Bioequivalence of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial

doi:10.21203/rs.3.rs-4954921/v1

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Bioequivalence of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial

https://doi.org/10.21203/rs.3.rs-4954921/v1

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Cefdinir is a broad-spectrum antibiotic with good antibacterial activity against gram-positive and gram-negative bacteria, and can be used for the treatment of various sensitive bacterial infections, such as community-acquired pneumonia, urinary tract infection and gonorrhea. Herein, a single-centred, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial with a 7-day washout was conducted to investigate the pharmacokinetics, bioequivalence and safety of cefdinir dispersible tablets and the reference formulation of cefdinir capsules in healthy Chinese volunteers. Fifty-six healthy subjects were recruited and randomly assigned to the fasting and fed groups. After a single oral dose of the test or reference formulation (0.1 g), the cefdinir concentrations in the plasma were determined via HPLC-MS/MS, and pharmacokinetic parameters were obtained from the concentration‒time profiles. Overall, 24 and 31 individuals completed the evaluation under fasting and fed conditions, respectively. The mean concentration‒time profiles for both formulations were similar, and the C_max, AUC_0–t and AUC_0–∞ values were entirely within the bioequivalence range of 80.00–125.00%. 3 subjects reported 5 AEs and 8 subjects experienced 13 AEs in the fasting and fed group, respectively, but no participants withdrew from the trial because of AEs. All adverse reactions were grade I in severity, and no serious AEs or deaths occurred. The results demonstrated that these formulations were bioequivalent in healthy Chinese subjects under fasting and fed conditions, supporting the further clinical development of cefdinir dispersible tablets. This trial was registered in the China Drug Trials Registry (registration number: CTR20210441; registration date: March 11, 2021).

bioequivalence

healthy Chinese volunteers

cefdinir dispersible tablets

pharmacokinetics

safety

Cefdinir (6R-[6a,7(Z)]-7)[[(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; FK482, BMY-28488. CI983, or PD134393) is an oral, extended-spectrum third-generation cephem antibiotic. Initially synthesized in 1988, cefdinir received approval from the United States Food and Drug Administration in 1997, specifically for the management of community-acquired infections(Chen et al., 2006). This pharmacological agent exhibits a broad range of activities against numerous pathogens, making it a significant option in the antimicrobial therapy arsenal(Guay, 2000).

Cefdinir, which is structurally and functionally analogous to the orally administered cephalosporin cefixime, has enhanced in vitro antimicrobial efficacy against methicillin-sensitive Staphylococcus aureus and Staphylococcus epidermidis. It also exhibits potent activity against various strains of Streptococcus spp. and Neisseria spp. Such enhanced activity can be attributed to the presence of an oximino side chain at the 7-position, which is a substitute for the carboxymethoxyimino group commonly found in most orally active cephalosporins. This structural modification results in steric hindrance that impedes the entry of the molecule into the active site of the TEM-1 β-lactamase, thereby increasing its resistance to enzymatic degradation(J. Li et al., 2012).

Cefdinir administration does not require consideration of food intake in drug instructions. The pharmacokinetic (PK) assessment following a single dose of 100 mg of cefdinir revealed several key parameters: the maximum plasma concentration (C_max) was 0.7 ± 0.19 µg/mL, the time to reach the maximum concentration (T_max) was 4.3 ± 0.5 h, the half-life (T_1/2) was 1.48 ± 0.12 h, and the area under the curve (AUC) from time zero to infinity (AUC_0−∞) was 4.04 ± 0.72 µg·h/mL. Moreover, healthy subjects demonstrated a renal clearance rate of 89.2 ± 6.0 mL/min. Furthermore, approximately 30.8 ± 8.2% of the administered dose was excreted unchanged in the urine within the first 24 h. These PK properties underscore the efficiency of renal excretion and drug bioavailability postadministration(Chen et al., 2006).

The bioavailability of cefdinir has been estimated to be 21% for the 300 mg capsules and 16% for the 600 mg capsules. The absolute bioavailability of the suspension formulation is approximately 25%. PK studies have revealed that both the rate and extent of cefdinir absorption decrease when the drug is administered with a high-fat meal(Perry & Scott, 2004). The susceptibility of an organism to a specific dosing regimen of an agent can be determined as the highest minimum inhibitory concentration (MIC) for bacteriologic efficacy for that agent(Jacobs, 2003). Notably, PK and bioequivalence (BE) studies of cefdinir dispersible tablets in healthy Chinese volunteers are lacking to date, indicating a gap in the literature and a potential area for future research(Su H, & Guo RC, 2022).

In this study, we aimed to evaluate the BE and safety of the generic drug cefdinir dispersible tablets and the branded drug cefdinir capsules (0.1 g) in healthy Chinese volunteers under fasting and fed conditions.

Product Source

The test generic drug (T) of cefdinir dispersible tablets (specification: 0.1 g; batch number: 20093003; period of validity: September 11, 2020 to September 11, 2023) was produced by Guangdong BoZhou Pharmaceutical Co. Ltd. The branded drug of cefdinir capsules by Choseido Pharmaceutical Co., Ltd., Kawauchi Factory (trade name: Cefzon) (specification: 0.1 g; batch number: 1940C01, period of validity: October 21, 2019 to September 2021) was used as the reference product (R).

Participants

The primary inclusion and exclusion criteria for the study are detailed in the Supplementary Data Content (SDC) ¹. Vital sign measurements, including blood pressure, pulse, and temperature, along with inquiries regarding adverse events (AEs), were conducted at each cycle, specifically 0 h before dosing (within 1 h prior to administration) and at 1 ± 0.5 h, 4 ± 0.5 h, 10 ± 0.5 h, and 16 ± 1.0 h after dosing. On day 9 of the study, the participants underwent a 12-lead electrocardiogram (ECG) and comprehensive laboratory tests. All individuals participating in the study signed informed consent forms.

Study Design

This study was a single-centre, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial. Fasting and fed assessments were conducted in 56 cases. The participants were individually screened for each group and admitted to the hospital the day prior to drug administration, at which point they were randomly assigned to either the TR sequence or the RT sequence. Those in the TR group received the test drug during the first period and the reference drug during the second period, whereas those in the RT group received the drugs in the reverse order. The two study periods were interspersed with a 7-day washout period to clear any residual effects of the drugs before their subsequent administration. Randomization was performed with SAS software (version 9.4), which employs a 1:1 randomized block scheme to ensure equal distribution and reduce potential bias across treatment groups.

All the participants fasted for at least 10 h. In the fasting arm, the participants received a single T or R drugs orally (0.1 g) with 240 mL of water. In the fed arm, participants consumed a standard high-fat breakfast of 800–1000 calories 30 min before each drug administration and followed the same schedule in subsequent periods. All the subjects were not allowed to drink water for 1 h before or after medication administration, and they fasted for 4 h after taking the medication. To minimize carryover effects between periods, there was a 7-day washout period. During the hospital-based study, participants were prohibited from engaging in rigorous exercise and were continuously monitored by experienced healthcare professionals. In accordance with the study protocol, researchers administered a standard lunch and dinner to participants in both groups following drug administration, ensuring consistency in dietary intake across the study population.

The study was conducted according to Good Clinical Practice, the guidelines of the International Conference on Harmonization, and all applicable regulatory requirements.

Blood Sampling

A series of blood samples (4 mL) were collected at different time points: predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, and 16 h after each administration. EDTA-K2 was used as an anticoagulant. The vacuum blood collection tubes containing the blood samples were gently inverted 7–8 times, mixed well, and stored temporarily at 20–30°C.

Bioanalytical Assay

After the addition of the internal standard (IS) cefdinir 15N2, 13C, the plasma concentrations of the test and reference products were quantified via protein precipitation and high performance liquid chromatography–tandem mass spectrometry (HPLC‒MS/MS).

The blood samples were centrifuged at 1700 × g for 10 min at 4°C (1–9°C). The supernatant was then separated into 2 parts for drug monitoring and reserve. Before the plasma samples were transferred to the refrigerator, they were placed at 1°C to 9°C (wet ice, ice‒water mixture). The centrifuged plasma samples were placed in a sample cryobox within 2 h after blood collection and stored at -10°C to -30°C or below until sample transportation. Bioanalysis was performed via a Shimadzu high-performance liquid chromatography (HPLC) 30-AD system linked to an API 6500 + Applied Biosystems Tandem quadrupole mass spectrometer. Chromatographic separation was conducted on an ACE Excel 3 C18 column (50 × 2.1 mm). Formic acid (0.4%) (phase A) and methyl formic acid (0.4%): acetonitrile formate (0.4%) (1:2) (phase B) were used as the mobile phases. Gradient elution was performed for chromatographic separation at a flow rate of 0.5 mL/min as follows: 0.00–0.49 mi (5% B), 2.40–2.99 min (100% B), and 3.00–3.99 min (5% B). Cefdinir 15N2, 13C was used as the IS. The mode of ionization was positive electrospray ((+) ES), the mode of scanning was multiple reaction monitoring (MRM), and the time of acquisition was 4 min. The MRM transitions of cefdinir and the IS were m/z 396.1→227.0 and m/z 399.0→230.1, respectively. The linearity was in the range of 10.0–5000 ng/mL. The intra- and interbatch precision values for cefdinir were < 7.02%. The IS-normalized recovery was 88.60%.

Sample Preparation

For the plasma samples, 50 µL of plasma was added to 20 µL of IS and extracted with 500 µL of methanol. The samples were subsequently centrifuged at 4°C for 5 min at 3200 × g. Finally, the supernatant (200 µL) was injected onto the HPLC–MS system for analysis.

PK Analysis

In this investigation, the PK parameters of cefdinir, such as the area under the plasma concentration‒time curve from time 0 to the last quantifiable concentration (AUC_0–t) and AUC_0∞, C_max, T_max, and elimination T_1/2, were quantified. Moreover, the within-subject variability for both the reference and test formulations of the drug was evaluated. These parameters were calculated via the noncompartmental analysis method in Phoenix WinNonlin software, version 8.1. AUC calculations were conducted employing the linear trapezoidal interpolation technique. For statistical analysis and descriptive statistics, SAS software version 9.4 (SAS Institute) was utilized.

BE Assessment

On the basis of the BE set, analysis of variance was performed after the logarithmic transformation of C_max, AUC_0–t and AUC_0–∞ to assess the sequence. If the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) (T/R) for C_max, AUC_0–t and AUC_0–∞ were within 80–125% of the statistical interval, the 2 drugs were considered bioequivalent. Data processing and statistical analyses were performed with SAS version 9.4.

Safety Assessment

During the study, safety and tolerability were assessed on the basis of AEs, physical examinations, vital signs, 12-lead ECGs, and clinical laboratory tests. The causal relationships between AEs and investigational products were assessed. The monitored vital signs included blood pressure, pulse, and temperature. In addition, clinical laboratory tests, including haematology, biochemistry, coagulation, urinalysis, and pregnancy tests, were performed to evaluate the safety of the interventions in the participants.

Study Population

Of the 140 subjects who were screened, 84 experienced screen failure. Thirty-two subjects were included in the fed study, and 24 subjects were included in the fasting study; overall, 54 participants completed the whole study, shown in Fig. 1. The demographic characteristics of the TRTR and RTRT sequences for each condition were comparable. The detailed demographic characteristics of the enrolled subjects are shown in Table 1. The demographic characteristics of the participants in each group are shown in Table S1.

Table 1

Demographic characteristics of the enrolled subjects
Characteristic	Fasting (N = 24)	Fed (N = 32)
Male	22 (91.70%)	23 (71.90%)
Female	2 (8.30%)	9 (28.10%)
Age (years)	28.8 (± 5.47)	29.0 (± 5.67)
Height (cm)	168.33 (± 6.95)	165.33 (± 7.79)
Weight (kg)	63.02 (± 8.12)	59.90 (± 7.43)
BMI (kg/m²)	22.17 (± 1.79)	21.85 (± 1.66)

N, indicates the number of participants in the calculation.

PK Properties

The mean plasma concentration–time curves constructed after a single oral dose of cefdinir dispersible tablets was administered to the subjects in the fasted and fed states are shown in Fig. 2. The PK parameters for the test and reference products are summarized in Table 2. As shown in the figure, in both the fasting and fed studies, the mean plasma concentration–time curves of the test and reference preparations essentially overlapped. Additionally, the C_max, AUC_0–t and AUC_0–∞ values in the fed state were significantly lower than those in the fasted state, indicating that food could interfere with the absorption of these two drugs.

Table 2

Pharmacokinetic parameters under fasting and fed conditions
	Mean ± SD
Parameter	Fasting (N = 24)		Fed (N = 32)
Parameter	Test	Reference	Test	Reference
T_max (h)	3.67 ± 0.87	3.80 ± 0.91	3.89 ± 0.93	4.52 ± 0.74
C_max (ng/mL)	1182.87 ± 373.85	1120.35 ± 404.29	753.97 ± 163.35	742.06 ± 206.32
AUC_0–t (ng·h/mL)	6518.15 ± 2453.89	6296.73 ± 2462.76	4330.77 ± 989.98	4536.84 ± 1171.11
AUC_0–∞ (ng·h/mL)	6565.25 ± 2484.51	6351.57 ± 2492.65	4384.53 ± 1005.49	4635.35 ± 1215.65
T_1/2 (h)	1.76 ± 0.18	1.73 ± 0.19	1.80 ± 0.31	1.85 ± 0.53

Data are expressed as mean ± standard deviation; N, indicates the number of participants in the calculation; C_max: maximum blood concentration; T_max, time to reach maximum blood concentration; AUC_0 − t, the area under the curve from time 0 (baseline) to time t; AUC_{0 − ∞}, the area under the curve from 0 to infinity; T_1/2, half-life of elimination.

Table 3

Bioequivalence under fasting and fed conditions
	Fasting (N = 24)			Fed (N = 32)
PK Parameters	GMR (%)	CV (%)	90% CI for GMR (%)	GMR (%)	CV (%)	90% CI for GMR (%)
C_max (ng/mL)	106.74	18.48	97.29–117.10	102.99	11.87	97.86-108.39
AUC_0–t (ng·h/mL)	103.55	22.71	92.46-115.98	96.44	9.95	92.40-100.67
AUC_0–∞ (ng·h/mL)	103.41	22.52	92.41-115.71	95.65	10.68	91.35-100.15

N, indicates the number of participants in the calculation; C_max: maximum blood concentration; AUC_0 − t, the area under the curve from time 0 (baseline) to time t; AUC_{0 − ∞}, the area under the curve from 0 to infinity; CV%, the variability within the volunteer; GM, the geometric mean value; F(%), the ratio of (T/R) geometric mean; 90% CI, 90% confidence interval;.

Safety and Tolerability

Among the 24 subjects included in the safety analysis under fasting conditions in the BE trials, 3 experienced 5 AEs, but no subjects withdrew from the test because of AEs. In the fed test, 8 subjects experienced 13 AEs, but no subjects withdrew because of AEs. All adverse reactions were grade I in severity, and no serious AEs or deaths occurred. The most common AEs in the fasted and fed groups were positive urine occult blood and positive urine white blood cells. Overall, the treatments were safe and well tolerated. The incidence of AEs is summarized in Table S3.

Cefdinir is an oral broad-spectrum third-generation cephalosporins that function as penicillin-like bactericidal agents that inhibit bacterial cell wall synthesis. The oral bioavailability of it is enhanced by the presence of a vinyl moiety at position 3 of the cephalosporin nucleus(Bansal, Aggarwal, Chandel, & Harikumar, 2013). Cefdinir has high efficacy against various gram-positive and gram-negative bacteria(Khan et al., 2011), making it suitable for treating conditions such as otitis media(Adler, McDonald, Trostmann, Keyserling, & Tack, 2000), soft tissue infections(Lin, Lin, Tsai, Wang, & Chi, 2021), and respiratory tract infections(Sader & Jones, 2007), including sinusitis, community-acquired pneumonia, and acute exacerbations of bronchitis. The absolute oral bioavailability of cefdinir has been reported to be only 21–25% (Perry and Scott, 2004), which is due mainly to its poor aqueous solubility(Khan et al., 2011). Studies have proven that there is no significant difference in the clinical efficacy and safety of patients using cefdinir dispersible tablets and original cefdinir capsules(Wang Z, et al., 2023). However, the PK profile and bioequivalence of cefdinir dispersible tablets compared original cefdinir capsules under fasting and fed conditions in healthy Chinese subjects has not been reported.

In the fasting groups, the PK parameters of both products were similar. However, under fasting conditions, the PK parameters in the reference group were slightly lower than those in the test group. Comparing with the fasting state, the C_max, AUC_0–t, AUC_0–∞ and T_max of test and reference group were significantly decreased in the fed state, indicating that the food reduced the absorption rate of the active ingredient in cefdinir dispersible tablets and cefdinir capsules, thereby affecting the bioavailability. Under the same conditions, the T_max and T_1/2 of the reference preparation were prolonged, whereas the test preparation had no significant change, suggesting that food only significantly delay the absorption rate of cefdinir capsules and has no effect on that of cefdinir tablets. These results suggest that interactions between food and this medicine affect drug bioavailability and that a high-calorie, high-fat diet is more likely to alter the physiological properties of the gastrointestinal tract and thus have a greater effect on drug bioavailability. The bioavailability of cefdinir is estimated to be 21% for the 300 mg capsules and 16% for the 600 mg capsules, with the suspension formulation exhibiting an absolute bioavailability of 25%. Studies indicate that both the rate and extent of cefdinir absorption are reduced when a high-fat meal is consumed³. This study further confirmed that a high-fat meal significantly altered the PK profile of cefdinir dispersible tablets in healthy Chinese subjects, which aligns with findings from previous studies.

According to these guidelines, the cleaning period generally more than seven times the half-life of the test doses(Xu et al., 2023; Zhang et al., 2023). According to the instructions, the T_1/2 of cefdinir is about 1.6 to 1.8h, so it is reasonable for this study to set the cleaning cycle (dosing interval) to 7 days, which is more than 7 times the T_1/2.

Intrasubject variability of preparations for PK parameters (C_max, AUC_0 − t, and AUC_0−∞) exceeding 30% are considered highly variable drugs(Z. Li et al., 2021; Su et al., 2023). Based on the Table 3, the CV (%) of cefdinir preparations for PK parameters were less than 30%, indicating that neither cefdinir dispersible tablets nor cefdinir capsules was a highly variable drug.

The BE analysis revealed that the 90% CIs of the GMR (T/R) of both formulations were in the range of 80–125% after logarithmic conversion, suggesting that the test and reference cefdinir tablets were bioequivalent. Moreover, the safety evaluation revealed that cefdinir dispersible tablets were safe and well tolerated. A total of 18 AEs were reported, all of which were grade I in severity, and there were no serious AEs or deaths. In summary, the text and reference formulations were bioequivalent, with no observable safety differences in the fasting/fed state.

The results of the present study revealed that the test cefdinir dispersible tablets were bioequivalent to the reference formulation in healthy Chinese subjects under both fasting and fed states, and the safety profiles of the test and reference formulations were similar. The absorption of both the test and reference formulations was affected by the ingestion of food. On the basis of these PK features, the cefdinir dispersal tablets, produced by Guangdong BoZhou Pharmaceutical Co., Ltd., is expected to be an alternative option to the reference tablet.

Acknowledgements The authors are grateful to the volunteers in this study and the Phase I Clinical Trial Center team members of Panyu Central Hospital.

Authors contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Z.X. and J.S.. The original draft of the manuscript was written by N.M. and B.W., with additional review and editing by X.L.. The inspection of sample testing process, data, report and calculation process was conducted by D.Z. and J.L.. All authors commented on previous versions of the manuscript and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Funding This work was supported by Guangdong Basic and Applied Basic Research Fund Enterprise Joint Fund [grant numbers 2023A1515220024], Medical Research Foundation of Guangdong Province [grant numbers 2024070], Guangdong Hospital Pharmaceutical Research Fund project funding [grant numbers 2024A31], the Research Funds from Guangzhou Panyu Central Hospital [grant numbers PY-2023-007, PY-2023-010, PY-2023-026].

Data availability Data are availability from corresponding author upon reasonable request but remain subject to all applicable legal requirements to protect the confdentiality of the study participants’ personal information.

Ethical approval This clinical trial was registered in the China Drug Trials Registry (http://www.chinadrugtrials.org.cn; registration number: CTR20210441; registration date: March 11, 2021). It was approved by the Ethics Committee of Panyu Central Hospital (Clinical Research Ethics Committee approval number: PYZXYYEC【2020-029】) and was conducted independently at the Phase I Clinical Trial Research Center of Panyu Central Hospital from March 15, 2021 to April 12, 2021. This study complied with the requirements of the Declaration of Helsinki (1989), Guidelines of Good Clinical Practice, and other related guiding principles.

Consent to participate Informed consent was obtained from all individual participants included in the trial.

Consent to publish No identifying details in this manuscript.

Competing interests The authors declare no competing interests.

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No competing interests reported.

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Bioequivalence of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial

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Abstract

Figures

Introduction

Materials and Methods

Product Source

Participants

Study Design

Blood Sampling

Bioanalytical Assay

Sample Preparation

PK Analysis

BE Assessment

Safety Assessment

Results

Study Population

PK Properties

Safety and Tolerability

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

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