Bioequivalence and Safety Assessment of 2 Formulations of Low-Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial.

The incidence of type 2 diabetes is high, and the existing metformin hydrochloride (MH) tablets of 250 mg cannot meet the demands of the Chinese drug market. This study aimed to evaluate the bioequivalence and safety of generic formulations of MH tablets (test formulation [T], 250 mg/tablet) and innovative products (reference formulation [R], 250 mg/tablet) under fasting conditions. This was an open-label, single-dose, 2-period, 2-sequence crossover, single-center, randomized phase I clinical trial. T and R were considered bioequivalent if the adjusted geometric mean ratios (GMRs) and 90% confidence intervals of the area under the curve (AUC) and maximum concentration (Cmax ) were within the range of 0.8-1.25. Thirty-five participants completed the trial. The T/R adjusted GMRs (95.7% for Cmax , 98.7% for AUC0→t , 98.8% for AUC0→∞ ) were within the acceptable bioequivalence range of 80%-125%. No serious adverse events or suspected or unexpected serious adverse reactions occurred during this trial. The study findings confirmed that generic MH is a well-tolerated and bioequivalent alternative to innovative products under fasting conditions in healthy Chinese participants. (www.chinadrugtrials.org.cn; registration no. CTR20190356).

Pharmacokinetics and Bioequivalence of Single-Oral-Dose Linagliptin: A Randomized, 2-Period Crossover Trial in Chinese Healthy Subjects Under Fasting and Fed Conditions.

The bioequivalence of the reference and test linagliptin formulations was assessed in healthy Chinese subjects under fasting and fed conditions. The study was designed as a single-dose, randomized, open-label, 2-period crossover study with a 35-day washout period between 2 administrations. Forty-eight healthy subjects received 5 mg of test and reference linagliptin formulation orally under fasting condition. The geometric mean of the maximum observed linagliptin concentration (Cmax ) for the test formulation was 4.9 ng/mL (reference, 5.0 ng/mL), the area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 ) was 154.7 ng · h/mL (reference, 157.4 ng · h/mL). Thirty-six subjects received 5 mg of test and reference linagliptin formulation orally under fed conditions. The geometric mean of Cmax for the test linagliptin formulation was 2.8 ng/mL (reference, 2.8 ng/mL), AUC0-72 was 133.5 ng · h/mL (reference, 136.6 ng · h/mL). The 90%CIs for the test/reference ratio for Cmax and AUC0-72 met the bioequivalence criteria (80%-125%). The test and reference formulations of linagliptin were well tolerated and bioequivalent under fasting and fed conditions.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a Monoclonal Antibody (SCTA01) Targeting SARS-CoV-2 in Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, Phase I Study.

SCTA01 is a novel monoclonal antibody with promising prophylactic and therapeutic potential for COVID-19. This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of SCTA01 in healthy adults. This was a randomized, double-blind, placebo-controlled, dose escalation phase I clinical trial. Healthy adults were randomly assigned to cohort 1 (n = 5; 3:2), cohort 2 (n = 8; 6:2), cohort 3, or cohort 4 (both n = 10; 8:2) to receive SCTA01 (5, 15, 30, and 50 mg/kg, respectively) versus placebo. All participants were followed up for clinical, laboratory, PK, and immunogenicity assessments for 84 days. The primary outcomes were the dose-limiting toxicity (DLT) and maximal tolerable dose (MTD), and the secondary outcomes included PK parameters, immunogenicity, and adverse events (AE). Of the 33 participants, 18 experienced treatment-related AEs; the frequency was 52.0% (13/25) in participants receiving SCTA01 and 62.5% (5/8) in those receiving placebo. All AEs were mild. There was no serious AE or death. No DLT was reported, and the MTD of SCTA01 was not reached. SCTA01 with a dose range of 5 to 50 mg/kg had nearly linear dose-proportional increases in Cmax and AUC parameters. An antidrug antibody response was detected in four (16.0%) participants receiving SCTA01, with low titers, between the baseline and day 28, but all became negative later. In conclusion, SCTA01 up to 50 mg/kg was safe and well-tolerated in healthy participants. Its PK parameters were nearly linear dose-proportional. (This study has been registered at ClinicalTrials.gov under identifier NCT04483375.).

Pharmacokinetic bioequivalence and safety assessment of two metformin hydrochloride tablet formulations using a phase I, randomized, open, two-period, two cross-over, single-dose, fed study in healthy Chinese adult subjects.

OBJECTIVES: To assess the bioequivalence and safety of generic metformin hydrochloride (test preparation) and glucophage (reference preparation) in healthy Chinese subjects. MATERIALS AND METHODS: A bioequivalence and safety assessment of two formulations of metformin (850 mg) using a randomized, open, two-period, two cross-over, single-dose, fed trial in 36 healthy Chinese adult subjects was performed at our center from March 22, 2018, to April 9, 2018. Bioequivalence was determined as two-sided 90% confidence intervals (CI) of the test-to-reference ratio of area under the curve (AUC) and peak concentration (Cmax) for each constituent within 80.00 - 125.00%. SAS 9.4 software was employed for the statistical analysis. RESULTS: One subject was excluded from the trial. The 90% CIs (95.36 - 101.43% for AUC0→t, 95.65 - 101.66% for AUC0→∞; 94.43 - 101.74% for Cmax) of test/reference preparation for these pharmacokinetic parameters were within the range of 80.00 - 125.00%. No severe adverse events were observed during this trial. The two preparations were safe and well-tolerated. CONCLUSION: It was concluded that generic metformin was bioequivalent and as safe as glucophage under fed conditions in healthy Chinese subjects.

A Phase I, Randomized, Single-Dose Study Evaluating the Biosimilarity of TAB008 to Bevacizumab in Healthy Volunteers.

Objective: This study compared the pharmacokinetics (PK), safety, and immunogenicity of the biosimilar TAB008 monoclonal antibody to bevacizumab (Avastin®) in normal healthy Chinese male volunteers. Methods: In this randomized, double-blind, parallel controlled study, a total of 100 healthy Chinese male subjects were randomized (1:1) to receive a single 1 mg/kg intravenous dose of TAB008 or Avastin® over a 90-min infusion. The subjects were followed for 99 days after drug administration. Primary endpoints were bioequivalence of major pharmacokinetic parameters (AUC0-t and AUC0-∞) and maximum observed serum concentration (Cmax). Secondary endpoints included safety and immunogenicity parameters. Results: The two groups of test subjects (49 subjects in the TAB008 group and 50 subjects in the Avastin® group) were well matched in regards to all demographic and baseline characteristics. The treatment group ratios of LS geometric means for the three primary PK parameters were fully contained within the bioequivalence limits of 80.00-125.00% (90% CI was 103.66-118.33% for Cmax, 94.32-111.72% for AUC0-t, and 94.69-112.23% for AUC0-∞). Treatment-emergent adverse events (TEAEs) were reported for 24 (49.0%) subjects in the TAB008 group and 22 (44.0%) subjects in the Avastin® group. TEAEs related to the study drug were reported for 19 (38.8%) subjects in the TAB008 group and 19 (38.0%) subjects in the Avastin® group. National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 3 TEAEs were reported for 1 (2.0%) subject in the TAB008 group and 3 (6.0%) subjects in the Avastin® group. There were no Grade 4 or 5 TEAEs or serious adverse events (SAEs) during the study. Anti-drug antibody generation was reported once only in each group, and neutralizing antibody (Nab) analysis was negative upon follow-up. Conclusion: TAB008 attained pharmacokinetic similarity to bevacizumab, and was safe and well tolerated.