drug being initially developed for prophylactic treatment against HCMV in HSCT recipients. It belongs to a class of anti-HCMV agents (terminase inhibitors) that inhibit the formation and release of infectious virus particles by targeting viral DNA processing. [5][6][7][8][9]

Cyclodextrin Based Nanoparticles for Drug Delivery and Theranostics

“…175,176 Additionally, HP-β-CD is known to reduce local irritation antiviral intravenous formulation of letermovir. 177 These studies unlock new avenues in the research of drug delivery science for better management opportunities of diseases and their side effects.…”

Assessment of Pharmacokinetic Interaction Between Letermovir and Fluconazole in Healthy Participants

“…A limitation of this study was that only single doses of fluconazole and letermovir were administered when it would be likely that these drugs would be coadministered in multiple doses. However, the PK of fluconazole 13‐15 and letermovir 16 after multiple‐dose administration was consistent with single‐dose administration, including the lack of expected accumulation. This suggests that the effects observed in this study following single doses are not expected to be different from those observed after multiple doses.…”

The Lord of the NanoRings: Cyclodextrins and the battle against SARS-CoV-2

“…For instance, HP-β-CD has been proved to be an effective excipient in the intravenous administration of Letermovir, an antiviral developed to deal with cytomegalovirus (CMV) in immunocompromised patients, such as transplant recipients or seropositive individuals (Fig. 3) (Erb-Zohar et al, 2017). The effectiveness of this formulation in phase III essays, without significant adverse events (Marty et al, 2017), lead to the approval of the treatment, now available as Prevymis TM Injection.…”