Drugs in Research & Development最新文献

Background and objective: Dordaviprone (ONC201) is a novel small molecule with antitumor effects in patients with glioma. The major elimination pathway of dordaviprone is metabolism via cytochrome P450 (CYP) 3A4. This study was designed to assess the effect of severe renal impairment (RI) on dordaviprone pharmacokinetics.

Methods: Eight participants with severe RI and eight participants matched for age, body mass index, and sex, with normal renal function, received a single oral 375-mg dose of dordaviprone. Plasma and urine samples were analyzed for dordaviprone using validated liquid chromatography tandem mass spectrometry methods. Plasma and urine pharmacokinetics, plasma protein binding, and safety profiles were evaluated.

Results: Dordaviprone exposure was increased in participants with severe RI. Geometric mean ratios (90% confidence intervals) of the severe RI cohort compared with the healthy matched cohort were 1.13 (0.92-1.39), 1.48 (0.98-2.23), and 1.47 (0.97-2.21), for maximum concentration (C_max), area under the plasma concentration-time curve from time zero to time of last measurable plasma concentration (AUC_last), and AUC from time zero to infinity (AUC_inf), respectively. Renal clearance of dordaviprone was negligible and similar in both cohorts. Plasma protein binding was similar in both cohorts, leading to similar increases in unbound dordaviprone C_max and AUC in severe RI versus healthy participants. All dordaviprone-related adverse events were mild, occurring in 50% of participants with severe RI and 37.5% of healthy matched participants.

Conclusions: Despite its minimal renal clearance, dordaviprone geometric mean AUC was increased by ~50% in severe RI participants, suggesting CYP3A4 activity may have been suppressed in these participants. The results of this study will be used to inform dordaviprone dosing in patients with RI.

Trial registration number: ACTRN12622000405718; Registered on March 9, 2022. Key Points Dordaviprone is a small molecule drug candidate for the treatment of glioma and is eliminated by non-renal mechanisms. In this clinical trial performed in severely renal-impaired participants, dordaviprone plasma concentrations were increased relative to those observed in healthy participants. This result suggests that the metabolic enzyme activity of CYP3A4 was reduced in severely renal-impaired participants.

Background and objectives: Flunarizine, a selective calcium channel blocker with vasodilatory and neuroprotective effects, is a mainstay for migraine prophylaxis and vertigo management. This study aimed to compare the bioequivalence, pharmacokinetics, and safety of test and reference flunarizine hydrochloride capsules after a single oral dose under fasting/fed conditions.

Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover bioequivalence study was conducted under fasting and fed conditions. Eligible healthy Chinese subjects received a single 5-mg dose of the test or reference flunarizine hydrochloride capsules, followed by a 21-day washout interval between periods. Blood samples were collected up to 36 h post-dose. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed via geometric mean ratios of the test/reference for primary pharmacokinetic parameters, along with 90% confidence intervals. Tolerability was evaluated during the entire study period.

Results: Twenty-four volunteers completed the fasting study, while 42 volunteers completed the fed study. The test formulation demonstrated bioequivalence to the marketed formulation, with 90% confidence intervals for geometric mean ratios of peak plasma concentration (fasting: 97.38-106.57%; fed: 92.71-109.58%), area under the curve from time 0 to 36 h (fasting: 98.20-108.09%; fed: 93.79-100.81%), and AUC from time 0 to infinity (fasting: 97.88-107.30%; fed: 93.63-100.53%), all within equivalence limits of 80.00-125.00%. High-fat meals delayed the time to maximum concentration by 2.5 h and increased exposure by 20%. Both the test and reference formulations were well tolerated, and no serious adverse events related to the study drug were reported during the study.

Conclusions: This study confirmed that test and reference flunarizine hydrochloride capsules were bioequivalent under fasting and fed conditions.

Clinical trial registration: ChiCTR1900026713.

Background and objective: This study aimed to evaluate the bioequivalence of a novel prefilled recombinant human follicle-stimulating hormone (rh-FSH) injection (GenSci008) compared with the existing rh-FSH for injection (Jinfollin^®) in healthy Chinese adult women.

Methods: This open-label, randomized, single-center, two-period, two-sequence crossover study involved 24 healthy female volunteers who received single subcutaneous doses of both formulations, separated by a 10-day washout period. Participants underwent pituitary down-regulation using Diphereline^® to minimize endogenous FSH levels. Pharmacokinetic parameters, including peak concentration (C_max), area under the drug-time curve from 0 to t (AUC_0-t), and AUC from 0 to infinity (AUC_0-∞) were measured, and bioequivalence was assessed based on the 90% confidence intervals (CIs) falling within the 80.00-125.00% range. Safety and immunogenicity were also evaluated.

Results: The geometric mean ratios (GMRs) and 90% CIs for baseline-corrected AUC_0-t, AUC_0-∞, and C_max of the test formulation relative to the reference formulation were 99.99% (93.57-106.86), 102.70% (93.31-113.03), and 93.41% (87.77-99.41), respectively; all within the predefined bioequivalence range. Safety profiles were similar between the two formulations, with no suspected unexpected serious adverse reaction (SUSAR) identified.

Conclusion: The novel prefilled rh-FSH injection (GenSci008) is bioequivalent to the reference formulation (Jinfollin^®), offering a user-friendly and precise alternative for subcutaneous administration in the treatment of infertility.

Background and objective: Nitroglycerin, a cornerstone therapy for acute angina pectoris, achieves rapid symptom relief through sublingual administration by bypassing hepatic first-pass metabolism. This study aimed to investigate the pharmacokinetics (PK), bioequivalence, and safety profiles between a test (T) formulation and a reference (R) formulation of nitroglycerin sublingual tablets in healthy volunteers (HVs).

Methods: In this single-center, randomized, open, single-dose, two-part formulations, four-cycle, two-sequence complete repeat crossover design, fasting-dose bioequivalence study, HVs (n = 36) were 1:1 divided into two groups (T-R-T-R and R-T-R-T) and received 0.6 mg of nitroglycerin sublingual with a 3 d washout. Venous blood was collected 3 h after each administration. Plasma levels of nitroglycerin were analyzed using a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique, and PK parameters were calculated using noncompartmental methods.

Results: For nitroglycerin, the bioequivalence between the test and reference formulations was assessed using the Reference-Scaled Average Bioequivalence (RSABE) method for the maximum plasma concentration (C_max), area under the curve (AUC) from t = 0 to infinity (AUC_0-∞) and AUC from t = 0 to the final measurable concentration (AUC_0-t). Results showed that the least squares geometric mean ratios (T/R) of C_max, AUC_0-t, and AUC_0-∞ for nitroglycerin (94.62%, 89.92%, and 89.44%, respectively) were in the range of 80.00-125.00%, and the upper limit of unilateral 95% confidence interval (CI) of C_max, AUC_0-t, and AUC_0-∞ for nitroglycerin (-0.06, -0.03, and -0.03, respectively) were less than 0. Safety profiles were comparable between formulations, with no serious adverse events (AE) reported.

Conclusions: The study confirmed bioequivalence between the test and reference formulations, demonstrating equivalent absorption rates (C_max) and extents (AUC). Rapid therapeutic plasma levels were achieved via sublingual administration, aligning with nitroglycerin's clinical need for prompt angina relief. These findings, combined with favorable safety data, support the test formulation as a therapeutically equivalent alternative.

Background and objective: Ketorolac tromethamine (KT), a nonsteroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor, is commonly used for the management of moderate to severe pain. The objective of this study was to compare the pharmacokinetic characteristics of KT in beagle dogs following oral administration of conventional tablets and a novel tablet-in-tablet (TIT) formulation.

Methods: A comparative dissolution study was conducted to evaluate the release profiles of both formulations. Non-compartmental analysis was used to determine the pharmacokinetic parameters of each formulation.

Results: Approximately 20% of the administered KT from the TIT formulation was released within the first 30 min, with a cumulative release exceeding 90% at 16 h. In contrast, the conventional tablets released about 50% of the drug within 30 min and completed the release at 4 h. In the single-dose study, the time to reach maximum plasma concentration (T_max) for conventional tablets was 1 h, while T_max for the TIT formulation was 5 h. Both maximum concentration (C_max) and area under the concentration-time curve (AUC) for the TIT formulation were lower than those for conventional tablets. In the repeated-dose study, when equivalent doses (35 mg) of conventional tablets were administered in divided daily doses, the TIT formulation showed no significant differences in most steady-state pharmacokinetic parameters, except for T_max,ss.

Conclusion: The results of this study suggest that the development of a novel KT tablet formulation utilizing the push-pull osmotic pump (PPOP) and tablet-in-tablet techniques warrants further investigation in clinical trials.

Background and objectives: Performing medical procedures on children can often be challenging because of the anxiety that these procedures may induce, the need for immobility that they may require, or age-related development capabilities. We assessed the effects of procedural sedation and analgesia drugs for anxiety management in children during medical procedures.

Methods: We searched PubMed Medline, Cochrane Library, American Academy of Pediatrics, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and references of eligible studies. We included parallel-arm randomized controlled trials comparing different active drugs of procedural sedation and analgesia in children undergoing diagnostic or therapeutic, painful or nonpainful procedures. Two authors independently screened titles/abstracts, reviewed full-texts, and extracted data related to study characteristics, methodology, participants, and results. Meta-analyses involved the Mantel-Haenszel random-effects approach.

Results: We included 98 studies (9161 children) in the qualitative analysis and 50 in the quantitative analysis. The probability of successful sedation rate was associated with dexmedetomidine versus midazolam alone (odds ratio [OR] 7.42, 95% confidence interval [CI] 4.08-13.48) and with midazolam and ketamine combined versus midazolam alone (OR 3.0, 95% CI 1.67-5.39). The probability of successful sedation rate was associated with dexmedetomidine 2 μg/kg versus 1 μg/kg (OR 5.21, 95% CI 1.90-14.27).

Conclusions: Dexmedetomidine, and the combination of midazolam and ketamine, seem interesting for sedating children during medical procedures.

Background and objective: Lumacaftor is an active ingredient in the US Food and Drug Administration-approved combination medication Orkambi^®, which is used for treating cystic fibrosis. Experimental evidence suggests that lumacaftor can be used as a monotherapy to improve brain perfusion and memory in heart failure. To clinically assess this therapeutic intervention, a formulation with demonstrated bioequivalence to the currently approved combination product is required.

Methods: This comparative bioavailability and food-effect study compared lumacaftor pharmacokinetics in healthy patients following: (i) oral administration of lumacaftor (400 mg; Test Product) or Orkambi^® (lumacaftor 400 mg/ivacaftor 250 mg; Reference Product) in the fed state and (ii) oral administration of lumacaftor (400 mg; Test Product) in the fasted to fed state. Plasma lumacaftor concentrations were measured with a standard liquid chromatography with tandem mass spectrometry approach.

Results: The "Test-to-Reference ratio" of the geometric least-square means for maximum plasma concentration and area under the curve met the Food and Drug Administration-defined criteria for bioequivalence; median times to maximum plasma concentration values were not statistically different. The "Fed to Fasted ratio" of the geometric least-square means for maximum plasma concentration and area under the curve indicated a clear food effect on bioavailability. Lumacaftor exposure was approximately two times higher when administered with fatty foods than when taken in a fasting state. The monosubstance formulation was well tolerated.

Conclusions: We conclude that the lumacaftor monosubstance formulation delivers lumacaftor exposure that is not meaningfully different than the currently approved combination product.

Clinical trial registration: ClinicalTrials.gov identifier: NCT05968612.

Introduction: Commercially available pancreatic enzyme replacement therapy (PERT) preparations differ significantly in their physical and enzyme properties, raising concern about the interchangeability of these preparations. The current study aimed to compare various commercially available PERT in Europe and Canada for physical properties, enzyme content, enzyme activities, release characteristics, and compliance with the label claim.

Methods: Particle size was determined using a dynamic image analyzer and represented as Feret Max at 10th (FERET Max D [v, 0.1]), 50th (FERET Max D [v, 0.5]), and 90th percentiles (FERET Max D [v, 0.9]). Particle imaging was performed using scanning electron microscopy and a Quorum sputter coater. Lipase activity was measured according to the European Pharmacopoeia (Ph. Eur) and International Pharmaceutical Federation (FIP) procedures. The measured activity was compared against the label claims to identify the percentage of deviations. Lipase release at different pH (release kinetics) was also determined subsequently.

Results: The particle size of the PERT preparations differed considerably. There were deviations in the actual lipase content from the label claim, ranging from 85.8% (Gastrozym 10000) to 177.5% (Pancreolan 6000). Under the simulated conditions, most PERT preparations released the enzyme lipase at an acidic pH present in the stomach before reaching the duodenum.

Conclusion: PERT preparations available in Europe and Canada exhibit significant differences in terms of physical and enzyme release kinetics. Careful evaluation is needed when interchanging these preparations, as it could impact the therapeutic outcomes.

Background & objectives: Contezolid (MRX-I) is a novel ortho-fluorophenyl dihydropyridone developed by MicuRx Pharmaceuticals, Inc. It has been approved for the treatment of drug-resistant Gram-positive bacterial infections with relatively lower toxicity than other oxazolidinones such as linezolid. However, the toxicity profile has not yet been completely revealed. The aim of this study was to disclose the toxicity of contezolid in Sprague-Dawley (SD) rats and compare its toxicity profile with linezolid in a standard 4-week toxicity study.

Methods: In this study, SD rats were orally administered with contezolid at doses of 20, 100, or 200/300 mg/kg/day for 28 consecutive days followed by a 28-day recovery period. Linezolid at doses of 100 or 200 mg/kg/day served as a comparator. Clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, and histopathological examinations were conducted.

Results: All females in the 200 mg/kg/day linezolid group were subjected to unscheduled death due to myelosuppression within the first 2 weeks. No abnormalities were noted in the 200 mg/kg/day contezolid group, and the dose level was escalated to 300 mg/kg/day from day 15. Myelosuppression or myelosuppression-associated effects were comparable between the 300-mg/kg/day contezolid group and the 100-mg/kg/day linezolid group. The 'no observed adverse effect level' (NOAEL) of contezolid was determined to be 100 mg/kg/day (with an average AUC_0-24 h of 268.4 μg*h/mL). At the same dose levels, the toxicity of contezolid was significantly lower than that of linezolid.

Conclusion: These findings demonstrate that contezolid exhibits a favorable safety profile compared with linezolid in this 4-week repeated-dose toxicity study in rats.