A first-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending oral dose study to assess the safety, tolerability, and pharmacokinetics of BZF961 with and without ritonavir in healthy adult volunteers

Background: Lactobacillus gasseri strain SBT2055 (LG2055) is a human intestine-originating probiotic bacterium and potent probiotic known to exert various health promotion effects, including prevention of abdominal adiposity in rats and humans. A recent finding in mice has suggested that oral administration of LG2055 induces a protective effect against influenza A virus infection. In this context, evidence for efficacy of LG2055 using a human clinical trial was imminently required.Methods: To confirm this in humans, a randomized, double-blind, placebo-controlled, parallel-group study in healthy adult volunteers was conducted to examine the effect of drinkable yogurt (DY) containing LG2055 on influenza vaccine-specific antibody responses as the primary objective and innate immune responses as the secondary objective. Subjects were asked to consume 100 g/day of DY with LG2055 (LG2055 group; n = 94) or without LG2055 (placebo group; n = 94) for 16 weeks. After 4 weeks, all subjects received a trivalent influenza vaccine. Results: We found that the intake of LG2055 DY increased hemagglutination inhibition titers against influenza viruses A/H1N1 and B and the rate of seroprotection against influenza B after vaccination as compared with the intake of placebo DY by healthy volunteers. In support of this result, we confirmed that total IgG and IgA levels in plasma and sIgA production in saliva were also higher in the LG2055 group than in the placebo group. Furthermore, the intake of LG2055 DY enhanced natural killer cell activity and myxovirus resistance A gene expression, which is one of the antiviral genes stimulated by type I or type III Interferons in peripheral blood mononuclear cells.Conclusions: These results strongly indicate that LG2055 activates both the innate and adaptive human immune responses, suggesting the potential to prevent influenza virus infections by providing specific probiotics as complementary foods.Keywords: human clinical trial, innate immunity, influenza virus, Lactobacillus gasseri, vaccine

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A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03393-14 ◽

2014 ◽

Vol 58 (10) ◽

pp. 6209-6214 ◽

Cited By ~ 43

Author(s):

F. Joel Leong ◽

Ruobing Li ◽

Jay Prakash Jain ◽

Gilbert Lefèvre ◽

Baldur Magnusson ◽

...

Keyword(s):

Adverse Events ◽

Oral Dose ◽

Dose Range ◽

Systemic Exposure ◽

Moderate Intensity ◽

Double Blind ◽

Double Blind Placebo ◽

Time Zero ◽

Dose Study ◽

Dose Proportional

ABSTRACTThis first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–∞) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (≤0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, theCmaxwas reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.

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