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Tegoprazan is a novel potassium-competitive acid blocker that treats gastric acid-related diseases. Clarithromycin was widely used as one of various regimens for eradicating Helicobacter pylori. This study compared the pharmacokinetic and safety profile of tegoprazan and clarithromycin between combination therapy and monotherapy to evaluate the potential drug-drug interaction. An open-label, randomized, 6-sequence, 3-period crossover study was conducted in 24 healthy subjects. According to the assigned sequence, the subject was administered the assigned treatment during 5 days in each period. PK parameters of tegoprazan and clarithromycin administered in combination were compared with those of the respective monotherapies. The co-administration of tegoprazan with clarithromycin increased maximum steady-state plasma concentration (Css,max) and area under the plasma concentration-time curve in dosing interval at steady-state (AUCss,tau) of tegoprazan (1.6-fold in Css,max and 2.5-fold in AUCss,tau) and M1 (2.0-fold in Css,max, 2.5-fold in AUCss,tau) than tegoprazan alone. The Css,max and AUCss,tau of 14-hydroxyclarithromycin increased 1.8- and 2.0-fold in co-administration, respectively. The AUCss.tau of clarithromycin was slightly increased in co-administration, but Css,max was not changed. Combination of tegoprazan and clarithromycin and those of the respective monotherapies were tolerated in 24 healthy subjects. There may exist drug interaction that lead to reciprocal increase in plasma drug concentrations when tegoprazan and clarithromycin were administrated in combination and no safety concerns were raised. It is suggested that an in-depth analysis of the concentration-response relationship is necessary to determine whether these concentration changes warrant clinical action. Trial Registration: ClinicalTrials.gov Identifier: NCT02052336.
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Background/Aims: Tegoprazan, a novel potassium-competitive acid blocker, is expected to overcome the limitations of proton pump inhibitors and effectively control nocturnal acid breakthrough. To evaluate the pharmacodynamics of tegoprazan versus dexlansoprazole regarding nocturnal acid breakthrough in healthy subjects. Methods: In a randomized, open-label, single-dose, balanced incomplete block crossover study, 24 healthy male volunteers were enrolled and randomized to receive oral tegoprazan (50, 100, or 200 mg) or dexlansoprazole (60 mg) during each of two administration periods, separated by a 7- to 10-day washout period. Blood samples were collected for pharmacokinetic parameter analysis; gastric monitoring was performed for pharmacodynamic parameter evaluation. Results: All 24 subjects completed the study. Average maximum plasma concentration, area under the plasma concentration-time curve, and mean time with gastric pH >4 and pH >6 for tegoprazan demonstrated dose-dependent incremental increases. All the tegoprazan groups reached mean pH ≥4 within 2 hours, whereas the dexlansoprazole group required 7 hours after drug administration. Based on pharmacodynamic parameters up to 12 hours after evening dosing, 50, 100, and 200 mg of tegoprazan presented a stronger acid-suppressive effect than 60 mg of dexlansoprazole. Moreover, the dexlansoprazole group presented a comparable acid-suppressive effect with the tegoprazan groups 12 hours after dosing. Conclusions: All the tegoprazan groups demonstrated a significantly faster onset of gastric pH increase and longer holding times above pH >4 and pH >6 up to 12 hours after evening dosing than the dexlansoprazole group.
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Derivados del Benceno , Inhibidores de la Bomba de Protones , Humanos , Masculino , Dexlansoprazol/farmacocinética , Estudios Cruzados , Inhibidores de la Bomba de Protones/farmacología , Derivados del Benceno/farmacologíaRESUMEN
AIMS: Nocturnal acid breakthrough has been considered an unmet need of proton-pump inhibitors. Tegoprazan, a novel potassium-competitive acid blocker, is expected to show improved properties for this unmet need. This study was aimed to compare night-time acid suppression by tegoprazan with that by vonoprazan or esomeprazole, and to explore the effect of CYP2C19 phenotypes on acid-suppressive effects. METHODS: A randomized, open-label, 3-period, 6-sequence crossover study was conducted. A single oral dose of tegoprazan 50 mg, vonoprazan 20 mg or esomeprazole 40 mg was administered at night in each period. Continuous intragastric pH was monitored at baseline and after each dosing. RESULTS: Sixteen healthy subjects (6 CYP2C19 extensive metabolizers, 5 intermediate metabolizers, 5 poor metabolizers) completed the study. After a single dose of tegoprazan, intragastric pH increased more rapidly to over 4 at approximately 1 hour compared to the other treatments, and elevated intragastric pH was maintained stably at night. Tegoprazan exhibited night-time acid suppression for slightly but not significantly longer than vonoprazan, and greater than esomeprazole; % time at pH ≥ 4 at night was 66.0%, 60.5% and 36.1% for tegoprazan, vonoprazan and esomeprazole, respectively. Night-time acid suppression by tegoprazan and vonoprazan was not dependent on CYP2C19 phenotypes, while that by esomeprazole tended to be influenced by CYP2C19 phenotypes. CONCLUSION: Tegoprazan produced more rapid, potent and well sustained night-time acid suppression vs. vonoprazan or esomeprazole when administered at night. Furthermore, tegoprazan showed no CYP2C19 phenotype dependency in acid suppression. It suggests the potential of tegoprazan, especially in preventing nocturnal acid breakthrough.
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Esomeprazol , Ácido Gástrico , Derivados del Benceno , Estudios Cruzados , Citocromo P-450 CYP2C19/genética , Esomeprazol/farmacología , Humanos , Concentración de Iones de Hidrógeno , Imidazoles , Inhibidores de la Bomba de Protones/farmacología , Pirroles , SulfonamidasRESUMEN
Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.
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This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug-drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator® and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure.
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This clinical trial was conducted to evaluate the pharmacokinetics and pharmacodynamics of tegoprazan when coadministered with amoxicillin/clarithromycin in healthy subjects. Cohort 1 was an open-label, randomized multiple-dose study to evaluate the mutual interaction of tegoprazan and amoxicillin/clarithromycin on the disposition of 3 tested drugs including tegoprazan M1 metabolite and 14-hydroxyclarithromycin (14-OH-clarithromycin). Cohort 2 was an open-label, randomized, active-controlled, parallel multiple-dose study to compare the intragastric pH profile after multiple oral doses of 50 or 100 mg tegoprazan coadministered with amoxicillin/clarithromycin 1000/500 mg for 7 days and pantoprazole-based triple therapy as the comparator arm. The coadministration of tegoprazan with amoxicillin/clarithromycin increased Css,max (2.2-fold) and AUCτ (2.7-fold) of tegoprazan and M1 (2.1- and 2.2-fold for Css,max and AUCτ , respectively) compared with administration of tegoprazan alone. The Css,max and AUCτ of 14-OH-clarithromycin increased by 1.7- and 1.8-fold, respectively; the disposition of amoxicillin and clarithromycin were not significantly changed. On days 1 and 7 of treatment, tegoprazan-based therapies (both 50- and 100-mg therapies) maintained pH above 6 for more than 88% of the 24-hour period, which was significantly longer compared with pantoprazole-based therapy. Tegoprazan either alone or in combination with amoxicillin/clarithromycin was well tolerated in healthy subjects. In conclusion, the exposure of tegoprazan was increased after coadministration of amoxicillin/clarithromycin, which led to increase pharmacodynamic response measured by intragastric pH compared with tegoprazan alone. Therefore, tegoprazan-based triple therapy would be effective therapeutic regimen to manage intragastric pH in terms of gastric or duodenal ulcers healing, treatment of gastroesophageal reflux disease, and Helicobacter pylori eradication.
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Amoxicilina/farmacocinética , Derivados del Benceno/farmacocinética , Claritromicina/farmacocinética , Fármacos Gastrointestinales/farmacocinética , Imidazoles/farmacocinética , Adulto , Amoxicilina/administración & dosificación , Amoxicilina/farmacología , Área Bajo la Curva , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacología , Claritromicina/administración & dosificación , Claritromicina/análogos & derivados , Claritromicina/metabolismo , Claritromicina/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/farmacología , Voluntarios Sanos , Humanos , Concentración de Iones de Hidrógeno , Imidazoles/administración & dosificación , Imidazoles/farmacología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
BACKGROUND: We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors. RESEARCH DESIGN AND METHODS: With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1. RESULTS: A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease. CONCLUSIONS: Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.
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Antineoplásicos/administración & dosificación , Arsenitos/administración & dosificación , Neoplasias/tratamiento farmacológico , Compuestos de Sodio/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Arsenitos/efectos adversos , Arsenitos/farmacocinética , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Compuestos de Sodio/efectos adversos , Compuestos de Sodio/farmacocinética , Resultado del TratamientoRESUMEN
The objective of study was to compare the pharmacokinetic and safety profiles of a fixed-dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160-mg amlodipine/valsartan tablet and a 20-mg atorvastatin tablet. This was a randomized, open-label, single-dose, 3-sequence, 3-period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference-scaled average BE approach was used if applicable, as well as the conventional limit of 0.80-1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (Cmax ) and the area under the curve to the last measurable concentration (AUCt ) between the FDC and separate formulations were within the 0.80-1.25 limit for all analytes but atorvastatin. The estimated within-subject standard deviation of the log-transformed values of the separate formulations, the reference intervention, was 0.3804 for the Cmax of atorvastatin, being set at 0.7489-1.3352 for the BE acceptance limit. For both the Cmax and AUCt for atorvastatin, the GMRs lay within 0.80-1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3-period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment-emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.
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Amlodipino/administración & dosificación , Atorvastatina/administración & dosificación , Valsartán/administración & dosificación , Adulto , Amlodipino/efectos adversos , Amlodipino/farmacocinética , Combinación Amlodipino y Valsartán/administración & dosificación , Combinación Amlodipino y Valsartán/efectos adversos , Combinación Amlodipino y Valsartán/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/farmacocinética , Área Bajo la Curva , Atorvastatina/efectos adversos , Atorvastatina/farmacocinética , Estudios Cruzados , Combinación de Medicamentos , Humanos , Masculino , Equivalencia Terapéutica , Valsartán/efectos adversos , Valsartán/farmacocinética , Adulto JovenRESUMEN
PURPOSE: Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines. METHODS: This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated. FINDINGS: Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 µg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects. IMPLICATIONS: Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.
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Antiinflamatorios no Esteroideos/farmacología , Celecoxib/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Adulto , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Celecoxib/sangre , Celecoxib/farmacocinética , Estudios Cruzados , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Femenino , Humanos , Masculino , Moxifloxacino/sangre , Moxifloxacino/farmacocinética , Moxifloxacino/farmacología , Adulto JovenRESUMEN
PURPOSE: We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects. METHODS: An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined. RESULTS: The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol. CONCLUSIONS: Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.
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Cilostazol/administración & dosificación , Citocromo P-450 CYP3A/genética , Interacciones Farmacológicas , Simvastatina/farmacocinética , Adulto , Cromatografía Liquida , Femenino , Voluntarios Sanos , Humanos , Masculino , Simvastatina/administración & dosificación , Simvastatina/análogos & derivados , Simvastatina/sangreRESUMEN
Fludarabine is used as a common component of conditioning regimens for haematopoietic stem cell transplantation (HSCT). However, knowledge regarding the pharmacokinetic characteristics of once-daily fludarabine dosing in children is limited. This study investigated the pharmacokinetics of fludarabine and evaluated its associations with clinical outcomes in paediatric patients. A total of 802 blood samples obtained from 43 paediatric patients who underwent HSCT were included in a population pharmacokinetic analysis using non-linear mixed-effects modelling. The relationships between systemic 9-ß-d-arabinofuranosyl-2-fluoroadenine (F-ara-A) exposure derived from the model and the clinical outcome variables were explored. A two-compartment model with proportional residual error adequately described the pharmacokinetics of F-ara-A. The body surface area and glomerular filtration rate were significant covariates for the clearance of F-ara-A. After the first dose of fludarabine at 40 mg/m2, the median (min-max) values for the area under the concentration-time curve (AUC) from dosing to infinity and the elimination half-life were 4696 (3056-10,477) ng·h/mL and 7.95 (4.78-10.88) h, respectively. No significant associations were found between systemic exposure and graft-vs.-host disease, neurologic and pulmonary complications, relapse or survival. Systemic exposure was comparable to that of previous reports from different populations and had no association with clinical outcomes.
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Trasplante de Células Madre Hematopoyéticas/métodos , Dinámicas no Lineales , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adolescente , Área Bajo la Curva , Superficie Corporal , Niño , Preescolar , Femenino , Tasa de Filtración Glomerular , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Masculino , Pediatría , República de Corea , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/farmacocinética , Vidarabina/farmacologíaRESUMEN
OBJECTIVE: This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and safety properties of the test (CJ-40001) and reference (NESP®) versions of darbepoetin alfa following a single subcutaneous (SC) or intravenous (IV) administration in healthy male subjects. METHODS: A single-blind, randomized, single-dose, two-period, two-intervention crossover study was conducted, with two separate parts consisting of SC or IV administration. In each period, either a test or reference product was administered via the SC or IV route. Serial blood samples for PK analysis and the reticulocyte, hematocrit, hemoglobin, and red blood cell counts for PD analysis were collected for up to 360 or 264 h after SC or IV administration, respectively. The PK and PD parameters were calculated using non-compartmental methods. The 90% confidence intervals of the geometric mean ratios for the PK and PD parameters between the two interventions were estimated. Safety and anti-drug antibody profile assessments were performed. RESULTS: The mean darbepoetin alfa concentration-time profiles were comparable between the two products for SC and IV administration. Additionally, the PD and safety profiles were similar between the two products. Anti-drug antibody reactivity was negative for all samples from both intervention groups for SC and IV administration. The time-matched serum darbepoetin alfa concentration and the PD markers presented a counter-clockwise hysteresis, which suggests a time delay between the exposure and response. CONCLUSION: The test and reference darbepoetin alfa formulations had similar PK, PD, and safety profiles. Thus, it is expected that the two formulations are able to be used interchangeably in clinical settings. ClinicalTrials.gov Identifier: NCT03542916.
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Biosimilares Farmacéuticos/farmacología , Biosimilares Farmacéuticos/farmacocinética , Darbepoetina alfa/farmacología , Darbepoetina alfa/farmacocinética , Adulto , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/química , Darbepoetina alfa/efectos adversos , Darbepoetina alfa/química , Recuento de Eritrocitos , Hematócrito , Hemoglobinas/metabolismo , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Reticulocitos/efectos de los fármacos , Método Simple Ciego , Adulto JovenRESUMEN
PURPOSE: To evaluate the pharmacokinetics and pharmacodynamics of candesartan and amlodipine in the absence and presence of each other in healthy subjects. METHODS: This study consisted of two parts: part 1, the effect of amlodipine on candesartan; part 2, the effect of candesartan on amlodipine. Each part was designed as a randomized, open-label, two-sequence, two-period, two-intervention crossover study with 20 subjects and performed separately in different populations. Pharmacokinetic assessments were performed over 48 hours for candesartan in part 1 and 72 hours for amlodipine in part 2 after drug administration on Day 10. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events. RESULTS: For both candesartan and amlodipine, the 90% confidence intervals for the geometric mean ratios of area under the concentration-time curve from time zero to the time of dosing interval of 24 hours and maximum concentration after drug administration fell within the bioequivalence acceptance criteria. Although this study was conducted in normotensive subjects, blood pressure lowering effects were observed in all intervention groups and co-administration of candesartan and amlodipine reduced blood pressure more than amlodipine alone, but similar to candesartan alone. No serious adverse event was reported throughout the study, and all treatment emergent adverse events were mild to moderate in severity and were recovered without sequelae. CONCLUSION: Co-administration of candesartan and amlodipine did not change the systemic exposure of each drug alone in healthy subjects. The administration of candesartan 32 mg alone, amlodipine 10 mg alone, and co-administration of candesartan and amlodipine were well tolerated during the study.
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Amlodipino/administración & dosificación , Amlodipino/farmacocinética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/farmacocinética , Tetrazoles/administración & dosificación , Tetrazoles/farmacocinética , Administración Oral , Adulto , Amlodipino/efectos adversos , Amlodipino/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/sangre , Bencimidazoles/efectos adversos , Bencimidazoles/sangre , Compuestos de Bifenilo , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/sangre , Estudios Cruzados , Esquema de Medicación , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , República de Corea , Tetrazoles/efectos adversos , Tetrazoles/sangre , Adulto JovenRESUMEN
OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.â©.
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Acetatos/administración & dosificación , Acetatos/farmacocinética , Cetirizina/administración & dosificación , Cetirizina/farmacocinética , Antagonistas de los Receptores Histamínicos H1 no Sedantes/administración & dosificación , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacocinética , Antagonistas de Leucotrieno/administración & dosificación , Antagonistas de Leucotrieno/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Acetatos/efectos adversos , Acetatos/sangre , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Cetirizina/efectos adversos , Cetirizina/sangre , Estudios Cruzados , Ciclopropanos , Composición de Medicamentos , Semivida , Voluntarios Sanos , Antagonistas de los Receptores Histamínicos H1 no Sedantes/efectos adversos , Antagonistas de los Receptores Histamínicos H1 no Sedantes/sangre , Humanos , Antagonistas de Leucotrieno/efectos adversos , Antagonistas de Leucotrieno/sangre , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Quinolinas/efectos adversos , Quinolinas/sangre , República de Corea , Sulfuros , Comprimidos , Adulto JovenRESUMEN
MB12066 is a molecule derived from ß-lapachone that shown effects on obesity in previous studies. The present studies were conducted to evaluate the tolerability and pharmacokinetics (PK) of MB12066 after the oral administration of single and multiple doses to healthy volunteers. The study comprised 2 independent, randomized, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials to evaluate the safety, tolerability and PK of MB12066 in healthy Korean volunteers. Subjects were randomly assigned to receive a single 10, 30, 100, 150, 200, 300 or 400 mg of MB12066 and multiple 100 or 200 mg of MB12066. The subjects' vital signs, 12-lead electrocardiograms, clinical laboratory tests, adverse event statuses, and physical examinations were assessed during the study. Blood and urine samples were collected to determine the concentration of MB12066 from predose to 72 hours after the single administration and from predose to 96 hours postdose of day 7 after the multiple administration. NADH:quinone oxidoreductase 1 genotyping was performed to analyze the association between genetic polymorphisms and PK. MB12066 was well tolerated after oral administration of single and multiple doses. The systemic exposure to MB12066 after a single administration tended to increase in a dose-dependent manner in the dose range of 30-200 mg. The overall fraction of MB12066 excreted unchanged in urine was <1% of the administered dose. A significant relationship was observed between NADH:quinone oxidoreductase 1 polymorphisms and exposure to MB12066 after multiple administrations, but the result was not conclusive because of the small number of subjects. A single dose of MB12066 within the dose range of 10-400 mg and multiple doses of 100 and 200 mg of MB12066 were safe and tolerated in healthy subjects. Additionally, MB12066 was mainly eliminated through metabolism in humans.
Asunto(s)
NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , Naftoquinonas/química , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Adulto JovenRESUMEN
AIMS: A novel necrosis inhibitor, LC28-0126, is expected to have a cellular protective effect from ischaemic reperfusion injury in acute myocardial infarction. The objective of this study was to investigate the safety, tolerability and pharmacokinetics of LC28-0126 after a single intravenous administration in healthy male subjects. METHODS: The study was a dose-block-randomized, double-blind, placebo-controlled, single ascending dose, first-in-human trial. Subjects were randomly assigned to receive 0.3, 1, 3, 10, 25, 50, 100 or 200 mg of LC28-0126. LC28-0126 was infused for 30 min and 5 min in cohorts 1 and 2, respectively. An interim analysis to assess the tolerability and pharmacokinetics was conducted in each dose group. Blood samples were taken to determine plasma LC28-0126 concentrations from predose to 48 or 144 h postdose, and urine samples were taken from predose to 48 or 72 h postdose. RESULTS: Overall, 89 subjects were randomly assigned to the dose groups of the two cohorts. LC28-0126 was well tolerated, and no serious adverse events were reported. LC28-0126 showed rapid disposition in the distribution phase. Overall, the fraction of unchanged LC28-0126 excreted during the 48 or 72 h after administration was below 5%. The systemic exposure of LC28-0126 tends to be increased in a dose-proportional manner in the dose range of 0.3-200 mg. CONCLUSIONS: A single intravenous dose of LC28-0126 was safe and well tolerated up to 200 mg. Furthermore, LC28-0126 demonstrated a predictable pharmacokinetic profile after a single intravenous infusion of doses ranging from 0.3 to 200 mg.
Asunto(s)
Necrosis/prevención & control , Adulto , Área Bajo la Curva , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Daño por Reperfusión Miocárdica/prevención & control , Nivel sin Efectos Adversos Observados , Adulto JovenRESUMEN
BACKGROUND: Fimasartan is a novel angiotensin II receptor blocker. Fimasartan is mainly eliminated via biliary excretion, and its urinary elimination is less than 3%. OBJECTIVE: Based on guidance from the United States Food and Drug Administration, a reduced pharmacokinetic (PK) study was conducted to evaluate the effect of renal function on the PK of fimasartan in patients with renal impairment and healthy volunteers. METHODS: A single centre, single-dose, open-label, healthy volunteer controlled trial was conducted in patients with renal impairment (RI) (estimated glomerular filtration rate lower than 30 mL/min/1.73 m(2)) and age-, weight- and sex-matched healthy volunteers (estimated glomerular filtration rate higher than 90 mL/min/1.73 m(2)). All participants received a single oral dose of fimasartan 120 mg, after which serial blood sampling for PK evaluation was conducted. Noncompartmental PK analysis of fimasartan was performed. A mixed-effects model approach was used to identify significant covariates and PK parameters. RESULTS: Sixteen subjects were enrolled (8 healthy volunteers and 8 RI patients). The maximum plasma concentrations and areas under the plasma concentration curves of the RI patients were higher than those of the healthy volunteers, with geometric mean ratios of 1.87 and 1.73, respectively. The relative bioavailability of fimasartan from the population PK analysis was 77% higher in the RI patients than in the healthy volunteers. CONCLUSION: The increased drug exposure of fimasartan in RI patients was explained by the increased relative bioavailability. This result can be explained from our knowledge concerning alterations in PK related to renal function.