Oral Favipiravir Exposure and Pharmacodynamic Effects in Outpatient Adults with Acute Influenza.

BACKGROUND: The pharmacokinetics of oral favipiravir and the relationships of plasma concentrations to antiviral effects are incompletely studied in influenza. METHODS: Serial plasma samples were collected from adults with uncomplicated influenza who were randomized to favipiravir (1800 mg BID on day 1, 800 mg BID on days 2 to 5)(N = 827) or placebo (N = 419) in two phase 3 trials. Post hoc analyses assessed the frequency of reaching an average Cmin ≥20ug/ml, its association with antiviral efficacy, and factors associated with reduced favipiravir exposure. RESULTS: Wide inter-individual variability existed in favipiravir concentrations, and this regimen failed to reach an average Cmin >20ug/ml in 41-43% of participants. Those attaining this threshold showed greater reductions in nasopharyngeal infectious virus titers on treatment days 2 and 3 (approximately 0.3-0.4 log10TCID50/ml) and lower viral titer AUCs compared to those who did not. Those with average Cmin <20ug/ml had over 2-fold higher mean ratios of the metabolite T-705-M1 to favipiravir, consistent with greater metabolism, and were more likely to weigh >80 kg (61.5-64%). CONCLUSIONS: Higher favipiravir levels with average Cmin >20ug/ml were associated with larger antiviral effects and more rapid illness alleviation compared to placebo and to favipiravir recipients with lower average Cmin values in uncomplicated influenza.

Favipiravir Treatment of Uncomplicated Influenza in Adults: Results of Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Trials.

BACKGROUND: We conducted double-blind, placebo-controlled trials assessing the efficacy and tolerability of favipiravir in acute influenza. METHODS: Otherwise healthy adults with influenza-like symptoms and fever of ≤48 hours were randomized to favipiravir (1800 mg twice daily [BID] on day 1, 800 mg BID on days 2-5) or placebo tablets (1:1 in US316; 3:1 in US317). The primary efficacy endpoint was the time to illness alleviation when 6 influenza symptoms were self-rated as absent or mild and fever was absent in the intention-to-treat, influenza-infected participants. RESULTS: In US316 (301 favipiravir, 322 placebo), favipiravir was associated with a 14.4-hour reduction (median, 84.2 vs 98.6 hours; P = .004) in time to illness alleviation vs placebo. In US317 (526 favipiravir, 169 placebo), favipiravir did not significantly reduce time to alleviation (median, 77.8 vs 83.9 hours). In both trials favipiravir was associated with reduced viral titers, RNA load area under the curve over days 1-5, and median times to cessation of virus detection (P < .001). Aside from asymptomatic hyperuricemia, no important differences in adverse events were found. CONCLUSIONS: This favipiravir dosing regimen demonstrated significant antiviral efficacy but inconsistent illness alleviation in uncomplicated influenza. Studies of higher doses and antiviral combinations for treating serious influenza and other RNA viral infections are warranted. Clinical Trials Registration. NCT02026349; NCT02008344.

Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer.

PURPOSE: Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. PATIENTS AND METHODS: This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). RESULTS: Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). CONCLUSION: Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.

CMR predictors of mitral regurgitation in mitral valve prolapse.

OBJECTIVES: We sought to assess the correlation between mitral valve characteristics and severity of mitral regurgitation (MR) in subjects with mitral valve prolapse (MVP) undergoing cardiac magnetic resonance (CMR) imaging. BACKGROUND: Compared with extensive echocardiographic studies, CMR predictors of MVP-related MR are unknown. The severity of MR at the time of diagnosis has prognostic implication for patients; therefore, the identification of determinants of MR and its progression may be important for risk stratification, follow-up recommendations, and surgical decision making. METHODS: Seventy-one MVP patients (age 54 ± 11 years, 58% males, left ventricular [LV] ejection fraction 65 ± 5%) underwent cine CMR to assess annular dimensions, maximum systolic anterior and posterior leaflet displacement, papillary muscle (PM) distance to coaptation point and prolapsed leaflets, as well as diastolic anterior and posterior leaflet thickness and length, and LV volumes and mass. Velocity-encoded CMR was used to obtain aortic outflow and to quantify MR volume. RESULTS: Using multiple linear regression analysis including all variables, LV mass (p < 0.001), anterior leaflet length (p = 0.006), and posterior displacement (p = 0.01) were the best determinants of MR volume with a model-adjusted R(2) = 0.6. When the analysis was restricted to valvular characteristics, MR volume correlated with anterior mitral leaflet length (p < 0.001), posterior mitral leaflet displacement (p = 0.003), posterior leaflet thickness (p = 0.008), and the presence of flail (p = 0.005) with a model-adjusted R(2) = 0.5. We also demonstrated acceptable intraobserver and interobserver variability in these measurements. CONCLUSIONS: Anterior leaflet length, posterior leaflet displacement, posterior leaflet thickness, and the presence of flail are the best CMR valvular determinants of MVP-related MR. The acceptable intraobserver and interobserver variability of our measurements confirms the role of CMR as an imaging modality for assessment of MVP patients with significant MR.