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BACKGROUND AND OBJECTIVES: Cilostazol improves ischemic symptoms and prevents recurrence following cerebral infarction, and rosuvastatin reduces cholesterol levels. However, no reports exist on the pharmacokinetic interactions between these two drugs in healthy adults. This study evaluated the pharmacokinetic (PK) interactions and safety of cilostazol and rosuvastatin when co-administered to healthy male participants. METHODS: A randomized, open-label, multiple-dosing, two-arm, two-period study was conducted. Arm A had 30 participants receiving 200 mg cilostazol daily and arm B had 27 participants receiving 20 mg rosuvastatin daily for 7 days. In period 2, both arms received a combination of 200 mg cilostazol and 20 mg rosuvastatin daily for 7 days following a 7-day washout period. Plasma concentrations of cilostazol, its metabolites, and rosuvastatin were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: Fifty-seven participants were randomized, and 44 completed the study. The geometric mean ratio (GMR) and 90% confidence intervals (CI) for maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCtau,ss) indicated no significant interaction between cilostazol and rosuvastatin. Safety assessments showed comparable profiles to individual drug administration, with no significant adverse events. CONCLUSION: The repeated co-administration of cilostazol and rosuvastatin in healthy male participants resulted in minor PK interactions and exhibited a safety and tolerability profile similar to those of the individual drugs. This suggested that the combined regimen is well tolerated and does not necessitate dose adjustments. REGISTRATION: ClinicalTrials.Gov identifier no. NCT06568133.
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CT-P13, a biosimilar of infliximab, is used to treat inflammatory diseases that arise from immune system complications, resulting in excessive and persistent inflammation. The subcutaneous (SC) formulation of CT-P13 overcomes the drawback of prolonged administration associated with the intravenous (IV) infliximab biosimilar, necessitating autoinjector (AI) administration. This randomized, open-label, two-arm, parallel-group, single-dose clinical pharmacology study aimed to evaluate the pharmacokinetics (PK) and safety of CT-P13 SC administration via AI compared with the existing pre-filled syringe (PFS) method. A total of 147 healthy participants were randomized into two groups, of which 139 completed the study. Blood samples were collected from before CT-P13 SC administration to 2016 h after the start of the administration. Serum concentrations were analyzed using the Meso Scale Discovery electrochemiluminescence method. Geometric mean ratios (90% confidence interval) of the AUCinf (areas under the concentration-time curve from zero to infinity) and Cmax (The maximum serum concentration) for CT-P13 SC AI versus CT-P13 SC PFS groups, were 94.15% (85.02%-104.26%), 92.48% (84.66%-101.01%), respectively. CT-P13 SC AI and CT-P13 SC PFS achieved comparable PK because the 90% CI was within the predefined equivalence margin. At the end of the study, immunogenicity results revealed that 70 (97.22%) and 73 (98.65%) participants tested positive for anti-drug antibody (ADA) in the CT-P13 SC AI and CT-P13 SC PFS groups, respectively. They were tested positive for neutralizing antibodies. No other significant safety differences were observed between the treatment groups. In conclusion, both administrations demonstrated PK equivalence and were both safe and well-tolerated.
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Biosimilares Farmacéuticos , Voluntarios Sanos , Infliximab , Jeringas , Humanos , Biosimilares Farmacéuticos/farmacocinética , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/sangre , Biosimilares Farmacéuticos/efectos adversos , Adulto , Masculino , Inyecciones Subcutáneas , Femenino , Infliximab/farmacocinética , Infliximab/administración & dosificación , Infliximab/sangre , Infliximab/inmunología , Adulto Joven , Persona de Mediana Edad , Equivalencia Terapéutica , Área Bajo la Curva , Anticuerpos MonoclonalesRESUMEN
A fixed-dose combination (FDC) of ezetimibe, atorvastatin, and amlodipine has been developed to improve medication adherence among patients with cardiovascular diseases. In a randomized, open-label, multiple-dose, fixed-sequence study involving 34 participants (Study 1), the potential drug-drug interaction between ezetimibe/atorvastatin FDC and amlodipine was evaluated. Additionally, a randomized, open-label, crossover study with 60 participants (Study 2) compared the pharmacokinetics (PKs) of ezetimibe/atorvastatin/amlodipine FDC to those of individual formulations. Co-administration of the ezetimibe/atorvastatin FDC and amlodipine did not significantly alter the PKs of either drug. However, amlodipine resulted in a slight increase in systemic exposure to atorvastatin by approximately 23%. Geometric mean ratios (FDC to individual formulations) and 90% confidence intervals of area under the time-concentration curve at steady state during dosing interval (AUCτ, ss) and maximum concentration at steady state (Cmax, ss) or amlodipine, atorvastatin, and ezetimibe were all within the bioequivalent range (0.8-1.25), confirming bioequivalence. Moreover, the FDC of ezetimibe, atorvastatin, and amlodipine exhibited comparable tolerability to corresponding individual formulations.
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INTRODUCTION: Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects. METHODS: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range. RESULTS: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158-1.0089)/0.9965 (0.9550-1.0397) and 1.0033 (0.9800-1.0271)/1.0067 (0.9798-1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953-1.0294)/0.9851 (0.9368-1.0359) and 1.0198 (0.9950-1.0453)/1.0003 (0.9694-1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814-1.2797 and 0.7415-1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082-1.1003)/1.0252 (0.9841-1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418-1.1997)/0.9888 (0.8792-1.1120) in studies 1 and 2, respectively. CONCLUSION: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations. TRIAL REGISTRATION: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.
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Amlodipino , Atorvastatina , Bencimidazoles , Compuestos de Bifenilo , Estudios Cruzados , Combinación de Medicamentos , Tetrazoles , Humanos , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/administración & dosificación , Amlodipino/farmacocinética , Amlodipino/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/administración & dosificación , Tetrazoles/farmacocinética , Tetrazoles/administración & dosificación , Masculino , Adulto , Femenino , Atorvastatina/farmacocinética , Atorvastatina/administración & dosificación , Adulto Joven , Área Bajo la Curva , Persona de Mediana Edad , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/administración & dosificación , Equivalencia Terapéutica , Antihipertensivos/farmacocinética , Antihipertensivos/administración & dosificación , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/administración & dosificación , Voluntarios SanosRESUMEN
The combined cilostazol and rosuvastatin therapy is frequently used for coronary artery disease treatment. This open-label, 3 × 3 crossover clinical trial evaluated the pharmacokinetics and safety of a fixed-dose combination (FDC) of cilostazol/rosuvastatin (200 + 20 mg) versus a concurrent administration of the separate components (SCs) under both fasted and fed conditions. Among 48 enrolled healthy adults, 38 completed the study. Participants were administered a single oral dose of cilostazol/rosuvastatin (200 + 20 mg), either as an FDC or SCs in a fasted state, or FDC in a fed state, in each period of the trial. Blood samples were taken up to 48 hours after dosing, and plasma concentrations were analyzed using validated liquid chromatography-tandem mass spectrometry. The geometric mean ratios of FDC to SCs for area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (Cmax) were 0.94/1.05 and 1.06/1.15 for cilostazol and rosuvastatin, respectively (AUClast/Cmax). Compared with that during fasting, fed-state administration increased the AUClast and Cmax for cilostazol by approximately 72% and 160% and decreased these parameters for rosuvastatin by approximately 39% and 43%, respectively. To conclude, the FDC is bioequivalent to the SCs, with notable differences in pharmacokinetics when administered in a fed state. No significant safety differences were observed between the treatments.
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Área Bajo la Curva , Cilostazol , Estudios Cruzados , Combinación de Medicamentos , Ayuno , Voluntarios Sanos , Rosuvastatina Cálcica , Humanos , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/efectos adversos , Masculino , Adulto , Cilostazol/administración & dosificación , Cilostazol/farmacocinética , Cilostazol/efectos adversos , Femenino , Ayuno/metabolismo , Adulto Joven , Administración Oral , Persona de Mediana Edad , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Equivalencia Terapéutica , Espectrometría de Masas en TándemRESUMEN
Administration of sedatives for post-resuscitation care can complicate the determination of the optimal timing to avoid inappropriate, pessimistic prognostications. This prospective study aimed to investigate the distribution and elimination kinetics of midazolam (MDZ) and its metabolites, and their association with awakening time. The concentrations of MDZ and its seven metabolites were measured immediately and at 4, 8, 12, and 24 h after the discontinuation of MDZ infusion, using liquid chromatography-tandem mass spectrometry. The area under the time-plasma concentration curve from 0 to 24 h after MDZ discontinuation (AUClast) was calculated based on the trapezoidal rule. Of the 15 enrolled patients, seven awakened after the discontinuation of MDZ infusion. MDZ and three of its metabolites were major compounds and their elimination kinetics followed a first-order elimination profile. In the multivariable analysis, only MDZ was associated with awakening time (AUClast: R2 = 0.59, p = 0.03; AUCinf: R2 = 0.96, p < 0.001). Specifically, a 0.001% increase in MDZ AUC was associated with a 1% increase in awakening time. In the individual regression analysis between MDZ concentration and awakening time, the mean MDZ concentration at awakening time was 16.8 ng/mL. The AUC of MDZ is the only significant factor associated with the awakening time.
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Hipnóticos y Sedantes , Midazolam , Humanos , Estudios Prospectivos , Cromatografía LiquidaRESUMEN
PURPOSE: In combined anterior-posterior adult spinal deformity surgery, the optimal combination of anterior and posterior procedures remains unclear. We aimed to demonstrate the radiological outcomes and relevant factors in oblique lateral interbody fusion (OLIF) for lumbosacral fractional curve (FC) correction combined with open posterior surgery in degenerative lumbar scoliosis (DLS). METHODS: This study involved 42 consecutive patients with DLS who had a major curve (MC) ≥ 20° and an FC (L4 to S1) ≥ 10°, and underwent a combined anterior-posterior surgery Changes in the MC, FC, coronal balance distance, type of coronal imbalance, coronal/sagittal disc angle at L4-5 and L5-S1, L4 and L5 tilt, and sagittal parameters were examined. The associations between FC correction and demographic, surgical, and radiological factors were analysed. RESULTS: The FC decreased from 16.9 ± 7.3° preoperatively to 6.6 ± 4.4° at the last follow-up (P < 0.001). The coronal disc angle at L4-5 and L5-S1 were, respectively, 6.8 ± 2.2° and 6.0 ± 4.1° preoperatively and decreased to 2.2 ± 2.1 and 1.2 ± 1.3° at the last follow-up (both P < 0.001). The changes in FC were greater in uppermost instrumented level > T10 (P < 0.001), and associated with the preoperative FC (r = 0.820, P < 0.001), L4 tilt (r = 0.434, P = 0.007), and L5 tilt (r = 0.462, P = 0.003). CONCLUSION: OLIF at the FC combined with open posterior surgery is an effective combined anterior-posterior correction strategy in DLS.
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Escoliosis , Adulto , Humanos , Escoliosis/diagnóstico por imagen , Escoliosis/cirugía , Procedimientos Neuroquirúrgicos , Región LumbosacraRESUMEN
The LEPR (leptin receptor) genotype is associated with obesity. Gut microbiome composition differs between obese and non-obese adults. However, the impact of LEPR genotype on gut microbiome composition in humans has not yet been studied. In this study, the association between LEPR single nucleotide polymorphism (rs1173100, rs1137101, and rs790419) and the gut microbiome composition in 65 non-obese Korean adults was investigated. Leptin, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels were also measured in all participants. Mean ± SD (standard deviation) of age, body mass index, and leptin hormone levels of participants was 35.2 ± 8.1 years, 21.4 ± 1.8 kg/m2, and 7989.1 ± 6687.4 pg/mL, respectively. Gut microbiome analysis was performed at the phylum level by 16S rRNA sequencing. Among the 11 phyla detected, only one showed significantly different relative abundances between LEPR genotypes. The relative abundance of Candidatus Saccharibacteria was higher in the G/A genotype group than in the G/G genotype group for the rs1137101 single nucleotide polymorphism (p=0.0322). Participant characteristics, including body mass index, leptin levels, and other lipid levels, were similar between the rs1137101 G/G and G/A genotypes. In addition, the relative abundances of Fusobacteria and Tenericutes showed significant positive relationship with plasma leptin concentrations (p=0.0036 and p=0.0000, respectively). In conclusion, LEPR genotype and gut microbiome may be associated even in normal-weight Korean adults. However, further studies with a greater number of obese adults are needed to confirm whether LEPR genotype is related to gut microbiome composition.
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Despite the variety of treatment methods, comminuted inferior pole fractures of the patella remain difficult and technically demanding to achieve stable internal fixation. The purpose of this study is to evaluate the clinical outcomes of rim plate-augmented separate vertical wiring with supplementary fixation in the management of comminuted inferior pole fractures, AO/OTA 34-A1, C2, and C3, which has the secondary horizontal fracture line on lower articular boundary. From our study, bony union was achieved in all patients at an average of 3.1 ± 1.4 months after surgery. There was no patient with loss of reduction, fixation failure, or infection during follow-up. The average final range of motion was 131.6° ± 7.2°. Lysholm knee scores gradually increased over 3, 6, 9, and 12 months postoperatively by 58.7, 74.0, 82.9, and 89.4, respectively. Isokinetic peak torque deficit of the knee extensor muscles in 3, 6, 9, and 12 months postoperatively was 59.9%, 49.7%, 35.7%, and 28.1%, respectively. The rim plate-augmented separate vertical wiring with supplementary fixation for the treatment of patellar fracture associated comminuted inferior pole is effective and can be safely applied AO/OTA 34-C2 or C3 with favorable outcomes.
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Fracturas Óseas , Traumatismos de la Rodilla , Procedimientos de Cirugía Plástica , Humanos , Fracturas Óseas/cirugía , Terapia por Ejercicio , Fijación Interna de FracturasRESUMEN
This study aimed to compare the pharmacokinetic (PK) and safety profiles of 2 fenofibric acid formulations under fasting and fed conditions. The reference was a 135 mg capsule, while the test was a 110 mg enteric-coated tablet. This randomized, open-label, two-sequence, two-period crossover phase 1 clinical trial was conducted in healthy Korean men. Sixty participants were enrolled in each of the fasting and feeding groups. Blood samples were collected 72 hours after drug administration. PK parameters were calculated using a non-compartmental method with Phoenix WinNonlin®. A total of 53 and 51 participants from the fasting and feeding groups, respectively, completed the study. The geometric mean ratio and 90% confidence intervals of the maximum concentration (Cmax) and area under the concentration-time curve to the last measurable plasma concentration were 0.9195 (0.8795-0.9614) and 0.8630 (0.8472-0.8791) in the fasting study and 1.0926 (1.0102-1.1818) and 0.9998 (0.9675-1.0332) in the fed study, respectively. The time to reach Cmax of the enteric-coated tablet compared to that of the capsule was extended by 1 and 3 hours under fasting and fed conditions, respectively. In conclusion, enteric-coated tablets have a higher bioavailability than capsules. In addition, the enteric-coated tablet was smaller than the capsule, making it easier for patients to swallow. Trial Registration: Clinical Research Information Service Identifier: KCT0007177, KCT0003304.
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AIM: To investigate the possible effect of haemodialysis (HD) on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. METHODS: A single-dose, open-label, parallel-group study of eight end-stage renal disease (ESRD) patients and eight matched healthy subjects was conducted. ESRD patients received a single oral dose of evogliptin 5 mg after and before HD with a 2-week washout between each dose, and healthy subjects received a single oral dose of evogliptin 5 mg. Serial blood, dialysate, and urine samples were collected to assess the PK and PD profiles of evogliptin. To compare PK parameters before and after HD, geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were calculated. RESULTS: The GMRs for the maximum concentration and area under the concentration-time curve from time 0 to the last measurable timepoint (AUClast ) of evogliptin when administered before HD compared with after HD were 0.7293 (90% CI 0.6171-0.8620) and 0.9480 (90% CI 0.8162-1.1010), respectively. The maximum DPP-4 inhibitory effect, area under the DPP-4 inhibitory effect-time curve, and time duration of more than 80% DPP-4 inhibition were comparable when evogliptin was administered before and after HD. Compared with healthy subjects, the mean AUClast of evogliptin was approximately 1.4-fold greater in ESRD patients, but the difference is unlikely to affect the safety and efficacy of evogliptin. CONCLUSION: The effect of HD on the PK and PD characteristics of evogliptin was not clinically significant; therefore, dose adjustment according to HD status is not necessary.
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Inhibidores de la Dipeptidil-Peptidasa IV , Fallo Renal Crónico , Humanos , Hipoglucemiantes , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Diálisis Renal , Fallo Renal Crónico/terapia , Inhibidores de Proteasas , Área Bajo la CurvaRESUMEN
The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics (PKs) of rhEGF eyedrops after the administration of single and multiple doses in healthy subjects. A phase 1, randomized, double-blind, placebo-controlled, and single-ascending dose (SAD) and multiple-ascending dose (MAD) study were conducted in three dose groups (10, 50, and 100 µg/mL). The subjects randomly received rhEGF eyedrops or the placebo in a 3:1 ratio. Serial blood and tear samples for PK analysis were collected up to 36 h and 180 h post-dose in SAD and MAD studies, respectively. In addition, the serum and tear EGF concentrations were measured. Immunogenicity evaluations were conducted using serum anti-EGF antibody levels. A total of 50 subjects were enrolled and 48 subjects completed the study. Adverse drug reactions were mild and transient. There were no serious adverse events in this study. The tear EGF concentrations rapidly increased and returned to baseline after 4 h without any serum EGF level change after the administration of rhEGF eyedrops. rhEGF eyedrops were safe and well-tolerated in healthy subjects in a dose range of 10-100 µg/mL, indicating suitability for further studies in patients with corneal injury.
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The interaction between statins and omega-3 fatty acids remains controversial. The aim of this phase 1 trial was to evaluate the pharmacokinetics of drug-drug interaction between atorvastatin and omega-3 fatty acids. Treatments were once-daily oral administrations of omega-3 (4 g), atorvastatin (40 mg), and both for 14 days, 7 days, and 14 days, respectively, with washout periods. The concentrations of atorvastatin, 2-OH-atorvastatin, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were determined with LC-MS/MS. Parameters of DHA and EPA were analyzed after baseline correction. A total of 37 subjects completed the study without any major violations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the co-administration of a single drug for the area under the concentration-time curve during the dosing interval at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.042 (0.971-1.118), 1.185 (1.113-1.262), 0.157 (0.091-0.271), and 0.557 (0.396-0.784), respectively. The GMRs (90% Cis) for the co-administration at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.150 (0.990-1.335), 1.301 (1.2707-1.1401), 0.320 (0.243-0.422), and 0.589 (0.487-0.712), respectively. The 90% CIs for most primary endpoints were outside the range of typical bioequivalence, indicating a pharmacokinetic interaction between atorvastatin and omega-3.
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Cenobamate (XCOPRI and ONTOZRY) is a novel antiseizure medication for the treatment of focal-onset seizures. Nonetheless, there is limited information on the pharmacokinetics (PKs), safety, and efficacy of cenobamate in Asian people, including Japanese people. This study aimed to evaluate the PKs and safety of cenobamate after a single oral dose in healthy Japanese subjects and to compare the PKs with that reported in non-Japanese subjects. A randomized, double-blind, placebo-controlled, single ascending dose study was conducted at four dose levels of 50, 100, 200, and 400 mg. Subjects were randomly assigned to cenobamate or placebo in a 6:2 ratio. Cenobamate was rapidly absorbed, reaching its maximum plasma concentration (Cmax ) in 0.75 to 2.25 h, and was eliminated with a mean half-life of 37.0 to 57.7 h. The Cmax increased dose proportionally, whereas area under the concentration-time curve increased more than dose proportionally, which was consistent with the findings in non-Japanese subjects. The systemic exposure of cenobamate was comparable between Japanese and non-Japanese subjects at all dose levels evaluated. All adverse events were mild in severity, and their incidence did not show dose-dependent trends. Furthermore, there were no clinically significant issues in safety parameters, including sedation tests, neurologic examinations, and Columbia Suicide Severity Rating Scale interviews. In conclusion, the systemic exposure of cenobamate after a single dose in Japanese subjects increased by dose, which was similar to the pattern in non-Japanese subjects. In addition, a single dose of cenobamate was well-tolerated in the dose range of 50 to 400 mg in healthy Japanese subjects.
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Carbamatos , Clorofenoles , Carbamatos/efectos adversos , Clorofenoles/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Japón , Tetrazoles/farmacocinéticaRESUMEN
Acetaminophen is known to be generally safe, and the occurrence of anaphylaxis due to acetaminophen has been rarely reported. We report a case of acetaminophen-induced anaphylaxis in a healthy male subject who participated in a clinical trial on the pharmacokinetics of ibandronate. The subject had not experienced an allergic reaction to acetaminophen prior to this incident. The patient received 1300 mg oral acetaminophen at about 12 hours after receiving 150 mg ibandronate. After about 10 minutes, the subject developed whole-body urticaria and hypotension. The temporal association suggested that the anaphylaxis was due to acetaminophen and not ibandronate. Anaphylaxis could occur due to acetaminophen even in the absence of allergic reactions in the first dosing.
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DHP107 is a newly developed lipid-based oral formulation of paclitaxel. We evaluated the in vivo tissue pharmacokinetics (PKs) of DHP107 in mice and patients using positron emission tomography (PET). Radioisotope-labeled [3 H]DHP107 and [18 F]DHP107 for oral administration were formulated in the same manner as the manufacturing process of DHP107. In vivo tissue PK were assessed in healthy ICR mice and breast cancer xenografted SCID mice. Two patients with metastatic breast cancer were clinically evaluated for absorption at the target lesion after internal absorbed dose estimation. Whole-body PET/computed tomography data were acquired in healthy and xenografted mice and in patients up to 10-24 h after administration. Tissue [18 F]DHP107 signals were plotted against time and PK parameters were determined. The amounts of radioactivity in various organs and excreta were determined using a beta-counter and are expressed as the percentage of injected dose (ID). Oral [18 F]DHP107 was well-absorbed and reached the target lesion in mice and patients with breast cancer. Significant amounts of radioactivity were found in the stomach, intestine, and liver after oral administration of [3 H]- and [18 F]DHP107 in healthy mice. The [18 F]DHP107 reached a peak distribution of 0.7-0.8%ID in the tumor at 5.6-7.3 h in the xenograft model. The [18 F]DHP107 distribution in patients with metastatic breast cancer was the highest at 3-4 h postadministration. Systemic exposures after administration of a DHP107 therapeutic dose were comparable with those in previous studies. PET using radioisotope-labeled drug candidates is useful for drug development and can provide valuable information that can complement plasma PK data, particularly in early phase clinical trials.
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Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel/farmacocinética , Administración Oral , Adulto , Animales , Neoplasias de la Mama/patología , Desarrollo de Medicamentos/métodos , Femenino , Radioisótopos de Flúor , Humanos , Ratones , Imagen Molecular/métodos , Paclitaxel/administración & dosificación , Paclitaxel/química , Tomografía de Emisión de Positrones , Radiofármacos , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Citrus sinensis , Malus , Derivados del Benceno , Voluntarios Sanos , Humanos , Imidazoles , Potasio , Pirimidinonas , TetrahidroisoquinolinasRESUMEN
Tegoprazan, a novel potassium-competitive acid blocker, is used to treat acid-related diseases. However, there is no information on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the marketed dosage of tegoprazan under various meal timings in a fed and fasted state. The study aimed to assess the effect of meal timing on PKs and PDs of tegoprazan 50 mg after a single administration in healthy male subjects. An open-label, single-dose, three-treatment, three-period crossover study was conducted. A total of 12 subjects were orally administered a single dose of tegoprazan 50 mg among various conditions: in a fasted state, at 30 min before or 30 min after a high-fat meal. PK parameters were estimated by the noncompartmental method. Continuous 24-h intragastric pH monitoring was done for PD analysis. The PKs and PDs of tegoprazan were compared among the various meal timings. Compared with the fasting condition, the PK profile of tegoprazan was similar when administered 30 min before a high-fat meal; however, delayed absorption with similar systemic exposure was observed when administered 30 min after a high-fat meal. The magnitude of acid suppression evaluated through the PD parameters increased when administered 30 min after a high-fat meal compared with fasting the condition and when administered 30 min before a high-fat meal. However, the increased difference in acid suppression was not clinically significant. Meal timing had no clinically significant effect on the PKs and PDs of tegoprazan 50 mg. Therefore, the marketed dosage of tegoprazan could be administered regardless of the meal timing. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tegoprazan, a novel potassium-competitive acid blocker, is used to treat acid-related diseases. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated the effect of food on pharmacokinetics (PKs) and pharmacodynamics (PDs) of tegoprazan under various mealtime conditions. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study showed that delayed absorption of tegoprazan was observed at "after meal condition," however, the amount of systemic exposure of "after meal condition" was similar to "fasting condition" and "before meal condition." In addition, gastric acid suppression of tegoprazan was similar between fasting condition and before meal condition, whereas increased gastric acid suppression was observed at after meal condition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? In the actual clinical environment, patients take medicine under various fed conditions. This study evaluated the effect of food on PKs and PDs of tegoprazan in various clinical conditions, and provided the important information about meal timing when administering tegoprazan.
Asunto(s)
Derivados del Benceno/farmacocinética , Interacciones Alimento-Droga/fisiología , Imidazoles/farmacocinética , Comidas/fisiología , Administración Oral , Adulto , Antiácidos/administración & dosificación , Área Bajo la Curva , Derivados del Benceno/administración & dosificación , Disponibilidad Biológica , Estudios Cruzados , Ayuno , Ácido Gástrico/metabolismo , Reflujo Gastroesofágico/tratamiento farmacológico , Voluntarios Sanos , Humanos , Imidazoles/administración & dosificación , Masculino , Úlcera Péptica/tratamiento farmacológico , Factores de TiempoRESUMEN
BACKGROUND: Potassium-competitive acid blockers (P-CABs) are emerging as novel treatments for acid-related disorders including gastroesophageal reflux disease. Tegoprazan and revaprazan are approved P-CABs in South Korea, but the pharmacodynamics and safety/tolerability of the two drugs have never been compared. AIMS: To evaluate the pharmacodynamics and safety/tolerability of tegoprazan and revaprazan after single and multiple oral doses METHODS: A randomised, open-label, active-controlled study was conducted in Helicobacter pylori-negative healthy Korean male subjects. Tegoprazan 50 mg or revaprazan 200 mg was administered orally, once daily for 7 days; 24-h intragastric pH monitoring and serum gastrin were measured for pharmacodynamic evaluation. Safety parameters including serum microRNA-122 (miR-122) level were also collected. RESULTS: After a single dose, the %Time pH ≥4 for tegoprazan was greater than that for revaprazan (54.5% vs 25.1%). After multiple doses, the %Time pH ≥4 for tegoprazan was also greater than that for revaprazan (68.2% vs 25.3%). %Time pH ≥4 during 12 hours at nighttime for tegoprazan was greater than that for revaprazan (71.8% vs 31.9%). The changes in the serum gastrin were not clinically significant for either drug. Despite the slight increases of serum miR-122 for each drug, tegoprazan and revaprazan were well tolerated considering other safety parameters including AST and ALT levels. CONCLUSION: Tegoprazan 50 mg showed stronger gastric acid suppression than revaorazan 200 mg. Both drugs were well tolerated.