A Phase 1, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of AVI-7100 in Healthy Subjects
Background: - Influenza (flu) is a virus that causes people to get sick. Most of the time, the flu causes only a mild illness, but some people can become seriously ill or even die from it. Currently, some pills and inhaled powders can be used to treat the flu, but they only make flu symptoms end about a day sooner. More treatment choices for the flu are needed, especially for those who become seriously ill. Researchers want to test a new drug, AVI-7100, that might keep a person who takes it from having a more serious case of the flu. Objectives: - To see how healthy adult volunteers tolerate the AVI-7100 anti-influenza drug. Eligibility: - Healthy volunteers of normal weight between 18 and 60 years of age. Design: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. A heart function test will also be performed. Participants will have either AVI-7100 or a placebo infusion. They will not know which infusion they have. . Participants will stay at the clinical center for a total of 8 hours after the infusion. Blood samples will be collected 1, 2, 4, and 8 hours after the end of the infusion Participants will return on Days 1, 2, 4, 10, and 28 after receiving the drug. Blood and urine samples will be collected. A heart function test will also be performed. There will be a second part of the study that is separate from the first one. Additional people will receive either AVI-7100 or placebo to test their reactions to a specific dose.
2018-01-01·British journal of clinical pharmacology2区 · 医学
Safety, tolerability, and pharmacokinetics of radavirsen (AVI-7100), an antisense oligonucleotide targeting influenza a M1/M2 translation.
2区 · 医学
作者: John H Beigel ; Jocelyn Voell ; Paula Muñoz ; Parag Kumar ; Kristina M Brooks ; Jianbo Zhang ; Patrick Iversen ; Alison Heald ; Michael Wong ; Richard T Davey
The aims of the present study were to assess the safety, tolerability and pharmacokinetics of radavirsen following single ascending doses and multiple doses given as intravenous infusions in healthy adults.
A phase I safety and pharmacokinetic study of radavirsen was performed in healthy volunteers. The study was divided into two parts. The first was a single-ascending-dose study of five cohorts of eight subjects each, randomized 6:2 to receive single intravenous doses of radavirsen ranging from 0.5 mg kg-1 to 8 mg kg-1 or placebo. The second was a multiple-dose study of 16 subjects randomized 12:4 to receive 8 mg kg-1 or placebo once daily for 5 days.
A total of 66 subjects were screened, and 56 subjects were dosed between 2013 and 2015. At least one adverse event occurred in 31/42 (74%) who received radavirsen, and 13/14 (93%) receiving placebo. The most common adverse events were headache and proteinuria, and were similar in incidence and severity among those receiving radavirsen or placebo. Single-dose pharmacokinetics demonstrated relatively linear and dose-proportional increases in maximal concentration and in area under the concentration-time curve from zero to 24 h (AUC0-24 ). At 8 mg kg-1 in the multiple-dose cohort, the day 4 geometric mean AUC0-24 was 57.9 μg*h ml-1 .
Single infusions of radavirsen up to 8 mg kg-1 , and multi-dosing at 8 mg kg-1 once daily for 5 days, appear to be safe and well tolerated in healthy subjects. The multi-dose day 4 AUC0-24 in the present study was comparable with that associated with protection from viral infection in a preclinical ferret influenza model. Further evaluation of radavirsen for the treatment of influenza infections is warranted.
2017-05-01·Bioanalysis4区 · 医学
Quantitative determination of AVI-7100 (Radavirsen), a phosphorodiamidate morpholino oligomer (PMOplus® ), in human plasma using LC-MS/MS.
4区 · 医学
作者: Min Meng ; Jianbo Zhang ; Aihua Liu ; Scott Reuschel ; Pete Sazani ; Michael Wong
AVI-7100 (Radavirsen) is a 20-mer phosphorodiamidate morpholino oligomer (PMOplus®) for the treatment of influenza. Results/methodology: An automated solid-phase extraction method was used to extract plasma samples (200 μl). The extracts were analyzed using liquid chromatography coupled with tandem mass spectrometry under the positive ionization mode. This method was fully validated over the calibration curve range of 5.00-1000 ng/ml. The between-run precision and accuracy ranged from 0.0 to 5.2% relative standard deviation and 91.6 to 100.0% of nominal for all quality control concentrations, including the lower limit of quantitation.
This is the first liquid chromatography coupled with tandem mass spectrometry method for the measurement of AVI-7100 concentrations in human plasma. It has been used to support regulated bioanalysis.