Study In Healthy Chinese Subjects Research Articles

Pharmacokinetics and safety of a new generic lurasidone: a phase I bioequivalence study in healthy Chinese subjects.

Latuda®is a novel antipsychotic drug for schizophrenia and bipolar depression. A bioequivalence trial was performed to investigate the bioequivalence of Latuda® and its generic drug lurasidone. Two independent trials were carried out, each involving 28 subjects. In the fasting trial, subjects were randomly assigned to two groups (1:1 ratio), receiving either 40mg of generic lurasidone or Latuda®. After a 7-day washout period, subjects entered the second period with a crossover administration of 40mg of generic lurasidone or Latuda®. The postprandial study design was similar to that of the fasting study. In the fasting study, the pharmacokinetic (PK) parameter values of generic lurasidone and Latuda® were as follows: the Cmax was 28.84 ± 19.34ng/ml and 28.22 ± 21.19ng/ml, respectively; the AUC0-t was 121.39 ± 58.47h*ng/ml and 118.35 ± 52.24h*ng/ml, respectively; and the AUC0-∞ was 129.63 ± 63.26h*ng/ml and 126.59 ± 57.99h*ng/ml, respectively. The primary pharmacokinetic parameter, Cmax, was assessed for equivalence using reference-scaled average bioequivalence (RSABE), while other parameters (AUC0-t, AUC0-∞) were evaluated using average bioequivalence (ABE). The results indicate that both Cmax and AUC meet the equivalence criteria. In the postprandial study, the PK values of generic lurasidone and Latuda® were as follows: the Cmax was 74.89 ± 32.06ng/ml and 83.51 ± 33.52ng/ml, respectively; the AUC0-t was 274.77 ± 103.05h*ng/ml and 289.26 ± 95.25h*ng/ml, respectively; and the AUC0-∞ was 302.44 ± 121.60h*ng/ml and 316.32 ± 109.04h*ng/ml, respectively. The primary pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞) were assessed for equivalence using ABE, and both met the equivalence criteria. In the study, lurasidone and Latuda® both exhibited acceptable safety and tolerability. The results displayed that lurasidone and Latuda® were bioequivalent and safe in healthy Chinese participants. Clinical Trial Registry: This trial is registered at chinadrugtrials.org.cn (no.: CTR20191717, date: 2019.08.29).

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33–104.96% for the maximum plasma concentration (Cmax), 97.21–102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0–t), and 97.22–102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0–∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28–110.69% for the minimal BIS value (BISmin), 99.23–101.17% for the area under the BIS time curve from time 0–60 min after administration (BISAUC0–60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00–125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number:http://www.chinadrugtrials.org.cn/index.html. # CTR20191836.

Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- andMultiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.

HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on thepharmacokinetic parameters of HEC122505 and its major metabolite HEC129870. The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned. Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (Tmax) ranged from 0.5 to 1.75h. In addition, maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics ofHEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100mg dose once daily for up to 8days. HEC122505 reached steady state after approximately 5days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred. HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.

2157. Phase 1 Study in Healthy Chinese Subjects of Novel Prodrug, MRX-4

Abstract Background MRX-4 is a prodrug of contezolid (MRX-1), a new oxazilidone approved in China. We evaluated the safety and pharmacokinetic (PK) profile of IV and oral MRX-4 and its metabolites. Methods This randomized, double-blind, placebo-controlled study was conducted at Huashan Hospital, (Shanghai, China) with four-arm design: a) IV, single-dose escalation group (500 mg, 1000 mg, 1500 mg, or 2000 mg); b) IV, repeated-dose group (2000 mg loading dose followed by 1000 mg maintenance dose, q12 h for 11 consecutive days using 1-1.5 hr infusion time); c) oral, single-dose escalation group (500 mg or 1500 mg); d) oral, repeated-dose group (1500 mg, q12 h for 11 consecutive days). Safety evaluation was conducted in each dose group. The blood and urine concentrations of MRX-4, MXR-1, and the inactive metabolites (MRX-1352) were measured, using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results A total of 70 subjects completed the trial. MRX-4 concentration was not possible to measure due to rapid hydrolisis into MRX-1352. In the MRX-4 group, 67 treatment-emergent adverse events (TEAEs) were observed in 27 of 55 subjects (49%); 24 TEAEs occurred in 14 subjects in the IV group (n = 36) and 43 TEAEs in 13 subjects in the oral group (n = 19). Six adverse drug reactions (ADRs) were observed in 4 subjects in the IV group, which were predominantly a mild transient decrease in white blood cells that self-resolved. In the oral group, 23 ADRs were observed in 9 of 19 subjects (47%), primarily nausea and vomiting that self-resolved in the 1500 mg repeated-dose group. No decrease in platelet count was observed in any dose group. PK parameters of the inactive intermediate metabolite (MRX-1352), and the active metabolite (MRX-I, contezolid) are shown: Conclusion MRX-4 was safe and well tolerated among Chinese healthy subjects, with treatment adverse events being mild and transitory. MRX-4, administered via IV or oral, demonstrated rapid and complete conversion to contezolid. PK parameters support the potential for use of MRX-4 as the IV companion to oral contezolid. Disclosures All Authors: No reported disclosures

A phase-I randomized euglycemic clamp study to demonstrate the pharmacokinetic and pharmacodynamic equivalence of an insulin degludec biosimilar (B01411) with the reference product in healthy Chinese volunteers

ABSTRACT Background B01411 is a biosimilar candidate manufactured by Jilin Huisheng Biopharmaceutical Co. Ltd for the reference insulin degludec (Tresiba) (IDeg). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of the two IDeg products and to assess the PK/PD similarity of B01411 compared with the reference IDeg product. Research design & methods A single-center, single-dose, randomized, crossover, open-labeled, phase I, euglycemic clamp study in healthy Chinese subjects to examine the bioequivalence of B01411 (0.4 U/kg) compared with the reference IDeg product. Blood samples were collected at a predefined time for the analysis of blood glucose (BG), IDeg, and C-peptide concentrations. The glucose infusion rate (GIR) was adjusted to maintain the BG at approximately 0.28 mmol/L below baseline throughout the clamp. Results Thirty-two subjects (20 males and 12 females) were enrolled, 31 of whom received both treatments. The 90% confidence intervals for the ratio of the least-squares geometric means for AUCIDeg,0–24 h, AUCGIR,0–24 h, IDegmax, and GIRmax were all in the range of 0.80–1.25. Only one adverse event of puncture site bruising occurred once in a subject in the B01411 group. Conclusion B01411 exhibited a pharmacokinetic and pharmacodynamic similarity to the reference product. Both IDeg products were well tolerated. Clinical trial registration http://www.chinadrugtrials.org.cn/index.html#. Identifier is CTR20192122.

Development and validation of LC-MS/MS methods for the quantification of 101BHG-D01, a novel, long-acting and selective muscarinic receptor antagonist, and its main metabolite M6 in human plasma, urine and feces: Application to a clinical study in healthy Chinese subjects

101BHG-D01 is a novel, long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD) and rhinorrhea in rhinitis. To support its clinical study, several liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the quantification of 101BHG-D01 and its main metabolite M6 in human plasma, urine and feces were developed. The plasma samples were prepared by protein precipitation, and the urine and fecal homogenate samples were pretreated by direct dilution, respectively. The chromatographic separation was performed on an Agilent InfinityLab Poroshell 120 C18 column with 0.1% formic acid and 10.0 mM ammonium acetate buffer solution in water and methanol as the mobile phase. The MS/MS analysis was performed by using multiple reaction monitoring (MRM) under a positive ion electrospray ionization mode. The methods were validated with regards to selectivity, linearity, lower limit of quantitation (LLOQ), accuracy and precision, matrix effect, extraction recovery, dilution integrity, batch size, carryover and stability. The calibration ranges were as follows: 1.00–800 pg/mL for 101BHG-D01 and 1.00–20.0 pg/mL for M6 in plasma; 0.0500–20.0 ng/mL for 101BHG-D01 and M6 in urine; 0.400–400 ng/mL for 101BHG-D01 and 0.100–100 ng/mL for M6 in feces. There was no endogenous or cross interference observed at the retention time of the analytes and internal standard in various biological matrices. Across these matrices, for the lower limit of quantitation quality control (LLOQ QC) samples, the intra- and inter-batch coefficients of variation were within 15.7%. For other QC samples, the intra- and inter-batch coefficients of variation were within 8.9%. The intra- and inter-batch accuracy deviations for all QC samples were within the range of − 6.2–12.0%. No significant matrix effect was observed from the matrices. The extraction recoveries of these methods at different concentrations were consistent and reproducible. The analytes were stable in different matrices under various storage conditions. The other bioanalytical parameters were also fully validated and met the criteria given in the FDA guidance. These methods were successfully applied to a clinical study in healthy Chinese subjects after a single dose administration of 101BHG-D01 inhalation aerosol. After inhalation, 101BHG-D01 was absorbed into plasma rapidly with the time to reach the maximum drug concentration (Tmax) of 5 min and eliminated slowly with a half-life time about 30 h. The cumulative urinary and fecal excretion rates revealed 101BHG-D01 was mainly excreted in feces, rather than urine. The pharmacokinetic results of the study drug laid a foundation for its further clinical development.

Development and validation of LC–MS/MS method for quantitation of sodium oligomannate in human plasma, urine and feces

Background: Sodium oligomannate was approved for marketing by the National Medical Products Administration of China in 2019 for improving cognitive functions in mild-to-moderate Alzheimer's disease patients. Method: LC-MS/MS methods were established and validated for the quantitation of sodium oligomannate in human plasma, urine and feces to support clinical development studies. Samples were prepared using liquid-liquid extraction and analyzed by ion-pair reversed-phase LC-MS/MS with calibration standard curve ranges of 25.0-5000ng/ml, 0.500-100μg/ml and 100-10,000μg/g in plasma, urine and feces, respectively. Results & conclusion: All validation parameters met the respective acceptance criteria established by US FDA and International Council for Harmonisation of Technical Requirements for Human Use guidelines. The validated methods were applied to a pharmacokinetics and excretion study in healthy Chinese subjects.

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects

ABSTRACT Background Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Research design & methods We designed a clinical study to demonstrate that the dasatinib tablet (YiNiShu®) (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Dasatinib (Bristol Myers Squibb) were bioequivalent under fasting and fed conditions. The whole study was structured into the fasting trial and the postprandial trial. Each period, subjects were given 50 mg dasatinib or its generic. The RSABE (reference scale average bioequivalence) and ABE (average bioequivalence) methods were employed to assess bioequivalence by pharmacokinetics (PK) parameters for a highly variable drug. Results 32 and 24 eligible volunteers were enrolled in the fasting and postprandial trials, respectively. In the fasting trial, the RSABE method was performed, and point estimates of Cmax, AUC0-t, and AUC0-∞ met the bioequivalence criteria. In the postprandial trial, the ABE method was performed, and the 90% CI of the geometric mean ratio (GMR) for PK parameters met the requirements of bioequivalence standards. Conclusion The results proved that the PK parameters of the two drugs were similar and bioequivalent, indicating that both drugs had a good safety profile. Clinical trial registration This trial was registered in ClinicalTrials.gov (Number: NCT05640804) and Drug Clinical Trial Registration and Information Disclosure Platform (Number: CTR20181708)

Pharmacokinetics and bioequivalence of Ezetimibe tablet versus Ezetrol®:an open-label, randomized, two-sequence crossover study in healthy Chinese subjects

BackgroundEzetimibe is a new class of antihyperlipidemic agent indicated for the prevention of atherosclerosis disease and for the treatment of hypercholesterolemia. Information on the pharmacokinetic profiles of ezetimibe tablet in healthy Chinese volunteers are lacking, and regulatory requirements necessitate a bioequivalence study of ezetimibe tablet versus Ezetrol® in China.MethodsA single-dose randomized, open-label, two-group, two-period crossover study was conducted in 59 healthy Chinese volunteers under fasting or fed conditions to assess the bioequivalence between two preparations. Eligible participants were randomly divided into fasted and fed groups. Blood samples were collected at specified time intervals, and the plasma concentrations of ezetimibe and ezetimibe glucuronide were determined by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. PK and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded.ResultsFifty-nine healthy volunteers were enrolled in the study. The main pharmacokinetic parameters of total ezetimibe in the plasma of the ezetimibe tablet (10 mg) and the Ezetrol® (10 mg) after a single fasting administration: Cmax were (65.73 ± 47.14), (71.32 ± 51.98) ng·mL− 1; Tmax were 1.75, 1.25 h; T½ were (17.09 ± 13.22), (17.35 ± 12.14) h; AUC0-t were (643.34 ± 400.77), (668.49 ± 439.57) h·ng·mL− 1; AUC0-∞ were (706.36 ± 410.92), (734.23 ± 468.26) h·ng·mL− 1. The main pharmacokinetic parameters of total ezetimibe in plasma of ezetimibe tablet (10 mg) and Ezetrol® (10 mg) after a fed administration: Cmax were (83.38 ± 38.95), (84.74 ± 34.62) ng·mL− 1; Tmax were 2.50, 2.50 h; T½ were (22.56 ± 12.68), (19.80 ± 15.59) h; AUC0-t were (494.21 ± 208.65), (536.69 ± 209.11) h·ng·mL− 1; AUC0-∞ were (573.74 ± 252.74), (604.75 ± 247.13) h·ng·mL− 1. The main pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ of the two drugs were analyzed by variance analysis after logarithmic transformation. The total ezetimibe under fasting state with 90% confidence intervals (CIs) were 85.29 ~ 97.19, 90.41% ~ 104.38%, and 90.81 ~ 106.05%; total ezetimibe in fed state were 86.36% ~ 109.17, 84.96% ~ 96.40, and 85.32% ~ 101.0%. The 90% CIs of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ of Ezetrol® and ezetimibe tablet both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80–1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. No severe adverse events were observed.ConclusionsThe test ezetimibe tablet and Ezetrol® were determined to be bioequivalent under both fasting and fed conditions in Chinese people.Trial registrationClinicaltrials, NCT05681247 (retrospectively registered in 11/01/ 2023).

Simple and Rapid LC-MS/MS Method for Determination of Perampanel in Human Plasma and Application to Bioequivalence Study

Background: Perampanel (PER) is a third-generation antiepileptic drug (AED). Several methods have been developed for the quantification of perampanel in plasma. The pharmacokinetic characteristics of perampanel in healthy Chinese ubjects have not been comprehensively reported. Objective: A simple, fast and sensitive LC-MS/MS method was established and validated for the quantification of perampanel in human plasma and its application to a bioequivalence study. Methods: Chromatographic separation was accomplished on a ZORBAX Eclipse XDB-Phenyl column (4.6 mm × 75 mm, 3.5 μm) using a binary gradient with mobile phase (A) (water containing 5 mmol/L ammonium acetate and 0.1% formic acid and (B) acetonitrile-water (95:5, v/v) at a flow rate of 0.9 mL/min and sample preparation was by one-step protein precipitation via acetonitrile. Results: The total run time in this study was 4.5 min and the retention time of perampanel and perampanel-d5 (internal standard) were 2.30 min and 2.32 min, respectively. The method was developed and validated over the concentration range of 2.00-500 ng/mL for perampanel, with a correlation coefficient greater than 0.9992. The inter-day precision was 3.1%-3.8% and accuracy was 98.9%-103.5%. The intra-day precision was 2.4%-6.8% and the accuracy was 97.6%- 104.9%. The extraction recovery ranged from 99.23%-103.84% and the matrix effect was not significant. Perampanel was proved to be stable in solution and human plasma under different tested conditions. The validated method was successfully applied to a randomized, open-label, 2- period, crossover bioequivalence study in healthy Chinese subjects, and the results indicated that bioequivalence was achieved for 2 formulations of the 4-mg perampanel tablet under both fasting and fed conditions, and both treatments were safe and well-tolerated by all study subjects. Conclusion: The validated method was successfully applied to a bioequivalence study of perampanel in human plasma and has achieved satisfactory results.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of a biosimilar of denosumab (LY06006): a randomized, double-blind, single-dose, parallel-controlled clinical study in healthy Chinese subjects

ABSTRACT Objectives To compare the pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity of LY06006 (denosumab biosimilar) and denosumab in healthy Chinese adult male subjects. Methods In this randomized, double-blind, parallel-controlled, single-dose, comparative biosimilar study, a total of 168 subjects received 60 mg of LY06006 or denosumab by subcutaneous (SC) abdominal injections in a 1:1 ratio with a follow-up period of 168 days. Results After a single SC abdominal injection of 60 mg LY06006/denosumab, the geometric mean ratio of the main pharmacokinetic parameters, Cmax and AUC0-∞, of the two drugs were 97.57% and 104.27%, respectively; the geometric mean ratio of the main pharmacodynamic parameters AUEC0-t and Emax, were 101.00% and 99.64%, respectively, and the 90% confidence interval was observed to be within 80–125%. The subjects in the test group (LY06006) and control group (denosumab) were all negative for anti-drug antibody (ADA). The incidence and severity of treatment-emergent adverse events (TEAEs)were similar for both groups, and no grade 3 or higher TEAEs occurred in either group. Conclusions This study demonstrated that LY06006 and denosumab have similar characteristics and bioequivalence in pharmacokinetics. Moreover, they had similar pharmacodynamic profiles, safety, and immunogenicity. Clinical trial registration www.clinicaltrials.gov identifier is NCT04973722

Pharmacokinetics and Safety of Erenumab after a Single Subcutaneous Injection Dose in Healthy Chinese Subjects.

Erenumab is the first-in-class, selective, and competitive human monoclonal antibody antagonist of the calcitonin gene-related peptide (CGRP) receptor that has been shown to be effective and well-tolerated in the preventive therapy of episodic and chronic migraine. The pharmacokinetics of erenumab may be affected by differences in race and ethnicity, which can lead to suboptimal outcomes. The present study was conducted to assess the single-dose pharmacokinetics and safety of erenumab in healthy Chinese subjects. This was an open-label, randomized, parallel group, non-confirmatory, single-dose study in healthy Chinese subjects. A total of 24 healthy Chinese subjects of both sexes aged between 14 and 45 years were administered a single subcutaneous injection of erenumab 70 mg or 140 mg. The serum concentration of erenumab was quantified using a validated enzyme-linked immunosorbent assay method and pharmacokinetic parameters were determined using non-compartmental models. Safety was also assessed. A total of 55 subjects were screened for eligibility and 25 subjects were randomized to receive study treatments (12 subjects to the 70-mg erenumab group and 13 subjects to the 140-mg erenumab group). Erenumab was absorbed slowly withmaximum serum concentration (Cmax)occurring 3-11 days after administration. The mean Cmax and area under the serum concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase (AUC0-∞)were 9.20 µg/mL and 296 day·µg/mL for the 70 mg dose group, and 15.6 µg/mL and 569 day·µg/mL for the 140 mg dose group, respectively. Serum concentrations of erenumab exhibited low to high variability, with variable coefficients ranging from 17.1 to 72.2% for the 70-mg dose and 32.5 to 88.5% for the 140-mg dose. All adverse events were mild or moderate in intensity, and all resolved without intervention. Erenumab was safe and well tolerated after a single subcutaneous injection in healthy Chinese subjects. The systemic exposure in Chinese subjects in terms of AUC0-∞ was 70% higher than that in White subjects as previously reported. ChiCTR2000032435.

A Reference-Scaled Average Bioequivalence Study of Azithromycin Tablets Manufactured in China and the United States: An Open-Label, Randomized, Single-Dose, 3-Way Crossover Study in Healthy Chinese Subjects Under Fasted and Fed Conditions.

Azithromycin (Zithromax) is an azalide antibiotic that binds to the 50S ribosomal subunit of the susceptible organism and thereby interferes with its protein synthesis. An open-label, randomized, single-dose, 3-way crossover bioequivalence study was conducted to compare the rate and extent of absorption of the azithromycin 250-mg tablet manufactured at Pfizer Dalian (China) and that at Pfizer Barceloneta (United States) under fasted and fed conditions in healthy Chinese subjects. This study aimed to support a generic consistency evaluation program, initiated by the National Medical Products Administration, for evaluating the quality and efficacy of the products manufactured in China. In the study, the within-subject standard deviation for area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fasted condition was <0.294, and the 90%CI for the ratio was within 80% to 125%; the within-subject SDs for serum peak concentration in the fasted condition, area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fed condition, and serum peak concentration in the fed condition, were all >0.294, with the upper confidence bounds being <0.00, and the point estimates of the ratios being within 80% to 125%. The results support the bioequivalence between azithromycin tablets manufactured in China and the United States in fasted and fed conditions, with both tablets showing an acceptable safety/tolerability profile in the studied population.

0453 Lemborexant Exposure Is Independent of Race

Abstract Introduction Some hypnotic treatments for insomnia require dosing consideration due to exposure differences based on patient characteristics. Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adult insomnia. LEM is not associated with exposure differences based on sex, age, or BMI that impact dosing. The potential impact of race on exposure was determined in two stand-alone pharmacokinetic (PK) studies and by modeling data from studies comprising the LEM clinical development program, which included healthy subjects and insomnia patients. Methods Study 003 (NCT02039089) was a single-center, multiple-dose, randomized, double-blind, placebo-controlled, parallel-group study in healthy Japanese and White subjects. Study 014 (NCT04555733) was a phase 1, single center, open-label, single and multiple oral dose study in healthy Chinese subjects. Additionally, effect of race on LEM exposure was independently examined as part of a population PK analysis incorporating LEM data from 9 Phase 1 studies (n=407), and Studies 201 (NCT01995838; n=235), 303 (NCT02952820; n=726) and 304 (NCT02783729; n=524) (Lalovic et al., 2020). Plasma concentrations of LEM were quantified from plasma by validated liquid chromatography with tandem mass spectrometry. Adverse events (AE) were recorded. Results Exposure of LEM increased in an approximately dose-proportional manner across the dose range (2.5 mg to 25 mg) in studies 003 and 014. There were no significant exposure differences between Japanese and White subjects following single LEM10 administration on Day 1 in Study 003 (maximum concentration [Cmax] mean[SD], ng/mL: Japanese, 46.5[25.8]; White, 47.3[28.1]; area under the curve from time zero to 24h [AUC0-24] mean[SD], ng·h/mL: Japanese, 231[40.2]; White, 208[83.4]) or when comparing PK data from Chinese subjects in Study 014 following single dose administration on Day 1 (Cmax mean[SD], ng/mL: LEM5, 29.8[12.8]; LEM10, 56.2[16.9]; LEM25, 116[46.8]; AUC0-24 mean[SD], ng·h/mL: LEM5, 106[29.9]; LEM10, 205[35.6]; LEM25, 549[116]) to Japanese and White subjects in Study 003. These results are supported by the cross-study, population PK model-based analysis, indicating no significant clinical or statistical differences in LEM PK attributable to the intrinsic factor race. Conclusion LEM exposure is not significantly affected by race. Therefore, dosing of LEM can be consistent across patient populations from different racial groups. Support (If Any) Eisai Inc.

Simultaneous determination of abiraterone and its five metabolites in human plasma by LC-MS/MS: Application to pharmacokinetic study in healthy Chinese subjects

In this study, a rapid, simple and sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously quantify abiraterone (ABI), a widely used anti-metastatic castration-resistant prostate cancer drug, and its metabolites comprising Δ4-abiraterone (D4A), 3-keto-5α-abiraterone (5αA), abiraterone N-oxide (A-NO), abiraterone sulfate (A-Sul) and abiraterone N-oxide sulfate (A-NO-Sul) in human plasma. The analytes were extracted by protein precipitation with acetonitrile and ideal chromatographic separation was achieved on ACE-C18 column (2.1 × 50 mm, 5 µm) using a gradient elution. Triple Quad™ 6500+ mass spectrometer equipped with an electrospray ionization (ESI) source was used and the multiple reaction mode (MRM) was performed. In terms of method validation, good linearity was observed in preassigned validated concentration range for each analyte of interest. Both intra- and inter-batch accuracy was within the range of 87.6–113.8% for all analytes, while intra- and inter-batch precision was below 14.0%. Additionally, both low matrix effects and high recovery were obtained. All analytes remained stable in human plasma at room temperature for 4 h, on wet ice for 8 h, at − 80 °C for 42 d, over three freeze-thaw cycles and under auto-sampler temperature (4 °C) for 48 h post sample preparation. Subsequently, the validated LC-MS/MS method was applied for pharmacokinetic study in healthy Chinese volunteers following an oral dose of 250 mg abiraterone acetate tablet under fasted conditions. Our study for the first time reported the pharmacokinetic parameters of the ABI metabolites in Chinese subjects.

A Euglycemic Glucose Clamp Study to Evaluate the Bioavailability of LY2963016 Relative to Insulin Glargine in Healthy Chinese Subjects.

Insulin glargine (IGlar) and LY2963016 (LY IGlar) are long-acting insulin analogs with identical primary amino acid sequences. We conducted a randomized, open-label, 2-treatment, 2-period, crossover study in healthy Chinese subjects to evaluate the relative bioavailability of LY IGlar to IGlar and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of LY IGlar. Subjects (n = 58) were randomized to receive single subcutaneous doses (0.5 U/kg) of LY IGlar and IGlar with a ≥7-day washout period between study treatments. Serum was collected before and up to 24 hours after dosing to assess PK characteristics. PD characteristics were assessed by euglycemic clamp up to 24 hours after dosing. Linear mixed-effects models were used to fit the log-transformed primary PK (maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours) and PD parameters (maximum glucose infusion rate and total amount of glucose infused during clamp period). The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar for maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours were 0.961 (0.887-1.04) and 0.941 (0.872-1.01), respectively. The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar were 0.91 (0.85-0.98) for maximum glucose infusion rate and 0.89 (0.82-0.97) for total amount of glucose infused during clamp period. LY IGlar demonstrated similarity to IGlar in PK and PD characteristics following single-dose (0.5 U/kg) administration in healthy Chinese subjects.

Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects

ObjectivesPolymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects. MethodsAn open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics. ResultsOne female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ± 1.1% and 8.1 ± 1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively. ConclusionsThis study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B.

Safety and pharmacokinetics of a biosimilar of denosumab (KN012): Phase 1 and bioequivalence study in healthy Chinese subjects

ABSTRACT Background KN012 is a proposed biosimilar candidate for the reference drug denosumab, with the brand name Prolia®. This study explored the tolerance, variability, and pharmacokinetics (PK) of denosumab and its biosimilar in healthy Chinese subjects. Research design and methods A randomized, double-blind, parallel, two-arm study was performed to analyze the bioequivalence of denosumab biosimilar (60 mg) compared with denosumab. Results The PK properties of denosumab biosimilar were similar to those of denosumab. When denosumab biosimilar was compared to denosumab, the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ were 98.74%, 102.54%, and 102.18%, respectively, and the 90% confidence interval was observed to be within 80–125%. The inter-subject variability ranged from 31.4% to 34.6%. Five subjects in the denosumab biosimilar group and one subject in the denosumab group were positive for anti-drug antibodies (ADAs) and negative for neutralizing antibodies (NAbs). Adverse reactions were observed in 100% (52 subjects) and 94.0% (47 subjects) of the subjects in the denosumab biosimilar and denosumab groups, respectively. Reductions in the blood calcium and phosphate levels were the most common adverse reactions. Conclusion The PK characteristics were comparable for the denosumab biosimilar and denosumab groups. Their safety profiles were also similar. Trial Registration : The trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html #CTR20181231).

A simplified and sensitive LC-APCI-MS/MS method for the quantification of propofol: Application to a bioequivalence study in healthy Chinese subjects

Propofol has become the preferred anesthetic in recent years due to its desirable pharmacologic properties. However, propofol possesses a very narrow therapeutic window between the favorable clinical effect and potentially lethal toxicity, therefore, a rapid, simplified, and sensitive liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) method is presented in this study for the quantification of propofol in human plasma using the isotope-labeled internal standard (IS) of propofol-d17, and then applied in a bioequivalence study. Sample preparation was accomplished through simple one-step precipitation of plasma protein with acetonitrile. Chromatographic separation was acquired on an ACE Excel 3 Super C18 column (2.1 × 50 mm, 3µm) using gradient elution at a flow rate of 0.5mL/min. The MS detection was achieved in the negative ion APCI by multiple reaction monitoring (MRM) mode using the transitions of m/z 177.2 → 161.0 for propofol and m/z 194.2 → 174.2 for IS, respectively. 30 healthy Chinese subjects were enrolled in the open-label, randomized, two-period, two-sequence, cross-over bioequivalence study after single-dose intravenous administration of propofol medium-chain triglyceride and long-chain triglyceride (MCT/LCT). The current method was precise and accurate at a linearity range of 4.00-1,000ng/mL without severe interference from the plasma matrix. The inter- and intra-batch precision (2.3 to 15.8%) and accuracy (-4.4 to 3.0%), IS-normalized matrix effect (coefficient of variation ≤4.6%), extraction recovery (107.1-117.1%), stability (coefficient of variation ≤8.0%), and dilution integrity were all within the acceptable range. The 90% confidence intervals (CIs) of the ratios of the geometric means (test/reference) were 86.44-104.88% for Cmax, 96.30-104.52% for AUC0-t, and 96.56-105.05% for AUC0-∞, which were all within the predefined bioequivalence range of 80-125%. Besides, both propofol MCT/LCT preparations were well tolerated in healthy Chinese subjects, and there were no serious adverse events during the study. The method is more simplified and sensitive than the previously reported modes of propofol detection. The two propofol MCT/LCT preparations were considered to be bioequivalent.

Safety, pharmacokinetics and pharmacodynamics of SYN023 alone or in combination with a rabies vaccine: An open, parallel, single dose, phase 1 bridging study in healthy Chinese subjects

BackgroundSYN023, a mixture of two anti-rabies humanized monoclonal antibodies (mAbs), namely, CTB011 and CTB012, has been developed as a safe and cost-effective alternative to RIG in the use of postexposure prophylaxis (PEP) after rabies exposure. MethodsThis phase I bridging study was designed to compare the pharmacokinetics (PK) of SYN023 (0.3 mg/kg) alone (cohort A, n = 8) or in combination with a rabies vaccine (cohort B, n = 24) in healthy Chinese subjects with those in American subjects to guide the design of further clinical trials. Their safety was assessed for the development of adverse events (AEs) by laboratory examinations. The levels of serum CTB011, CTB012 and anti-drug antibodies (ADAs) were measured longitudinally for 85 days. Serum rabies virus neutralizing antibody (RVNA) levels were measured as a pharmacodynamic (PD) surrogate. ResultsSome subjects with injectable SYN023 at 0.3 mg/kg developed temporary AEs and adverse drug reactions (ADRs) of Grade 1 or 2, particularly in cohort B, probably due to vaccine coadministration. SYN023 injection displayed a typical and reliable PK, similar to that of human IgGs. Following injection with SYN023, Chinese subjects had slower absorption with higher exposures for CTB011 but lower exposures for CTB012 than American subjects. The SYN023 recipients achieved protective levels of RVNA (≥0.5 IU/mL) on day 3 post injection. A few subjects developed temporary ADA, which did not affect the safety and PK/PD of SYN023 in Chinese subjects. ConclusionSYN023 at 0.3 mg/kg is relatively saf e and effective and can be selected for further clinical trials in Chinese subjects. The clinical trial registration number is CTR20190281. http://www.chinadrugtrials.org.cn/eap/clinicaltrials.searchlist?a=a®_no=CTR20190281.