Bioequivalence and safety evaluation of two preparations of metformin hydrochloride sustained-release tablets (Boke® and Glucophage®-XR) in healthy Chinese volunteers: a randomized phase I clinical trial.

BACKGROUND: As per the National Medical Products Administration (NMPA) requirements, the quality and efficacy of generic drugs must be consistent with those of the innovator drug. We aimed to evaluate the bioequivalence and safety of generic metformin hydrochloride sustained-release (MH-SR) tablets (Boke®) developed by Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., China and the innovator product metformin hydrochloride extended-release tablets (Glucophage®-XR) manufactured by Bristol-Myers Squibb Company, New York, NY, in healthy Chinese volunteers. MATERIALS AND METHODS: We performed a bioequivalence and safety assessment of MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) tablets in a randomized, open-label, two-period, two-sequence crossover, single-dose oral study in 48 healthy Chinese adult participants under fasting conditions (Chinese Clinical Trial Registration No. CTR20171306). The washout period was seven days. Bioequivalence (80.00-125.00%) was assessed using adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (Cmax) for each component. RESULTS: The 90% CIs of the test/reference preparation for key pharmacokinetic parameters were 97.36-108.30% for AUC0→t, 97.26-108.09% for AUC0→∞ and 96.76-111.37% for Cmax. No severe adverse events (AEs) were observed. However, 38 adverse drug reactions (ADRs) occurred, including metabolic or nutritional conditions (n = 8), infections (n = 2), gastrointestinal conditions (n = 10) and abnormal inspection (n = 18). No significant difference was observed between MH-SR (23 ADRs, 10 participants) and Glucophage®-XR (15 ADRs, 12 participants) (p = .500). Bioequivalence was concluded since the 90% CIs of the main pharmacokinetic parameters were within the equivalence interval (80.00-125.00%). CONCLUSIONS: MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) were found to be bioequivalent and safe under fasting conditions in healthy Chinese participants. Thus, the market demand for MH-SR tablets (500 mg/tablet) can be met using the generic alternative.KEY MESSAGESGeneric MH-SR tablets (500 mg, Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., Beijing, China) and innovator MH-SR tablets (Glucophage®-XR, 500 mg, Bristol-Myers Squibb Company, New York, NY, USA) were bioequivalent and safe in healthy Chinese volunteers under single-dose administration and fasting conditions.The main goal of this study is to support an increase in the supply of MH-SR tablets in China by proving the efficacy and safety of a generic alternative.Although no sugar was administered in the BE trial of the MH-SR tablets under fasting conditions, no hypoglycaemic event occurred. The method used in this study is expected to serve as a reference for BE studies of different MH-SR formulations.

Analysis of mutational characteristics of the drug-resistant gene katG in multi-drug resistant Mycobacterium tuberculosis L-form among patients with pneumoconiosis complicated with tuberculosis.

The aim of the present study was to investigate the mutational characteristics of drug­resistant genetic mutations in the katG gene to isoniazid (INH) in multi­drug resistant Mycobacterium tuberculosis (MTB) L­form among patients with pneumoconiosis complicated with tuberculosis (TB), in order to reduce the occurrence of drug resistance in patients, and gain further insight into the mechanisms underlying drug resistance in MDR­TB L­form. A total of 114 clinically isolated strains of MTB L­forms were collected. The MDR­TB L­forms were identified using a conventional antimicrobial susceptibility test (AST). The DNA genomes were extracted, the target genes were amplified by polymerase chain reaction technology and the hotspot mutational regions in the katG gene were analyzed by direct sequencing. The results of AST analysis demonstrated that there were 31 strains of MDR­TB L­forms in 114 clinical isolates. The mutation rate of katG was 61.29% (19/31) in INH­resistant isolates, mainly concentrated in codon 315 (Ser315Thr, 48.39% and Ser315Asn, 9.68%) and 431 (Ala431Val, 3.23%). Base substitutions were identified, however, no multisite mutations were found. No mutations in katG were identified in 10 INH­sensitive strains that were randomly selected. INH­resistance was more severe in MDR­TB L­form isolates among patients with pneumoconiosis complicated with TB. The substitution of highly conserved amino acids encoded by the katG gene resulted in the molecular mechanisms responsible for INH resistance in MDR­TB L­form isolates. It was also verified that the katG gene was in diversiform. The katG Ser315Thr mutation is one of the main causes of resistance to INH in MDR­TB L-form isolates.

Decitabine, independent of apoptosis, exerts its cytotoxic effects on cell growth in melanoma cells.

Decitabine is a synthesized cytosine analog that is a potent inhibitor of DNA methylation. There have been a few reports on the in vitro anti-melanoma effect of decitabine or its functional mechanisms. We investigated the anti-proliferation effect of decitabine on the cultured murine melanoma cell line K1735M2. MTT assay showed that decitabine had strong inhibition on melanoma K1735M2 in a time- and dose-dependent manner in vitro. Morphological observation showed that decitabine could induce melanoma K1735M2 cells to produce dendrite-like structures with the increase of decitabine concentration and incubation time. Decitabine could effectively induce K1735M2 cells to differentiate in vitro. Additionally, decitabine could induce a dose-dependent G2/M cell cycle arrest in K1735M2 cells. We provided experimental evidences that the anti-proliferation effect of decitabine on murine K1735M2 melanoma cells was associated predominately with G2/M cell cycle arrest and the induction of differentiation rather than apopotosis.