Pharmacokinetic and Safety Study of Bismuth Potassium Citrate Formulations in Healthy Subjects

This single-center randomized open double-cycle crossover single oral administration phase I trial was performed in healthy fasting Chinese volunteers. This trial was conducted at the Phase I Clinical Research Center of Changsha Central Hospital Affiliated with South China University. This trial is a comparative study on the pharmacokinetics of a single administration in healthy fasting subjects. This study was approved by the ethics committee of Changsha Central Hospital. All participants provided written informed consent.

According to the Technical Guidelines for Clinical Pharmacokinetic Research of Chemical Drugs issued by the CFDA, the number of subjects in each group should be 8–12. Therefore, this study enrolled 12 subjects. The inclusion criteria were as follows: (1) age ≥ 18 years of age, both male and female, and (2) weight ≥ 50.0 kg, for males, and weight ≥ 45.0 kg, for females, with a body mass index (BMI) of ~ 19.0–26.0 kg/m² (including boundary values).

Drugs, diseases, and physiological factors that may have affected the results of this trial. Therefore, according to the medication manual for bismuth potassium citrate, the exclusion criteria were as follows: (1) patients with any clinically severe diseases, such as circulatory system diseases, endocrine system diseases, nervous system diseases, digestive system diseases, respiratory system diseases, hematological diseases, immunological diseases, psychiatric disorders, metabolic abnormalities, or patients with any other diseases that can interfere with the test results, such as known severe bleeding tendencies or gastric ulcers; (2) patients who were allergic to any component of the investigational drug, food, or other substances; (3) patients who underwent surgery within 4 weeks prior to the trial or who planned to have an operation during the trial period; (4) those who have used any medication or health products (including Chinese herbal medicine) within 14 days before the trial; (5) patients who have used any clinical trial drug or were enrolled in any drug clinical trial within the first 3 months prior to the trial; (6) patients who donated or lost blood more than 400 mL of blood within 3 months before the trial; (7) patients who were unable to take one or more non-pharmacological contraceptive measures during the trial period or women during pregnancy or lactation; (8) those who have special dietary requirements and cannot follow a unified diet; (9) drinking excessive amounts of tea, coffee, or caffeinated beverages (over 2000 mL) every day for the first 3 months prior to the trial; (10) patients who had consumed or planned to consume any food or drink containing caffeine (such as coffee, strong tea, or chocolate) or substances rich in xanthine (such as sardine or beef liver) within 48 h before taking the study drug for the first time; (11) patients who smoked more than five cigarettes per day in the 3 months prior to the trial; (12) alcoholics or those who frequently drank alcohol within the 6 months prior to the trial, that is, those who drank more than 5040 mL of beer or 630 mL of 40% alcohol or 2100 mL of wine per week; (13) patients who were drug abusers or had used marijuana drugs within 3 months prior to the trial, or who had taken drugs such as cocaine and phencyclidine within 1 year prior to the trial; (14) patients who had irregular bowel movements within the week before the trial; (15) subjects with clinically significant abnormalities in vital signs, such as blood pressure and pulse or physical examination, electrocardiogram, laboratory examination, alcohol testing, or drug abuse screening; and (16) subjects who may not be able to complete this trial for other reasons or because the researchers believe that they should not be included.

The test (T) formulation was produced by Hunan Warrant Pharmaceutical Co., Ltd., and the reference (R) formulation was produced by Astellas Pharma Ltd. The doses were all 120 mg. On the morning of the trial day, a single oral administration of the T or R formulation was administered with 240 mL of water; drinking water was prohibited before and within 1 h after administration, and standard meals were consumed 4 or 10 h after administration.

The blood drug concentration data were estimated and analyzed using Phoenix WinNonlin 7.0 software for non-compartmental analysis of pharmacokinetic parameters, and the main pharmacokinetic parameters were calculated to comprehensively reflect the characteristics of drug absorption, distribution, metabolism, and excretion in the bodies of the healthy subjects. The main pharmacokinetic parameters included time taken to reach C_max (T_max), C_max, area under the concentration–time curve (AUC)_0–t, AUC_0–∞, and λ_z. For the pharmacokinetic parameters (C_max, AUC_0–t, and AUC_0–∞), a mixed linear model was used for multivariate analysis of variance after logarithmic conversion of the data; furthermore, a t-test was used to analyze differences between the two formulations. Based on the research objectives and noninferiority testing methods, the following pharmacokinetic evaluation criteria were used: if the upper limit of the one-sided 95% confidence interval (CI) of the least squares geometric mean ratio (test formulation/reference formulation) of each pharmacokinetic parameter (C_max, AUC_0–t, and AUC_0–∞) is less than e[0.15*In(μ)] (μ_R is the point estimate of the least squares geometric mean of the R formulation), then the concentration of bismuth in the human blood of the T formulation was not greater than that of the R formulation, and the safety of the T formulation was considered to meet the requirements. The bioanalytical methods and methodological validation results for bismuth potassium citrate are listed in Supplementary Material 1 and Table S1.

Vital signs were measured during the check-in, before administration (0 h), and at 1, 2, 4, 6, 8, 12, 24, and 36 h after administration. During the screening period and group physical examination laboratory test indicators, including routine blood, routine urine, liver and kidney function, blood glucose, blood lipids, serum electrolytes, coagulation function, blood transfusion, and blood pregnancy indices, were also evaluated. All adverse events were recorded during the trial. Throughout the entire research process, the severity of adverse events and reactions was evaluated in relation to the investigational drug.

A total of 65 subjects were screened via the fasting test, and 12 subjects ultimately completed two cycles of the experiment. The mean age of the 12 participants was 25 ± 5 years old, with a mean weight of 60.0 ± 8.2 kg, a mean height of 165.0 ± 7.0 cm, and a mean body mass index of 22.0 ± 2.2 kg/m². The demographic information of the subjects is shown in Table 1.

Pharmacokinetic evaluations were also conducted on 12 subjects. The average concentration–time curves of the T and R formulations under fasting conditions were similar (Fig. 1). The main pharmacokinetic parameters of the T formulation treatment were as follows: C_max = 25.6 ± 29.4 ng/mL, AUC_0–t = 96.3 ± 123.8 h·ng/mL, and AUC_0–∞ = 117.8 ± 136.2 h·ng/mL. The C_max, AUC_0–t, and AUC_0–∞ of the R formulation were 46.6 ± 39.6 ng/mL, 137.8 ± 121.3 h·ng/mL, and 147.6 ± 126.9 h·ng/mL, respectively (Table 2). The mean plasma concentration–time curve of a single dose of bismuth potassium citrate is shown in Fig. 1. There was no significant difference in the C_max, AUC_0–t, or AUC_0–∞ between the T and R formulations. The upper limits values of the one-sided 97.5% confidence intervals for the least squares geometric mean ratios of C_max, AUC_0–t, and AUC_0–∞ of the T and R formulations were lower than the noninferiority margin values, respectively (Table 3). The results indicate that the concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation, and, thus, the safety of the T formulation met the established requirements. Moreover, analysis of variance (ANOVA) was used to analyze the pharmacokinetic (PK) parameters, as shown in Table S2. The results showed that the administration sequence factor was related to the pharmacokinetic parameters.

In this clinical trial, four adverse events occurred in two patients after treatment with the T formulation, yielding an incidence rate of 16.7%. One subject developed hypertriglyceridemia, and one subject experienced three adverse events, namely, an elevated white blood cell (WBC) count, an elevated monocyte count, and an elevated lymphocyte count. The severity of adverse events was level 1 for all patients. No adverse reactions occurred. Among the subjects treated with the R formulation, three subjects experienced a total of four adverse events, yielding an incidence rate of 25.0%. One subject suffered from hyperuricemia, one subject suffered from ST segment elevation, and one subject suffered from hypoglycemia and hyperuricemia The severity of adverse events was level 1 for all patients. Two patients experienced a total of two adverse reactions, yielding an incidence rate of 16.7%. The severity of adverse reactions was level 1 for all patients. No serious adverse events occurred in any of the subjects (Table 4).