Comparison of pharmacokinetics and safety between CE-fosphenytoin sodium, fosphenytoin sodium, and phenytoin sodium after intravenous and intramuscular administration in healthy volunteers.

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

Solving nonlinear equation systems via clustering-based adaptive speciation differential evolution.

In numerical computation, locating multiple roots of nonlinear equations (NESs) in a single run is a challenging work. In order to solve the problem of population grouping and parameters settings during the evolutionary, a clustering-based adaptive speciation differential evolution, referred to as CASDE, is presented to deal with NESs. CASDE offers three advantages: 1) the clustering with dynamic clustering sizes is used to set clustering sizes for different problems; 2) adaptive parameter control at the niche level is proposed to enhance the search ability and efficiency; 3) re-initialization mechanism motivates the algorithm to search new roots and saves computing resources. To evaluate the performance of CASDE, we select 30 problems with different features as test suite. Experimental results indicate that the speciation clustering with dynamic clustering sizes, niche adaptive parameter control, and re-initialization mechanism when combined together in a synergistic manner can improve the ability to find multiple roots in a single run. Additionally, our method is also compared with other state-of-the-art methods, which is capable of obtaining better results in terms of peak ratio and success rate. Finally, two practical mechanical problems are used to verify the performance of CASDE, and it also demonstrates superior results.

A phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX04 to reference bevacizumab sourced from the United States, the European Union, and China in healthy Chinese male volunteers.

PURPOSE: To compare the pharmacokinetic profiles, safety and immunogenicity of proposed bevacizumab biosimilar HLX04 with reference bevacizumab in healthy Chinese males. METHODS: In this double-blind Phase 1 study, healthy volunteers (N = 208) were randomized 1:1:1:1 to a single 3 mg/kg intravenous infusion of HLX04 or reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) or China (bevacizumab-CN). Co-primary endpoints were area under the serum concentration-time profile (AUC) from time zero extrapolated to infinity (AUC0-inf) and from zero to last quantifiable concentration (AUClast). Secondary endpoint was the maximum serum drug concentration (Cmax). Study participants were monitored for treatment-emergent adverse events (TEAEs) and samples were collected for anti-drug antibody (ADA) testing throughout the study. RESULTS: Pharmacokinetic parameters were similar across groups. The respective geometric least-squares mean ratios (GLSMR) of AUC0-inf, AUClast and Cmax were: 95.7%, 96.0% and 101.8% for HLX04 versus bevacizumab-US; 94.3%, 94.6% and 100.5% for HLX04 versus bevacizumab-EU; and 90.0%, 90.4% and 98.2% for HLX04 versus bevacizumab-CN. For all test-to-reference comparisons, two-sided 90% confidence intervals of GLSMR for AUC0-inf, AUClast and Cmax fell in the pre-specified bioequivalence range (80-125%). There were no notable differences in the frequency, nature and/or grade of TEAEs. No deaths were reported and no ADAs were detected during the study. CONCLUSION: HLX04 had similar safety and pharmacokinetic profiles to reference bevacizumab in healthy Chinese males, supporting the confirmatory Phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with metastatic colorectal cancer (NCT03511963). CLINICAL TRIAL REGISTRATION: The study was registered with Clinicaltrials.gov, NCT03483649.

Pharmacokinetics, safety, and immunogenicity of HLX03, an adalimumab biosimilar, compared with reference biologic in healthy Chinese male volunteers: Results of a randomized, double-blind, parallel-controlled, phase 1 study.

The primary objective of this randomized, double-blind, parallel-controlled study (from December 2016 to October 2018) was to evaluate pharmacokinetic (PK) equivalence of adalimumab biosimilar HLX03 and reference adalimumab in healthy volunteers, and to assess safety, and immunogenicity of HLX03. The primary PK endpoints were maximum observed plasma concentration (Cmax ) and area under the concentration curve from time zero to the last quantifiable concentration (AUC0-t ). Equivalence was determined if the 90% confidence interval (CI) of geometric least square mean ratio between the two treatment groups were within the predefined range of 80%-125%. Safety and immunogenicity were monitored during the study. Healthy Chinese males (N = 220) were randomized 1:1 to receive a single subcutaneous 40 mg dose of HLX03 or China (CN)-sourced adalimumab. The ratios of the geometric mean of Cmax and AUC0-t were 102.2% and 105.7%, respectively, with corresponding 90% CIs falling in the predefined margins, which demonstrated PK equivalence between HLX03 and CN-adalimumab. The incidence of treatment-emergent adverse events (TEAEs) was similar in the two groups (73.8% and 66.0% in the HLX03 and CN-adalimumab groups, respectively). Grade 3-4 TEAEs were reported in 7.5% and 5.7% of participants, respectively. The incidences of participants with antidrug antibodies (HLX03: 96.2%; CN-adalimumab: 93.4%) or neutralizing antibodies (HLX03: 40.6%, CN-adalimumab: 41.4%) were comparable between groups. This study demonstrated PK bioequivalence between HLX03 and CN-adalimumab, with similar safety and immunogenicity profiles. These data support further clinical development of HLX03 as an adalimumab biosimilar.

Interaction mechanism of ferritin protein with chlorogenic acid and iron ion: The structure, iron redox, and polymerization evaluation.

Ferritin is an iron-containing protein and functions in the maintenance of iron balance in organisms. Currently the interaction among ferritin, ion iron, and food bioactive compounds is still unclear. In this study, the mechanism underlying the interaction of ferritin, ion iron, and chlorogenic acid was investigated, as well as the effect of chlorogenic acid on the physicochemical properties of ferritin. The results showed that chlorogenic acid could interact with Fe(III) to form chlorogenic acid-Fe(III) complexes, which then bonded with ferritin via hydrogen bonds in the ferritin-chlorogenic acid-Fe(III) complexes. The chlorogenic acid showed a high efficiency in Fe(II) chelation and hydroxyl radical (•OH) capture, and could promote iron oxidation and iron release induced by ferritin. Chlorogenic acid could also effectively reduce the polymerization extent of ferritin induced by Fe(III) and Fe(II). This study elucidates the interactions of multiple components in foodstuffs by using a protein-metal-polyphenol model.

A phase I study of fluzoparib tablet formulation, an oral PARP inhibitor: effect of food on the pharmacokinetics and metabolism after oral dosing in healthy Chinese volunteers.

OBJECTIVE: To evaluate the effect of food on the pharmacokinetics (PK) of fluzoparib capsule. METHODS: PK data were obtained after fluzoparib treatment in a crossover design study. Single-dose fluzoparib (120 mg) was administered under fasted and fed conditions to 16 healthy subjects. Metabolism and transformation fluzoparib were analyzed by liquid chromatograph-tandem mass spectrometry in the first period. Safety was also assessed. RESULTS: The absorption rate of fluzoparib was slower in the fed group (tmax delayed by 3 h), and peak exposure (Cmax) of fluzoparib in plasma decreased by 19.8% (p < 0.05) compared with the fasted group. The area under the curve (AUC) of fluzoparib was not statistically different between the fasted and fed conditions. The 90% confidence intervals for the Cmax and AUC0-∞ were 69.77-92.24% and 84.88-102.26%, respectively. Five, seven, and five fluzoparib metabolites were isolated from plasma, urine, and feces samples, respectively. Most treatment-emergent adverse events were grade I or II. CONCLUSIONS: The presence of food decreased the absorption rate and peak exposure time of fluzoparib; however, the AUC did not significantly change compared with the fasted condition. Therefore, oral administration does not alter the efficacy and safety profile of fluzoparib.

A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.

PURPOSE: QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects. DESIGN: A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug. RESULTS: QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts. CONCLUSION: The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.

A Phase I, Randomized, Double-Blind, Single-Dose, Parallel-Group Study to compare Pharmacokinetic Similarity, Safety, and Immunogenicity Between BAT2506 and Golimumab in Healthy Chinese Male Subjects.

Background: To compare the pharmacokinetic (PK) profile, safety, and immunogenicity between golimumab and the biosimilar BAT2506 in healthy Chinese male subjects. Research design and methods: A total of 180 healthy male subjects were recruited for this randomized, double-blinded, single-dose, parallel study. They received 50 mg BAT2506 or golimumab (1:1 ratio) by single subcutaneous injection. The evaluation index included maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC0-t, AUC0-∞), safety, and immunogenicity. Results: The results showed that the 90% confidence interval (CI) of the geometric mean ratio (GMR) of BAT2506 to reference drug (golimumab) for Cmax, AUC0-∞ and AUC0-t were 99.26% (90.59-108.76%), 102.06% (93.31%-111.64%), and 102.05% (93.51-111.38%), respectively. All 90% CIs were within the range of 80-125% range, which is the limitation of the equivalence margin. Furthermore, similarity of treatment-emergent adverse events was also found between the two drugs. A total of 14 subjects (7.8%) developed anti-drug antibody after administration. Conclusions: Our study confirmed the PK similarity between BAT2506 and golimumab, and showed good tolerance of BAT2506 in healthy subjects. There were no differences in safety and immunogenicity between the two drugs. Therefore, BAT2506 meets the criteria for biosimilarity to golimumab. Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04152759).

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects.

OBJECTIVE: This study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects. METHODS: This is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva® (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva® was administered to the subjects, who were followed up for 134 days. RESULTS: Similar PK properties as those of Xgeva® were exhibited by QL1206. When compared to QL1206 with Xgeva®, the 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0-∞ were observed to be within 80-125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva® groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva® groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva® groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva® groups, respectively. CONCLUSION: Similar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva®. The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva® were found to be similar.

Pharmacokinetics, Safety, and Tolerability of Intravenous Felbinac Trometamol in Healthy Chinese Volunteers: A First-in-Human Single- and Multiple-Dose Escalation Phase I Study with a Randomized, Double-Blind, Placebo-Controlled Design.

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/ ).

Clinical evaluation of efficacy, tolerability and pharmacokinetics of yimitasvir phosphate in patients infected with hepatitis C virus.

OBJECTIVE: Yimitasvir phosphate, an inhibitor of nonstructural protein 5A (NS5A) replication complex of hepatitis C virus (HCV), was evaluated in a double-blind, placebo-controlled, parallel, multiple-dose study. METHODS: Twenty-four patients with chronic HCV genotype 1 infection were randomized to receive a 7-day course of yimitasvir phosphate at daily doses of 30, 100 or 200 mg or placebo. Antiviral efficacy, resistance profile, pharmacokinetics (PK), safety and tolerability were assessed. KEY FINDINGS: The maximal reduction in HCV RNA from baseline was 5.17 log10 IU/ml. However, most patients experienced viral rebound on or before day 3 after yimitasvir treatment was initiated. The PK profile revealed median peak plasma concentrations at 4-12 h postdose and a mean terminal half-life of 14.47-17.09 h, the basis for daily dosing. Steady drug state was achieved following 5 days of daily dosing. The accumulation rate was low (1.29-1.73). There were no significant alterations in vital signs and laboratory findings among all participants. CONCLUSIONS: This study shows that yimitasvir phosphate was well tolerated, and the PK profile supported daily dosing regimens. A 1-week (7-day) treatment course led to a quick and significant reduction in HCV RNA level in this cohort with HCV GT-1 infection.