Drugs in Research & Development最新文献

Background and objective: Multidrug-resistant tuberculosis remains a major global health challenge, and bedaquiline has become an essential drug for its treatment. However, the high cost of the originator product Sirturo^® limits accessibility, underscoring the need for affordable generic drugs supported by bioequivalence studies. The aim of this study was to evaluate the bioequivalence of bedaquiline fumarate tablets manufactured by Zhejiang Haizheng Pharmaceutical Co., Ltd. with the reference product Sirturo^® under fasting and postprandial conditions in healthy Chinese subjects and to assess their pharmacokinetic profile and safety to support generic drug registration in China.

Methods: This study comprised a single-dose, open-label, randomized, crossover trial that was independently conducted under two conditions: fasting and postprandial. All subjects were randomized to receive the single-dose subject formulation and the reference formulation in two separate cycles. Plasma samples were collected at multiple timepoints after dosing and bedaquiline concentrations were determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Key pharmacokinetic parameters including maximum plasma concentration and area under the plasma concentration-time curve from time 0 to 72 h were calculated using a non-atrial model and bioequivalence was assessed using analysis of variance and 90% confidence intervals.

Results: A total of 40 cases were included in the fasting group and 50 healthy subjects in the postprandial group. The geometric mean ratio of the single-dose subject formulation to the reference formulation within both groups fell within the 80.00-125.00% bioequivalence range for the 90% confidence interval of maximum plasma concentration to area under the plasma concentration-time curve from time 0 to 72 h. Overall drug exposure levels (area under the plasma concentration-time curve) were higher in the postprandial state than in the fasting state, but the subject formulation remained consistent with the reference formulation. All subjects completed the study and no serious adverse events were observed.

Conclusions: Bedaquiline fumarate tablets of Zhejiang Haizheng Pharmaceutical Co., Ltd. showed good bioequivalence and tolerability with Sirturo^® under fasting and postprandial conditions, which supports its use as a generic drug in the treatment of multidrug-resistant tuberculosis.

Clinical trial registration: ChiCTR2500105414.

Background and objective: Post-traumatic sepsis is associated with high mortality and limited treatment options. This study aimed to evaluate the safety and efficacy of ulinastatin in adult patients with post-traumatic sepsis, assess its potential as a therapeutic option, and provide a foundation for future large-scale trials.

Methods: A single-blind, randomized controlled trial was conducted involving 60 patients treated at the Eastern Theater General Hospital from October 2022 to June 2024. The primary endpoint was 28-day all-cause mortality. Secondary endpoints included the Sequential Organ Failure Assessment (SOFA) score, C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT) levels, Activities of Daily Living (ADL) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, ICU length of stay, duration of mechanical ventilation, and other laboratory indicators.

Results: No statistically significant difference was observed in 28-day mortality between the ulinastatin and control groups (p > 0.05). However, the ulinastatin group exhibited significantly shorter ICU and hospital stays compared with the control group (p < 0.05), while the duration of mechanical ventilation showed no significant difference (p > 0.05). The ulinastatin group demonstrated significant improvements in CRP, IL-6, PCT levels, as well as SOFA and APACHE II scores (p < 0.05). Safety evaluations revealed a significant reduction in ALT and AST levels in the ulinastatin group (p < 0.05), with no serious adverse events reported.

Conclusion: While the 28-day mortality rate did not differ significantly between the two groups, ulinastatin was associated with shorter ICU and hospital stays, improvements in inflammatory markers and organ function, and demonstrated a favorable safety profile.

Omadacycline is a novel tetracycline with a wide range of antibacterial activity. A comprehensive understanding of the factors influencing its metabolic processes is essential to optimize its therapeutic benefits and minimize any potential negative effects. It was found that the metabolism of omadacycline does not rely on UDP-glucosyltransferase or cytochrome P450 enzymes, which gives it a clear advantage in terms of drug interactions, bioavailability, and metabolic stability. The review offers a thorough analysis of the many elements influencing the pharmacokinetics of omadacycline, including its intrinsic properties, individual differences, dietary influences, and possible drug interactions. To achieve maximum efficacy and safety in clinical practice, a thorough understanding of the pharmacokinetic properties of omadacycline is essential, which helps to better customize dosing regimens and maximize therapeutic outcomes.

Background and objectives: ET-26 is a novel etomidate analog with reduced adrenal suppression. This study evaluated its pharmacokinetics (PK), pharmacodynamics (PD), and safety in subjects with mild to moderate renal impairment.

Methods: In this phase I trial, 24 subjects (normal renal function, mild renal impairment, moderate renal impairment; n = 8/group) received a single intravenous bolus ET-26 dose. PK parameters (C_max, AUC_0-∞, CL), urinary excretion, PD (time to unconsciousness, area under the curve [AUC] of the Bispectral Index [BIS]), and safety were assessed.

Results: Systemic exposure (AUC_0-∞) differed by < 16% between renal impairment and normal groups (geometric mean ratios: 84.70-86.85%). C_max was ~ 46% lower in renal impairment groups, but PD responses were comparable. Renal clearance was minimal (CL_r ≤ 0.0085 L/h; urinary excretion ≤ 0.02%) with no correlation between estimated glomerular filtration rate (eGFR) and PK parameters. Safety profiles were similar across groups; mild myoclonus (25% per cohort) was the most common adverse event. No renal impairment-specific safety concerns emerged.

Conclusion: Mild-to-moderate renal impairment minimally affects ET-26 exposure or efficacy due to predominant non-renal elimination. No dosage adjustment is needed for ET-26 0.8 mg/kg in these patients. However, patients with severe renal impairment or those receiving dialysis were not studied, and dedicated investigations are required before extrapolating dosing recommendations to these populations.

Trial registration: CDE Clinical Trial Registry CTR20233783. Registered on 23 November 2023. http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml.

Background and objectives: Vancomycin (VCM) pharmacokinetic parameters vary widely between individuals. Existing models developed domestically and internationally may not apply universally because of differences in patient populations and testing methodologies. Therefore, the present study aimed to address the clinical challenge of optimizing individualized VCM dosing in pediatric patients at the study institution by developing a VCM population pharmacokinetic model and identifying key factors influencing VCM clearance, thereby providing a reference for safe and effective clinical dosing strategies.

Methods: Data regarding 124 effective VCM concentrations and 100 pediatric patients who received intravenous VCM were retrospectively collected. We used a non-linear mixed-effects model with forward inclusion and backward elimination to create the final VCM population pharmacokinetic model. The model was internally validated using bootstrapping, goodness of fit, and visual predictive check. The Monte Carlo method was used to simulate the range of trough concentrations in pediatric patients with renal insufficiency and normal function under different dosing regimens.

Results: A one-compartment model adequately described the pharmacokinetic behavior of VCM in vivo. The typical values of clearance and volume of distribution were 8.22 L/h and 113 L, respectively. Renal function and body weight were the most important factors affecting the clearance of VCM. The model was validated as stable and reliable.

Conclusions: The VCM population pharmacokinetic model established during this study can assist physicians with the development and optimization of dosing regimens for pediatric patients.

Background and objectives: New coronavirus disease 2019 (COVID-19) therapeutics, including intramuscular (IM) formulations, may increase patient access. In COMET-TAIL, sotrovimab 500 mg IM was non-inferior to 500 mg intravenous (IV) in reducing the risk of COVID-19 progression; however, 250 mg IM was associated with more hospitalizations, despite similar viral load (VL) reductions to 500 mg IM.

Methods: COMET-PEAK was a randomized, three-part study to assess safety, tolerability, and viral pharmacodynamics of sotrovimab in adults with early, mild-to-moderate COVID-19. Parts B/C evaluated sotrovimab 500-mg IV infusion versus 500-mg or 250-mg IM injection. The primary objective was to compare virologic response of sotrovimab IM versus IV (mean area under the curve from day 1 to day 8 [AUC_D1-8] of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] VL); 90% confidence interval (CI) limits of 0.5-2.0 indicated equivalence.

Results: Parts B/C included 167 and 157 participants, respectively. Median age range was 42-47 years, and approximately 50% of participants had one or more risk factor for severe disease. The primary objective was met: the ratio of geometric mean VL AUC_D1-8 of sotrovimab IM versus IV was 1.04 (90% CI 0.98-1.09; Part B) and 1.02 (90% CI 0.94-1.11; Part C). No new safety signals emerged for sotrovimab; IM administration was well tolerated, with few injection-site reactions.

Conclusions: Both sotrovimab IM doses were equivalent to 500 mg IV with respect to SARS-CoV-2 VL change. IM administration was safe and well tolerated. The validity of VL as a biomarker for COVID-19 progression warrants further study.

Clinical trial registration: NCT04779879 (date of first registration: March 3, 2021), https://classic.

Clinicaltrials: gov/ct2/show/NCT04779879 .

Background and objective: Perampanel has been approved for the adjunctive treatment of partial-onset seizures and primary generalized tonic-clonic seizures. The oral suspension formulation benefits patients who have difficulty swallowing tablets. The unavailability of an affordable generic perampanel oral suspension formulation increased the need for a cheaper bioequivalent alternative to the marketed reference product. The study aimed to assess the bioequivalence of two formulations of perampanel oral suspension (0.5 mg/mL) administered under fasting conditions focusing on providing a cost-effective and accessible alternative to current formulations.

Methods: This was an open-label, two-period, two-sequence, crossover, bioequivalence study conducted under fasting conditions. Healthy subjects were randomized to receive single doses of perampanel oral suspension (12 mg), Lepsiramp and Fycompa^® separated by a 6-week washout period. The maximum concentration and area under the concentration-time curve up to 72 h were the primary pharmacokinetic parameters used to assess bioequivalence.

Results: The geometric mean ratio of test to reference formulations and 90% confidence interval were 109.55 (99.49-120.64) for maximum concentration and 98.15 (90.68-106.23) for the area under the concentration-time curve up to 72 h_, which were within the 80-125% bioequivalence range. The adverse events were mild headache and dizziness.

Conclusions: The two oral suspension formulations were bioequivalent, safe, and well tolerated. This provides a beneficial affordable alternative for patients requiring non-tablet oral formulations.

Clinical trial registration: The ClinicalTrials.gov registration number is NCT06969963, retrospectively registered on 13 May, 2025.

Background and objectives: The emergence of severe acute respiratory syndrome coronavirus 2 variants against which sotrovimab has lower in vitro neutralisation activity has led to the exploration of higher (> 500-mg intravenous) doses. This study evaluated the safety, tolerability and pharmacokinetics of intravenous sotrovimab 3000 mg.

Methods: We conducted a phase I, open-label, single-arm study in healthy adults. Participants were administered a single 3000-mg dose of intravenous sotrovimab (100 mg/mL) over 60 min (50 mg/min). Adverse events, serious adverse events and adverse events of special interest were assessed through week 35. Sotrovimab pharmacokinetics were evaluated through week 24.

Results: Of 100 participants enrolled, 98 received sotrovimab (median age 42.5 [range 18-64] years; 52% male; mean body mass index 25.25 kg/m²) and 96 completed the study. Overall, 37% (n = 36/98) of the participants reported adverse events, five of which were considered to be treatment related. The most common type of event was infection (13%; n = 13/98) with upper respiratory tract infection (9%; n = 9/98) being frequent. Two Grade 1 adverse events of special interest were reported. There were no serious adverse events, deaths or adverse events leading to discontinuation. Pharmacokinetic results were in line with expectations for this dose of sotrovimab, assuming linear dose-proportional pharmacokinetics, based on the population pharmacokinetic model of sotrovimab.

Conclusions: Intravenous sotrovimab 3000 mg, administered over 60 min, was generally well tolerated by healthy volunteers, with a low incidence of adverse events and adverse events of special interest, no documented serious adverse events and no adverse events leading to discontinuation. Pharmacokinetic results were in line with expectations for a 3000-mg dose, assuming linear dose-proportional pharmacokinetics.

Clinical trial registration: ClinicalTrials.gov NCT05280717; date of registration 4 March, 2022.

Background and objectives: This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics of omecamtiv mecarbil with multiple oral doses at 25 mg twice daily, followed by titration to either 37.5 or 50 mg twice daily in healthy Chinese participants.

Methods: Fifty healthy participants were enrolled and randomly assigned into three groups: Group A (20 subjects) received omecamtiv mecarbil 25 mg in period 1 and either 37.5 mg or 25 mg in period 2; Group B (20 subjects) received omecamtiv mecarbil 25 mg in period 1 and either 50 mg or 25 mg in period 2; and Group C (10 subjects) received a placebo in both periods.

Results: The pharmacokinetics of omecamtiv mecarbil were well characterized in healthy Chinese participants. Across all subgroups, the mean terminal elimination half-life ranged from 18.3 to 21.3 h. Mean accumulation ratios of area under the curve from time 0 to 12 h ranged from 4.54 to 5.01 in period 1 and 2. The mean maximum observed concentration/plasma concentration before dosing ratios varied between 1.23 and 1.31 on days 8 and 34 across subgroups. No subjects experienced serious adverse events. The most frequently reported adverse events were an increased blood creatine kinase levels (12.5% of subjects in the omecamtiv mecarbil group, 10% in the placebo group), increased blood glucose levels (7.5%, 0), and bradycardia (10%, 0).

Conclusions: Omecamtiv mecarbil was well tolerated at the dose levels of 25-50 mg in healthy Chinese participants according to a pharmacokinetic-based titration scheme. Exposure of omecamtiv mecarbil was dose proportional, and no dose-related trends were observed in treatment-emergent adverse events.