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Objective: We aimed to evaluate the similarity of BAT2206 to its originator, ustekinumab, including pharmacokinetic profiles, immunogenicity, and safety in healthy Chinese male subjects. Methods: This was a double-blinded, randomized, single-dose, parallel-group clinical trial, in which 270 healthy male subjects were enrolled to receive a single subcutaneous injection (45 mg) of either BAT2206 or ustekinumab (European Union or USA) at a 1:1:1 ratio. The pairwise pharmacokinetic similarities and the safety and immunogenicity of both drugs were evaluated and compared. Results: The results showed that the 90% confidence interval of the geometric mean ratio for primary pharmacokinetic parameters (maximum plasma concentration and area under the plasma concentration–time curve from time zero to infinity) among BAT2206 and ustekinumab (USA or European Union sourced) groups were all within the predefined equivalent interval of 80–125%. Furthermore, all the groups had similar incidences of treatment-emergent adverse events, in which the majority of cases belonged to Common Terminology Criteria for the Classification of Adverse Events Grade 1 or 2. Anti-drug antibodies were detected in 54 (20.1%) subjects, namely 24 (26.7%), 13 (14.8%), and 17 (18.9%) patients in the BAT2206, ustekinumab (European Union), and ustekinumab (USA) groups, respectively. In contrast, the incidences of positive neutralizing antibodies were similar among the three groups. Conclusions: Pharmacokinetic similarity between BAT2206 and ustekinumab (USA or European Union sourced) was confirmed. The three groups had similar safety profiles, and the investigational drugs were well tolerated by subjects. Clinical Trial Registration: This study was registered with ClinicalTrials.gov (NCT04371185). [ABSTRACT FROM AUTHOR]

Smartphone usage has brought great convenience to our daily life. However, the detrimental consequences of smartphone dependence also require special attention. Based on the theory of planned behavior (TPB), this study designed a questionnaire to investigate college students' withdrawal from smartphone dependence. The reliability and validity of the questionnaire were tested. The results showed that the reliability of the questionnaire was good (α = 0.84–0.94). The principal component analysis was conducted, contribution rates of these factors were moderately high (62.06%–82.35%). The validity was verified through confirmatory factor analysis. All the model fit indices were higher than the acceptable standard, which indicated the construct validity of the TPB questionnaire is good. The results of the multi-group structural equation model revealed that the model provided excellent fit to the data in each demographic group. The results of structural equation model presented that, in most demographic groups, students' attitude, subjective norm, and perceived behavioral control of withdrawal from smartphone dependence positively influenced their behavioral intention. Furthermore, subjective norm was the most effective predictors in each group. However, part of the paths from intention to behavior failed to reach the significant level, and their coefficients are relatively small. This reveals the gap between college students' withdrawal intention and their actual behavior, and there may be other factors influence the relationship between the two variables. [ABSTRACT FROM AUTHOR]

Background: Felbinac trometamol, an anti-inflammatory and analgesic drug, has been used to treat immediate postoperative pain.Objective: The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single or multiple intravenous infusions of felbinac trometamol in healthy Chinese volunteers.Methods: A total of 56 healthy subjects were enrolled in a single-ascending dose study (11.78-377.00 mg), meanwhile 36 subjects were enrolled in a multiple-ascending dose study (47.13-188.50 mg). Safety endpoints included treatment-emergent adverse events, vital signs, electrocardiograms, and laboratory parameters. Pharmacokinetic endpoints included exposure of subjects to felblinac and metabolites of the drug in plasma, urine, and feces.Results: Felblinac time to maximum plasma concentration was obtained at 0.5 h, corresponding to the end of the infusion. Maximum plasma concentration and area under the curve increased in a dose-dependent manner for felblinac and its metabolite, showing linear pharmacokinetic characteristics at single and multiple doses. After intravenous infusions of multiple doses three times (30 min each time) per day, the accumulation ratio of felblinac and its metabolite based on the area under the curve had a range of 1.34-1.45 and 1.60-1.87, respectively, across cohorts. After administration of the fourth dose, the plasma concentration of both felblinac and its metabolites was maintained at a steady state. Felbinac trometamol was well tolerated. Neither treatment-emergent adverse event frequency nor severity increased with increasing felbinac trometamol dose.Conclusions: Felbinac trometamol was well tolerated in our study. Based on the dose range in this study, 94.25 mg is the recommended target dose for a phase II study.Clinical Trial Registration: CTR20170496 and CTR20180896. The dates of registration are 2017-06-19 and 2018-07-02 ( https://www.chinadrugtrials.org.cn/ ). [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the tolerance, variability, and pharmacokinetics (PK) of bevacizumab biosimilars (MIL60, BAT1706, IBI305) in Chinese healthy male subjects.Methods: This randomized, double-blind, two-arm, parallel studies included three separate investigations, which were conducted by three sponsors to investigate the bioequivalence of bevacizumab biosimilars (MIL60, BAT1706, IBI305) with that of bevacizumab-EU as a reference drug. Subjects received a single-dose of 1 or 3 mg/kg of the bevacizumab biosimilars or bevacizumab-EU and were followed up for 70-99 days. Serum concentrations of bevacizumab, antidrug antibody (ADA), and neutralizing antibody (NAb) were measured using electrochemiluminescence. In addition, the PK parameters were determined using non-compartmental methods. The safety assessments included adverse events, hematology tests, and biochemistry tests.Results: The three bevacizumab biosimilars exhibited similar PK properties to that of bevacizumab-EU. Bevacizumab demonstrated linear PK properties and a concentration-dependent disposition. When comparing the three biosimilars with bevacizumab-EU, the 90% CIs of the ratios for Cmax, AUC0-t, and AUC0-∞ were within 80-125%. The inter-CV ranged from 12.6 to 23.3%. Three subjects in the biosimilar groups and bevacizumab-EU were positive for the ADA and negative for the NAb. Treatment-related mild or moderate adverse events were reported in 56-80 and 36-80% of subjects in the biosimilar and bevacizumab treatment arms, respectively.Conclusions: The bevacizumab biosimilars exhibit similar PK characteristics to that of the reference product bevacizumab-EU. The inter-CV is moderate and less than 25% in all cases. The safety profile was similar among bevacizumab biosimilars and bevacizumab-EU with significant adverse events. [ABSTRACT FROM AUTHOR]

Background: Pradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir. Methods: Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group. Results: The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration ( C ) and area under the curve (AUC) of serum pradefovir ranged from (21.41 ± 12.98) to (447.33 ± 79.34) ng/mL and (46.10 ± 29.45) to (748.18 ± 134.15) ng h/mL across the dose range, respectively. The C and AUC of serum PMEA ranged from 18.10 ± 4.96 to 312.33 ± 114.19 ng/mL and 72.65 ± 28.25 to 1095.48 ± 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)]. Conclusions: The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events. Trial registration number: CTR20140341. [ABSTRACT FROM AUTHOR]

The compound series of traditional anticholinergics [atropine (Atr), anisodamine (Ani), anisodine (AT3), and scopolamine (Sco)], naturally occurring belladonna alkaloid, have been approved for numerous therapeutic uses since 1970s. Tiotropium, a novel M receptor antagonist for the treatment of chronic obstructive pulmonary disease, was structurally modified based on atropine-like drugs. Clinical phenomena suggested that the changes of substituent group were related to the pharmacokinetic and pharmacodynamic characteristics of the agents. In an attempt to compare the pharmacokinetics of the series of anticholinergics and investigate the subsets motivating selective anticholinergic potencies, a sensitive LC-MS/MS method was established to analyze the differences of pharmacokinetic parameters. In this paper, we determined the pharmacokinetics of atropine, anisodamine, anisodine, scopolamine, and tiotropium after i.v. and i.g. single dose administration. After i.v. administration, the maximum drug plasma concentrations ( C) of Atr, Ani, AT3, and Sco were 274.25 ± 53.66, 267.50 ± 33.16, 340.50 ± 44.52, and 483.75 ± 78.13 ng/mL. Tiotropium had a slightly higher area under the curve with a significant increase of C value. Because of their partial solubility, Atr, Ani, AT3, and Sco had different bioavailability in rats of 21.62, 10.78, 80.45 and 2.52 %, respectively. Following i.g. administration of tiotropium, the C value below 20 ng/mL revealed the very low oral absorption. The urinary excretion rates of Atr, Ani, AT3, Sco and tiotropium were 11.33, 54.86, 32.67, 8.69 and 73.91 %. This work provided relatively comprehensive preclinical data on the series of anticholinergics, which may be used to explain the clinical adverse effects and applications. [ABSTRACT FROM AUTHOR]

Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development. [ABSTRACT FROM AUTHOR]

Dicycloplatin, as a new antitumor supramolecule, was considered to have higher solubility and higher stability compared with carboplatin. The aim of the present study was to evaluate the pharmacokinetic characteristics of platinum originating from dicycloplatin. A rapid, sensitive, and specific method with inductively coupled plasma mass spectrometry (ICP-MS) has been developed for the determination of platinum in bio-samples. The study was performed in male rats and dogs at a single dose of 10 and 5 mg kg separately by intravenous injection. Pharmacokinetic parameters were calculated by non-compartmental method, and the dose of platinum was used in the calculation of these parameters. Results showed that plasma concentrations of platinum began to decrease rapidly initially but decline slowly with a long terminal phase. The mean half-life was 27.39 and 100.98 and clearance was 0.77 and 0.08 L/h/kg for rats and dogs separately. Tissue distribution showed that platinum originating from dicycloplatin had a certain distribution in testis and prostate. Plasma protein binding proportion of platinum was increased with time. In conclusion, this research investigated the pharmacokinetic characteristics including plasma kinetics, tissue distribution, and plasma protein binding of platinum originating from dicycloplatin in rats and dogs in detail for the first time by ICP-MS. [ABSTRACT FROM AUTHOR]