LZM008, a proposed tocilizumab biosimilar: Pharmacokinetics, safety, and immunogenicity profiles compared with ACTEMRA® in Chinese healthy male subjects.

Background: This study aimed to investigate the pharmacokinetics, safety, and immunogenicity of recombinant humanized anti-human IL-6R monoclonal antibody injection, LZM008, and evaluate the pharmacokinetic similarity between LZM008 and tocilizumab (ACTEMRA®) in Chinese healthy male subjects. Research design and methods: In this randomized, double-blinded, paralleled, two-center Phase I clinical trial, 96 subjects were randomized with a 1:1 ratio to receive 4 mg/kg intravenous dose of LZM008 or ACTEMRA® and evaluated for 28 days. The pharmacokinetic bioequivalence was assessed by the maximum serum concentration (Cmax), the area under the serum concentration-time curve (AUC) from time 0 to the last detectable drug concentration (AUC0-t), and AUC0-∞. The statistical analysis was conducted using SAS Enterprise Guide statistical software. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Anti-drug antibodies (ADAs) were measured by a bridged electrochemiluminescence immunoassay. Results: LZM008 (N = 49) and ACTEMRA® (N = 47) groups showed similar pharmacokinetic properties. After a single intravenous infusion of 4 mg/kg LZM008, the Cmax and AUC0-∞ values of LZM008 reached 87.99 µg/mL and 11,526.70 h*µg/mL, respectively, with Tmax 1.98 h, and the half-life (t1/2) was 83.45 h. The 90% confidence intervals of ratios for Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00%-125.00%. After infusion, one (2.0%) subject in the LZM008 group and three (6.4%) subjects in the ACTEMRA® group showed positive ADA test results. The incidence of treatment emergent adverse events (TEAEs) was comparable in LZM008 and ACTEMRA® groups (98.0% versus 100%), with the decrease in blood fibrinogen and neutrophil counts being the most common TEAEs. Conclusion: The pharmacokinetic characteristics and immunogenicity exhibited by LZM008 were similar to those of the reference product, ACTEMRA®. The safety profiles of LZM008 were similar in the two groups with mild-moderate adverse effects. Trial Registration: The trial is registered at www.chinadrugtrials.org.cn (CTR20190889).

Bioequivalence Study of Palbociclib Capsules in Healthy Chinese Subjects Under Fasting and Fed Conditions.

BACKGROUND AND OBJECTIVE: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinase 4/6 used for the treatment of advanced breast cancer. This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of palbociclib capsules in healthy Chinese subjects under fasting and fed conditions and evaluated the bioequivalence of two palbociclib products to obtain sufficient evidence for the marketing approval of the new generic drug. METHODS: A randomized, open-label, two-period crossover study was conducted in healthy Chinese volunteers under both fasting and fed conditions (30 subjects/condition). Eligible healthy subjects received a single 125-mg dose of the palbociclib test or reference formulation followed by a 14-day washout period. Serial blood samples were collected at scheduled timepoints, and plasma concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. A non-compartment method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUC0-t), the AUC from time 0 to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to maximum plasma concentration, and the elimination half-life. The geometric mean ratios and the corresponding 90% confidence intervals of palbociclib were acquired for the bioequivalence analysis. Safety and tolerability were assessed by monitoring adverse events, laboratory assessments, vital signs, physical examinations, and 12-lead electrocardiograms. RESULTS: Under the fasting condition, the pharmacokinetic parameter values of the test formulation were similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 94.35-103.82% for Cmax, 94.79-103.26% for AUC0-t, and 94.82-103.38% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. Meanwhile, under the fed condition, the pharmacokinetic parameter values of the test formulation were also similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 96.65-103.56% for Cmax, 98.06-103.61% for AUC0-t, and 97.88-103.46% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. The test and reference products were well tolerated, and no serious adverse events occurred during the study. CONCLUSIONS: Pharmacokinetic bioequivalence of palbociclib in healthy subjects was established between the palbociclib test formulation and the reference formulation under fasting and fed conditions according to predetermined regulatory criteria. The two formulations were safe and well tolerated.

Safety, tolerability and pharmacokinetics of WXFL10203614 in healthy Chinese subjects: A randomized, double-blind, placebo-controlled phase â study.

Objective: This study was conducted to investigate the safety, tolerability and pharmacokinetics (PK) of WXFL10203614 after single and multiple oral doses in healthy Chinese subjects. Methods: A single-center, randomized, double-blind, placebo-controlled phase Ⅰ study was performed on healthy Chinese subjects. In the single-dose study, Subjects were randomized into 7 dose levels of WXFL10203614 (1 mg group, n = 2; 2, 5, 10, 17, 25 and 33 mg groups with placebo, 8 subjects per group, 2 of them given placebo). In the multiple-dose study, subjects received 5 or 10 mg WXFL10203614 once daily (QD), 5 mg twice daily (BID) or placebo for 7 consecutive days. Safety, tolerability and PK of WXFL10203614 were all assessed. Results: A total of 592 subjects were screened, 50 subjects were enrolled in the single-dose study and 30 in the multiple-dose study. All adverse events (AEs) were mild or moderate and resolved spontaneously. No Serious Adverse Events (SAEs) or deaths were reported during the study. WXFL10203614 was absorbed rapidly after dosing with Tmax of 0.48-0.98 h, Cmax, AUC0-t and AUC0-∞ were all increased in a dose-related manner over the range of 1-33 mg. Renal excretion was the major route of elimination of WXFL10203614. Steady-state PK parameters (Cmax,ss, AUC0-t,ss and AUC0-∞,ss) were elevated after once-daily administration of 5-10 mg WXFL10203614 and non- and weak drug accumulations were observed, whereas moderate drug accumulation occurred in the 5 mg BID group. Conclusion: WXFL10203614 exhibited good safety, tolerability and favorable PK profiles in healthy Chinese subjects, supporting further clinical development in patients with rheumatoid arthritis. Clinical Trials Registration Number: http://www.chinadrugtrials.org.cn/index.html, #CTR20190069 and CTR20200143.

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects.

Objective: This study was performed to investigate the effect of food on the pharmacokinetics (PK) of WXFL10203614 in healthy Chinese subjects. Methods: This was a randomized, open-label, single-dose, two-treatment (fed vs fasted), two-period, two-sequence, crossover study. 14 eligible subjects were averagely randomized into 2 sequences and then received 10 mg WXFL10203614 under fasted or fed condition. In each period, the blood samples were collected from 0 h (pre-dose) and serially up to 72 h post-dose, and plasma concentrations were detected using the high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The effect of food on the PK profile and safety of WXFL10203614 were assessed. Results: 70 subjects were screened, and 14 subjects (10 male and 4 female) were enrolled and completed the study. Under the fasted condition, WXFL10203614 was absorbed rapidly with a Tmax of 0.98 h. The absorption rate was slower, Tmax delayed by 2.98 h, and the Cmax decreased by 16.3% when WXFL10203614 administered after the high-fat and high-calorie diet, other PK parameters were not affected. The 90% confidence intervals (CIs) for the ratio (fed/fasted) of geometric means of the Cmax, AUC0-t and AUC0-∞ were 0.73-1.01, 0.90-1.03 and 0.90-1.03, indicating that the high-fat and high-calorie diet might impact the absorption process of WXFL10203614. Although the Cmax was slightly decreased, there was no significant difference in the Cmax under fasted and fed conditions. Thus, it was not considered clinically significant owing to the small magnitude of changes in Cmax. All Treatment-emergent adverse events (TEAEs) were mild and resolved spontaneously without treatment. Conclusion: Food had no clinically relevant effects on drug system exposure of WXFL10203614. It was well tolerated under fasted and fed conditions in healthy Chinese subjects, so WXFL10203614 could be administered orally with or without food. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20191636.

Safety, Tolerability, and Pharmacokinetic Study of 101BHG-D01 Nasal Spray, a Novel Long-Acting and Selective Cholinergic M Receptor Antagonist, in Healthy Chinese Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation, First-In-Human Study.

BACKGROUND AND OBJECTIVE: 101BHG-D01 nasal spray is the first novel long-acting cholinergic M receptor antagonist under development to treat rhinorrhea in rhinitis. This first-in-human study aimed to evaluate the safety, tolerability, and pharmacokinetics of 101BHG-D01 nasal spray following single intranasal doses in healthy Chinese subjects. METHODS: A randomized, double-blind, placebo-controlled, single-dose escalation study was conducted in healthy Chinese volunteers after intranasal doses of 101BHG-D01 nasal spray or placebo ranging from 40 µg to 960 µg (total of six doses). Blood samples were collected at scheduled time points, and plasma concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. A non-compartmental method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t), the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to maximum plasma concentration (Tmax), and the elimination half-life (t1/2). Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), anterior rhinoscopy, ophthalmic examination, and ambulatory ECG monitoring. RESULTS: Following single intranasal dosing, 101BHG-D01 was rapidly absorbed with a median Tmax of 0.34-0.50 h and eliminated slowly with a mean t1/2 ranging from 4.29 to 46.76 h for different dose groups. The Cmax and AUC of 101BHG-D01 increased linearly across the examined dose range of 40-960 µg. 101BHG-D01 nasal spray was well tolerated, all AEs were mild, and no serious adverse events occurred during the study. CONCLUSIONS: 101BHG-D01 nasal spray was safe and well tolerated in healthy Chinese subjects when administered intranasally in single escalating doses. The mean Cmax and AUC increased proportionally to the studied dose. The pharmacokinetic, safety, and tolerability profiles of 101BHG-D01 nasal spray indicate that it is a good candidate for further development as a treatment for rhinorrhea in rhinitis.

A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects.

Objective: This study was conducted to compare the pharmacokinetics, safety and immunogenicity of HOT-1010 with bevacizumab (Avastin®) in Chinese healthy male subjects. Methods: A single-center, randomized, double-blind, single-dose, parallel trial was performed in 84 Chinese healthy male subjects who randomly (1:1) received a single intravenous infusion of 1 mg/kg HOT-1010 or Avastin® for 90 min and followed up for 85 days. Serum concentrations of bevacizumab were analyzed by enzyme-linked immunosorbent assay. Primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞, were calculated and evaluated the bioequivalence between HOT-1010 and Avastin®, the safety and immunogenicity of investigational drugs were also assessed. Results: A total of 82 subjects completed the study. The 90% Confidence Intervals for geometric mean ratios of Cmax, AUC0-t and AUC0-∞ were 91.81-103.64%, 85.19-95.39% and 85.04-95.36%, which were all within the bioequivalence margin. Treatment-emergent adverse events were reported in 27 (65.9%) subjects in HOT-1010 group and 23 (56.1%) subjects in Avastin® group. Most TEAEs were mild or moderate. No TEAEs, Serious Adverse Events or deaths leading to discontinuation was reported. Subjects were all tested negative for Anti-drug Antibody. Conclusion: HOT-1010 exhibited the similar pharmacokinetics, safety and immunogenicity profiles of bevacizumab (Avastin®) in Chinese healthy male subjects. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, CTR20181610.