Pharmacokinetics of Icosapent Ethyl: An Open-Label, Multiple Oral Dose, Parallel Design Study in Healthy Chinese Subjects.

Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester that has been approved to lower triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. Before this study, there were no pharmacokinetics (PK) or safety data in Chinese patients after receiving IPE. The purpose of this study was to evaluate the PK of EPA in plasma and red blood cells and safety after oral administration of IPE capsules for 28 consecutive days in healthy Chinese subjects. It was a randomized, open-label, parallel-designed multiple-dose, phase I study. Twenty-four subjects were enrolled and randomly assigned to 2 groups, including 6 men and 6 women in each group. Group A received IPE 2.0 g/day (1×1 g twice daily), and group B received IPE 4.0 g/day (2×1 g twice daily) with dosing after standard meals for 28 days. During the treatment period, PK samples were collected from all subjects before the morning dose on days 1, 14, 26, and 28. Following completion of the last study drug administration in the morning on day 28, an 18-day posttreatment PK sample collection period was followed. Twenty-four eligible subjects were enrolled in this study, and 1 subject withdrew from the study. The main PK parameters (baseline-corrected maximum observed plasma concentration and area under the plasma concentration-time curve during a dosing interval) of plasma total EPA, RBC EPA, and plasma unesterified EPA increased with dose. Chinese healthy subjects who took IPE capsules orally in the dose range of 2.0 to 4.0 g/day for 28 consecutive days were safe and tolerable.

Pharmacokinetic Interaction of Chiglitazar with CYP3A4 Inducer or Inhibitor: An Open-Label, Sequential Crossover, Self-Control, 3-Period Study in Healthy Chinese Volunteers.

Chiglitazar, a pan agonist of non-thiazolidinedione peroxisome proliferator-activated receptor, has the potential to regulate blood sugar, improve lipid metabolism, and reduce cardiovascular complications. This study aimed to examine the effect of cytochrome P450 (CYP) 3A4 inhibitors/inducers on the in vivo metabolism of chiglitazar and provide a reference for the clinical combination use of chiglitazar. A single-center, open-label, sequential crossover, and self-control study was carried out in 24 healthy subjects to determine the pharmacokinetics of chiglitazar dosed with and without CYP3A4 inhibitors and inducers. The findings showed that the CYP3A4 inhibitor itraconazole had no apparent pharmacokinetic drug interaction with chiglitazar, whereas rifampicin did. When combined with rifampicin after continuous dosing, chiglitazar exposure was not theoretically reduced but increased compared to a single dose of chiglitazar. The possible explanation may be the transporters of bile salt export pump, but this needs to be confirmed. The safety of chiglitazar in single or combination doses was well tolerated. The findings of this study provide a basis for clinical combinations of chiglitazar with CYP3A4 inhibitors or inducers.

Evaluating the bioequivalence and safety of liraglutide injection versus Victoza® in healthy Chinese subjects: a randomized, open, two-cycle, self-crossover phase I clinical trial.

Background: Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analog, and its pharmacokinetic and pharmacodynamic properties as a GLP-1 receptor (GLP-1R) agonist make it an important therapeutic option for many patients with type 2 diabetes mellitus. This study compared the bioequivalence and safety of liraglutide with the originator product in healthy Chinese adult subjects. Methods: Subjects (N = 36, both sexes) were randomized in a 1:1 ratio into two groups (18 cases each) for a two-cycle, self-crossover trial. Each cycle involved a single subcutaneous injection of the test and reference drugs, with a washout period of 14 days. The plasma drug concentration was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The main pharmacokinetic parameters were statistically analyzed to assess drug bioequivalence. Furthermore, the safety of the drugs was assessed throughout the trial. Results: The geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ were 103.73%, 103.01%, and 103.03%, respectively, and their 90% confidence intervals (CIs) were consistent with the range of 80.00%-125.00%, indicating that the two formulations had similar pharmacokinetics. Meanwhile, safety results showed that both drugs were well tolerated. Conclusion: Studies have shown that the test drug has similar bioequivalence and safety to the reference drug. Clinical trial registration: (http://www.chinadrugtrials.org.cn/index.html), identifier (CTR20171303).

Identification of dominant conformational epitopes from the whole structure of the proprotein convertase subtilisin/kexin type 9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of LDLR, has emerged as an important target for the treatment of hypercholesterolemic cardiovascular disease, and monoclonal antibodies alirocumab and evolocumab against it have been widely used in clinical practice. The vaccine research of PCSK9 is considered a promising option for the long-term treatment and prevention of cardiovascular disease, but progress has been slow. The selection of safe and effective epitopes is one of the key steps in vaccine development. In this study, we designed a phage display library of cascaded peptides for affinity screening with two antibody drugs, and found that the two peptides PC3 and PS6, which are adjacent to each other in protein spatial structure, both have superior binding activity to the screening antibodies. We performed in vitro recombination design on the dominant sequences, and obtained recombinant sequences that can respond to the dominant conformational epitope of PCSK9, which provides a meaningful reference for epitope selection in subsequent PCSK9 vaccine development.

Pharmacokinetics, Pharmacodynamics, Safety and Immunogenicity of CMAB807, a New Denosumab Biosimilar, in Healthy Chinese Subjects.

Objective: Pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity studies were conducted to evaluate the bioequivalence of CMAB807, a biosimilar to denosumab (Prolia®), which is the only approved RANKL inhibitor for the treatment of osteoporosis. Methods: In this randomized, double-blind, single-dose phase I study, 132 healthy Chinese male subjects received a subcutaneous injection of 60 mg of CMAB807 or denosumab at a 1:1 ratio. The PK, PD, safety and immunogenicity results were assessed prior to and up to 126 days after administration. Results: The PK profiles of CMAB807 and denosumab were similar. The geometric mean ratios of the maximum concentration (Cmax), AUC0-t and AUCo-∞ were 102.41, 104.15 and 103.89%, respectively, and the 90% confidence interval was observed to be within 80.00-125.00%, which indicated the bioequivalence of CMAB807 and denosumab. The PD profiles of the two groups were also comparable. The production of the C-terminal cross-linking telopeptide of type I collagen (CTX1) was inhibited by up to 85% for 10 days, and this inhibition was sustained for up to 126 days in both the CMAB807 and denosumab groups. No subjects in the CMAB807 group, three subjects in the denosumab group before administration, and two subjects in the denosumab group after administration were positive for anti-drug antibody (ADA). Adverse events (AEs) were observed in 98.5% of subjects in both groups. The most common AE recorded was increased parathyroid hormone (PTH) levels, with incidences of 92.4 and 95.5% in the CMAB807 and denosumab groups, respectively. No clinically meaningful differences were observed in safety and immunogenicity between CMAB807 and denosumab. Conclusion: CMAB807 represents a new potential treatment option for patients with osteoporosis. Clinical Trial Registration: https://clinicaltrials.gov (Registration No. NCT03925051), http://www.chinadrugtrial/org.cn/index.html (Registration No. CTR20190800).

Pharmacokinetics of Sugammadex: An Open-Label, 3-Period, Fixed-Sequence, 3-Single-Doses Study in Healthy Chinese Subjects.

The main purpose of this study was to assess pharmacokinetic parameters (area under the plasma concentration-time curve from time 0 to infinity, area under the plasma concentration-time curve from time 0 to the last measurable concentration, maximum concentration, and apparent terminal half-life) after administration of 3 single intravenous (IV) doses of sugammadex to evaluate the safety and tolerability in healthy nonanesthetized subjects. This was an open-label, 3-period, nonrandomized, single-rising-dose study in 12 healthy Chinese subjects 18 to 45 years of age. In each period, every subject received a single IV dose of sugammadex in a fixed sequence (1, 2, and 4 mg/kg) under fasting conditions. There was a 3-day washout phase between dosing in each treatment period. In this study, a total of 11 (6 men and 5 women) Chinese subjects (with mean age of 25 ± 4.0 years; body weight, 64 ± 6 kg; height, 167 ± 6 cm; and body mass index, 22.9 ±1.2 kg/m2 ) received single doses of sugammadex 1, 2, and 4 mg/kg sequentially, with a 3-day washout phase between consecutive doses, and completed the study. The geometric mean maximum concentrations were 16.81, 30.99, and 60.55 µg/mL for sugammadex 1, 2, and 4 mg/kg, respectively. The median time to maximum concentration was 0.03 hour after bolus administration, and plasma sugammadex concentrations declined with a mean apparent terminal half-life of ≈1.7 hours across all 3 doses. Single-dose IV administration of sugammadex 1, 2, and 4 mg/kg was generally safe and well tolerated in healthy Chinese male and female subjects.

Pharmacokinetics, Safety and Tolerability of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein (CETP) Inhibitor, After Single and Multiple Doses in Healthy Chinese Subjects.

INTRODUCTION: Anacetrapib is a novel, powerful cholesteryl ester transfer protein (CETP) inhibitor with bidirectional lipid regulation, which was developed for dyslipidemia. The aim of this study is to evaluate the single- and multiple-dose pharmacokinetics (PK), safety and tolerability of anacetrapib in healthy Chinese subjects and assess the PK difference between Chinese and other populations. METHODS: Forty subjects were enrolled in an open-label study consisting of three panels (50 mg single dose; 100 mg single dose followed by 100 mg once-daily multiple doses for 10 days; a 200 mg single dose). Safety and tolerability were evaluated by monitoring adverse events, laboratory safety tests, ECGs, vital signs and physical examination. PK were evaluated and compared with historical data in black and white subjects. RESULTS: Anacetrapib was absorbed after administration of a single oral dose, with a median Tmax of 3.0-5.0 h and elimination half-life of 105.3-122.3 h. The AUC and Cmax of anacetrapib increased in a slightly less than dose-proportional manner over a dose range of 50-200 mg. Once-daily administration of 100 mg of anacetrapib for 10 days resulted in a median Tmax of 5.0 h with an apparent half-life of 193.7 h on Day 10 of multiple dosing. Anacetrapib accumulation ratios (Day 10 of multiple dosing/Day 1) were 1.39 (AUC0-24 h), 1.11 (Cmax) and 2.57 (C24 h). CONCLUSION: The PK properties of anacetrapib in Chinese subjects are comparable to those observed in the black population and in white subjects. Single and once-daily administration of anacetrapib was generally well tolerated in healthy Chinese subjects observed in this study. TRIAL REGISTRATION: chinadrugtrials.org.cn identifier number CTR20130983.

Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of Benfotiamine in Healthy Subjects.

PURPOSE: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials. METHODS: Healthy subjects were sequentially enrolled into one of five SAD (150-1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4-9, followed by a single morning dose on day 10. RESULTS: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC. CONCLUSION: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.

Platelet inhibitory activity, tolerability, and safety of vicagrel, a novel thienopyridine P2Y12 inhibitor.

Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of vicagrel in healthy Chinese subjects.This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive vicagrel or placebo. Platelet function was assessed using VerifyNow P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of vicagrel.Although the number of adverse events (AEs) increased with vicagrel dose, none were considered serious, suggesting that vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%-93.0%, mean ΔPRU 206.6-240.0) for doses of 40 to 75 mg of vicagrel. In contrast, for 5 mg vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study.The results suggest that vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that vicagrel may be a highly effective and well-tolerated antiplatelet agent.

[(3R,4S)-4-(4-Fluoro-phen-yl)-1-methyl-piperidin-3-yl]methyl 4-methyl-benzene-sulfonate.

In the title compound, C(20)H(24)FNO(3)S, the piperidine ring adopts a chair conformation. The dihedral angle between the aromatic rings is 47.01 (17)°.