Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

Abstract

Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

Cytomegalovirus as an Uninvited Guest in the Response to Vaccines in People Living with HIV

“…Although the indications of this new drug remain strictly limited for now, the development of this new molecule may well be a game changer in the understanding and management of CMV infection. Other drug candidates include maribavir, a UL97 inhibitor currently in Phase III clinical trial for CMV infection treatment, and filociclovir, a UL54 inhibitor, which recently completed Phase I assessment [ 82 , 83 ].…”

Small Molecules—Prospective Novel HCMV Inhibitors

“…As these data demonstrate high efficiency in animal models, the compound was evaluated for the treatment of HCMV infections in humans. In a phase Ib clinical trial, no serious adverse events were observed when filociclovir was administrated to healthy volunteers [ 20 ]. A planed phase II clinical trial will provide more insights into the efficiency in solid organ transplant recipients.…”

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

“…In single-dose rat toxicology studies, filociclovir was well tolerated up to 300 mg/kg [88]. Preclinical studies and data from a single-dose (range 35-1350 mg) human study suggest that filociclovir is primarily eliminated via renal excretion [89]. An L-valine ester prodrug, valcyclopropavir, with 95% bioavailability in mice was synthesized [90] but has not been further developed for clinical use at this time.…”

“…A phase 1b ascending dose (100 mg, 350 mg, or 750 mg once daily for 7 days) trial was conducted in normal, healthy volunteers [89]. No serious adverse events were reported.…”