Safety, Pharmacokinetics and Pharmacodynamics of Multiple Escalating Doses of PEGylated Exenatide (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: At present, the deficiency of ß-cell function is progressive in patients with type 2 diabetes mellitus. Exenatide cannot only control blood glucose well, but also promotes the regeneration and proliferation of islet ß-cells and improves the function of ß cells. However, it needs to be given twice a day, and there are many adverse reactions such as nausea. PEGylated exenatide (study code: PB-119) needs to be administered only once a week. The purpose of this experiment was to evaluate the safety, pharmacokinetics and pharmacodynamics of an escalating dose regimen of subcutaneous PEGylated exenatide injections in healthy subjects. METHODS: Twelve healthy young adult subjects in each group received once-weekly subcutaneous injections of 165 µg, 330 µg, and 660 µg PEGylated exenatide for 6 weeks. Plasma drug concentration was determined in venous blood collected across selected time points. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, and electrocardiogram. Blood glucose, insulin,  glucagon and C peptide were monitored at different time points to evaluate the pharmacodynamics of PEGylated exenatide. RESULTS: A total of 11, 10, and 12 subjects completed the study in 165 µg, 330 µg, and 660 µg dose groups, respectively. After 6 consecutive weeks of administration, the t1/2 in the 165 µg, 330 µg, and 660 µg dose groups was 55.67 ± 11.03 h, 56.99 ± 21.37 h, and 54.81 ± 13.87 h, respectively. The Cavg was 4.22 ± 0.78 ng/ml, 6.03 ± 1.43 ng/ml, and 10.50 ± 3.06 ng/ml, respectively. AUCss was 708.59 ± 131.87 h•ng/ml, 1012.63 ± 240.79 h•ng/ml, and 1763.81 ± 514.50 h•ng/ml, respectively. The accumulation index was 1.15 ± 0.07, 1.17 ± 0.11, and 1.14 ± 0.07. The CLss/F was 241.25 ± 51.13 ml/h, 341.53 ± 73.62 ml/h, and 450.06 ± 313.76 ml/h, respectively. A total of 10 of 36 (27.78%) subjects in the three dose groups developed specific antibodies after consecutive subcutaneous injections of PEGylated exenatide. The Cavg and Cmax were higher than those of antibody-negative subjects. Furthermore, in antibody-positive subjects, CLss/F, t1/2, AUCτ, accumulation index, MRT(0-inf) and other parameters were lower than those of antibody-negative subjects. In the 165 µg dose group, two subjects (16.67%) experienced 4 adverse events. In the 330 µg dose group, no subjects reported adverse events. In the 660 µg dose group, 8 subjects (66.67%) reported 16 adverse events, which were mostly gastrointestinal. There were no significant changes in the pharmacodynamic parameters except the glucagon level at day 36 in the 660 µg dose group, the 2h postprandial insulin and C peptide levels at day 36 and day 50 in the 165 µg dose group compared with baseline (- 1 day). CONCLUSION: A once-weekly subcutaneous injection of 165 µg and 330 µg PEGylated exenatide is safe. No significant effects on blood glucose or pancreatic hormone levels were observed in the subjects within these dose groups. The pharmacokinetic parameters of PEGylated exenatide may be affected by immunogenicity. CLINICAL TRIALS REGISTRATION: The study is registered at clinicaltrials.gov (No. NCT03062774).

Is chemoprophylaxis necessary for all latent tuberculosis infection patients receiving IL-17 inhibitors? A cohort study.

The tuberculosis (TB) burden is high in China, with a 32% prevalence of latent tuberculosis infection (LTBI) in Beijing. Screening for LTBI and the chemoprophylaxis of positive patients are recommended prior to biologic therapy. To evaluate the TB-related safety of secukinumab (SEC) in a cohort of plaque psoriasis patients with LTBI receiving different treatments. Plaque psoriasis patients eligible for SEC treatment were screened for TB. LTBI patients (QuantiFeron-TB test positive, QFT+) receiving SEC were closely monitored by chest radiograph, ESR or hs-CRP, and blood counts every 12 to 20 weeks for active TB infection. QFT_patients receiving SEC treatment were screened for LTBI every 6 to 12 months. Of 42 patients treated with SEC, 19 were QFT+ (45.24%). A QFT_patient became QFT+ after 6 months treatment. Two patients started SEC treatment from 2015 to 2016 and were followed up 268 and 216 weeks later, respectively. Three patients received chemoprophylaxis, 17 did not because of safety concerns or being unable to complete the process. During the 16- to 268-week follow-up, no signs of TB reactivation were observed in the 20 LTBI patients receiving SEC. Plaque psoriasis patients with LTBI who received no chemoprophylaxis could be safely treated with SEC.

A Randomized Study of the Single-Dose Safety, Pharmacokinetics, and Food Effect of Chinfloxacin and Its Effect on Thorough QT/QTc Interval in Healthy Chinese Volunteers.

Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single-ascending-dose study to assess safety and tolerability of chinfloxacin. The single-dose pharmacokinetic study, a food effect study, and a multiple-dose pharmacokinetics study were conducted in parts B, C, and D, respectively. Part E was a randomized, placebo-controlled and positive-control single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/corrected QT (QTc) interval. The results suggest that single and multiple oral administrations of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis, and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to peak plasma concentration (Tmax and Cmax, respectively) was about 2 h, and the half-life was 14 to 16 h. Food slightly affected the drug's rate and extent of absorption, increasing the Tmax from 1.60 to 2.59 h and reducing the Cmax by 13.6% and area under the concentration-time curve by 8.95%. Chinfloxacin at 400 mg had no effect on prolongation of QT/QTc intervals. Although 600 mg chinfloxacin had a mild effect on the prolongation of the QT/QTc interval, the effect was less pronounced than that of the positive control, 400 mg moxifloxacin. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at www.ChiCTR.org.cn under identifiers ChiCTR-TRC-10001619 for parts A to D and ChiCTR1800015906 for part E.).

Effects of Nemonoxacin on Thorough ECG QT/QTc Interval: A Randomized, Placebo- and Positive-controlled Crossover Study in Healthy Chinese Adults.

PURPOSE: Nemonoxacin, a nonfluorinated quinolone, has been approved in Taiwan and mainland China for the treatment of bacterial infection. Whether nemonoxacin is associated with the adverse events of other quinolones, such as the risk for QT-interval prolongation, which has led to the withdrawal of several fluoroquinolones from the market, needs to be elucidated. METHODS: The effects of nemonoxacin on thorough QT/QTc interval was investigated in this randomized, placebo- and positive-controlled crossover study conducted according to the International Conference on Harmonisation E14 guideline. Forty-eight healthy adults received a single oral dose of nemonoxacin 500 mg (therapeutic dose), nemonoxacin 750 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 cohorts (Williams Latin square design) in the fasted condition. After a 7-day washout, 6 male and 6 female subjects were orally administered a 500-mg dose of nemonoxacin after high-fat food intake. The primary end point was the change in QT interval corrected for heart rate using the Fridericia formula (QTcF). The secondary end point was the change in QT interval corrected for heart rate using the Bazett formula (QTcB). FINDINGS: The study revealed that nemonoxacin was classified as not likely dangerous at the therapeutic dose (500 mg) and as potentially dangerous at the supratherapeutic dose (750 mg). The Tmax of nemonoxacin was 1 to 2 hours after administration, and the elimination half-life was 5 to 7 hours, in the fasted conditions. High-fat food intake had significant effects on the Tmax, Cmax, AUC0-∞, and QT/QTc interval of nemonoxacin compared with these values in the fasted condition. A correlation between QTcF and the plasma drug concentration of nemonoxacin was not observed. IMPLICATIONS: Nemonoxacin at the clinically therapeutic and supratherapeutic doses had a prolongation effect on QT/QTc. ClinicalTrials.gov identifier: NCT03362853.

[Two cases report and literature review of IgA nephropathy combined with primary membranous nephropathy].

OBJECTIVE: To describe the clinical and pathological characteristics and prognosis of IgA nephropathy coexisting with membranous nephropathy (MN). METHODS: Two cases were confirmed to have IgA nephropathy as well as primary MN by immunofluorescence and immuno-electron microscopy for renal biopsy and clinical data. Clinical and pathological manifestations were collected and prognosis was investigated. RESULTS: The pathological characteristics included IgA deposit in mesangium but IgG deposit in subepithelial site mainly. Two patients presented moderate to heavy proteinuria, minimal hematuria, and normal renal function. During 9 months of follow up, the renal function remained normal. CONCLUSIONS: The combined form of membranous nephropathy and mesangioproliferative IgA nephropathy was uncommon. The clinical characteristics of the two cases in this study were more similar to those of MN. Coexistence of two kinds of primary glomerulonephritis did not result in a particularly deterioration in clinical outcome.

[Variable number of tandem repeats polymorphism of MUC20 is associated with the progression of IgA nephropathy].

OBJECTIVE: The MUC20 gene is a novel up-regulated gene that was identified in renal tissues of patients with IgA nephropathy (IgAN) by restriction endonucleolytic analysis of differentially expressed sequences. The variable number of tandem repeats (VNTR) polymorphism of MUC20 was detected in different cell lines. In this study we determined the distribution of MUC20 VNTR polymorphism in the healthy population, and the association between the MUC20 VNTR polymorphism and the pathogenesis or progression of IgAN. METHODS: 282 healthy and 503 proved IgAN patients by biopsy were involved in this investigation. 113 patients had been followed-up for 3.5 +/- 1.5 years. Genomic DNAs were extracted from peripheral blood leucocytes. MUC20 VNTR polymorphism was detected by PCR amplification and several representational PCR products were confirmed by sequencing. The MUC20 genes were divided into small alleles (repeat times 3) according to the repeat times of MUC20 VNTR. These patients were classified into group SS, SL and LL. MUC20 allele frequencies and genotypes of IgAN patients were analyzed and compared with healthy population. In addition, the associations of MUC20 polymorphism with the clinical and pathological parameters at the time of renal biopsy were analyzed. The data followed up in different groups were compared. RESULTS: There was MUC20 VNTR polymorphism in healthy population with 2 - 6 repeats. The repeat fragment was 57bp. The most frequent alleles included 3(R(3)) and 4(R(4)) repeats; otherwise the least ones included 6(R(6)) repeats. The most frequent genotype was R(3)R(4), then R(3)R(3) and R(4)R(4); the least ones were R(2)R(2), R(3)R(6) and R(5)R(5). The frequencies of MUC20 alleles and genotypes in the IgAN patients were similar to healthy population. Initial ages, blood pressure, proteinuria, and renal function did not differ significantly among the three groups. There was no difference of the urinary osmotic pressure, urinary NAG (N-acetyl-B-D-glucosaminidase) and alpha1 microglobulin (alpha1-MG), and the semiquantitative scores of renal interstitial fibrosis and tubular atrophy in the three groups. IgAN patients with SL/LL genotype had higher odds ratio for progression of renal function (OR = 7.29, 95% CI: 1.68 - 31.60, P = 0.008) than the SS genotype. CONCLUSIONS: There were MUC20 VNTR polymorphisms in the healthy population. The polymorphism did not associate with the pathogenesis and the clinico-pathological parameters at the time of renal biopsy. The SL/LL genotype was likely to be a risk factor for rapid progression of renal function in the patients with IgAN.