RESUMEN

This study evaluated the pharmacokinetics and pharmacodynamics of the antiplatelet agent prasugrel, and explored its optimal dose regimens via modeling and simulation using NONMEM. We measured platelet aggregation and the serial plasma concentrations of the inactive (R-95913) and active metabolites (R-138727) of prasugrel after a single oral dose of 10-60 mg in 20 healthy adult male volunteers. A pharmacokinetic model for R-95913 and R-138727, and a pharmacodynamic model between the concentration of R-138727 and maximal platelet aggregation measured by light transmittance were constructed. The predictability of the model for platelet aggregation was evaluated by comparing the model prediction values with the observed ones not used in the construction of the model. Pharmacokinetic data were best described by a 3-compartment models for R-95913, a 1-compartment model for R-138727 with transit compartment model for absorption delay, and first-pass metabolic conversion of R-95913 into R-138727 during absorption. The association-dissociation model between R-138727 and its receptor in platelets was applied for the inhibitory effect of prasugrel on platelet aggregation. Prasugrel rapidly inhibited platelet aggregation after oral administration, with a prolonged duration of action; however, the concentration of the active metabolite decreased rapidly, which may have been due to the slow dissociation rate of R-138727 from its target receptor in platelets. The external validation suggests that our model could be used to individualize prasugrel treatment in various clinical situations. Simulation showed rapid onset of inhibitory effect with great magnitude and consistent inhibition after therapeutic dose of prasugrel.

Asunto(s)

Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Adulto , Masculino , Humanos , Clorhidrato de Prasugrel/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Pruebas de Función Plaquetaria , Voluntarios Sanos

RESUMEN

PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.

Asunto(s)

Anticoagulantes/farmacología , Hirudinas/farmacología , Modelos Biológicos , Fragmentos de Péptidos/farmacología , Adulto , Anticoagulantes/farmacocinética , Simulación por Computador , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Medicamentos Genéricos , Hirudinas/farmacocinética , Humanos , Masculino , Método de Montecarlo , Fragmentos de Péptidos/farmacocinética , Tiempo de Protrombina , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacología , Resultado del Tratamiento , Adulto Joven

RESUMEN

PURPOSE: A combination of clopidogrel and aspirin is the standard treatment for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Two novel antiplatelet agents, ticagrelor and prasugrel, have been shown to rapidly and more effectively inhibit the P2Y12 receptor compared with clopidogrel. The aim of this study was to evaluate and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor and prasugrel in healthy male Korean volunteers. METHODS: Two separate studies were conducted. One study was performed by using a single-sequence, open-label, crossover design in 12 volunteers who received a single oral dose of ticagrelor (180 mg) and then a single oral dose of prasugrel (60 mg for 4 volunteers and 30 mg for 8 volunteers) with a 7-day washout period. The other study was a randomized, open-label, parallel-group investigation in which 8 volunteers received a single oral dose of prasugrel (10 mg for 4 volunteers and 30 mg for 4 volunteers). In each study, blood samples for PK and platelet aggregation inhibition analysis were serially collected after the administration of each dose. Plasma concentrations of ticagrelor, AR-C124910XX (the active metabolite of ticagrelor), R-95913 (the inactive metabolite of prasugrel), and R-138727 (the active metabolite of prasugrel) were measured by using a validated LC-MS/MS method. PK was analyzed by using a noncompartmental method. Maximal platelet aggregations were assessed with light transmission aggregometry after induction with 20 µmol/L of adenosine diphosphate. FINDINGS: Twenty healthy male Korean volunteers participated in the 2 studies. Plasma concentrations of ticagrelor and AR-C124910XX were obtained from 12 subjects, R-95913 from 20 subjects, and R-138727 from 8 subjects. Both ticagrelor and prasugrel were rapidly absorbed, with the shortest median Tmax of 2.0 and 2.25 hours for ticagrelor and AR-C124910XX, respectively, and a Tmax of 0.5 hour for both R-95913 and R-138727. Strong inhibition of platelet aggregation was shown after administration of both ticagrelor and prasugrel, with slightly stronger and more rapid inhibition with prasugrel in the tested doses. Inhibitory activities of prasugrel lasted longer than those of ticagrelor, reflecting the difference in binding kinetics between the 2 drugs. IMPLICATIONS: Prasugrel 30 and 60 mg exhibited slightly stronger, more rapid, and sustainable platelet inhibitory effects compared with ticagrelor 180 mg. These differing effects should be considered when determining the efficacy and adverse effects of ticagrelor and prasugrel. ClinicalTrials.gov identifier: NCT01876797 and NCT02075268.

Asunto(s)

Adenosina/análogos & derivados , Inhibidores de Agregación Plaquetaria/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Clorhidrato de Prasugrel/administración & dosificación , Adenosina/administración & dosificación , Adenosina/farmacocinética , Adenosina/farmacología , Adulto , Pueblo Asiatico , Plaquetas/efectos de los fármacos , Estudios Cruzados , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel/farmacocinética , Clorhidrato de Prasugrel/farmacología , Espectrometría de Masas en Tándem , Ticagrelor , Adulto Joven

RESUMEN

OBJECTIVE: Gemigliptin is a selective DPP4 inhibitor used to treat type 2 diabetes. The objective of this study was to evaluate the pharmacokinetics (PKs) of gemigliptin, rosuvastatin, and irbesartan monotherapies and combination therapies. RESEARCH DESIGN AND METHODS: Randomized, open-label, three-treatment, six-sequence, three-period, crossover studies were performed on healthy male volunteers. The three treatments were: 50 mg gemigliptin alone; 20 mg rosuvastatin (part A) or 300 mg irbesartan alone (part B); and rosuvastatin or irbesartan with concomitant gemigliptin. Each drug was administered as part of once daily, 7 day, repeated dosing regimens with a 14 day washout period. CLINICAL TRIAL REGISTRATION: NCT01823133 (part A) and NCT01825850 (part B). MAIN OUTCOME MEASURES: The primary PK parameters - Cmax and AUCτ - were compared to the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) that were determined for the combination therapies and monotherapies. RESULTS: A total of 60 participants were administered the study drugs, and 52 participants (27 participants in part A; 25 participants in part B) were analyzed as part of the PK dataset. In part A, the GMRs (gemigliptin + rosuvastatin/gemigliptin) of the Cmax and AUCτ values of gemigliptin were 0.955 (90% CI = 0.874-1.044) and 1.023 (90% CI = 0.991-1.057), and those of rosuvastatin were 1.012 (90% CI = 0.946-1.084) and 1.086 (90% CI = 1.032-1.142), respectively. In part B, the GMRs of the Cmax and AUCτ values of gemigliptin were 1.046 (90% CI = 0.964-1.134) and 1.035 (90% CI = 1.005-1.065), and those of irbesartan were 0.966 (90% CI = 0.897-1.040) and 1.050 (90% CI = 0.993-1.111), respectively. The limitations of this study include its relatively short treatment period and small sample size, as only healthy participants were included. CONCLUSIONS: Gemigliptin does not affect the PK properties of rosuvastatin or irbesartan; also, rosuvastatin and irbesartan do not affect the PKs of gemigliptin.

Asunto(s)

Compuestos de Bifenilo/farmacocinética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fluorobencenos/farmacocinética , Piperidonas/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Tetrazoles/farmacocinética , Adulto , Área Bajo la Curva , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Monitoreo de Drogas , Quimioterapia Combinada , Voluntarios Sanos , Humanos , Hipoglucemiantes/farmacocinética , Irbesartán , Masculino , Persona de Mediana Edad , Rosuvastatina Cálcica

RESUMEN

PURPOSE: Megestrol acetate oral suspension is an appetite stimulant indicated for cachexia. It is available in a conventional formulation and as a nanocrystal dispersion. The aim of this study was to compare the tolerability and pharmacokinetics of these formulations under fed conditions in healthy Korean volunteers. METHODS: This was a randomized, single-dose, 3-treatment, 3-period, 6-sequence, crossover study in healthy Korean volunteers. In each period, participants received single oral doses of conventional formulation 800 mg/20 mL (reference), nanocrystal dispersion 650 mg/5.2 mL (test 1), and nanocrystal dispersion 675 mg/5.4 mL (test 2) after a high-calorie, high-fat meal. The periods were separated by a washout period of 14 days. Serial blood samples were collected up to 120 hours after dosing. The plasma concentrations of megestrol acetate were determined with a validated LC-MS/MS method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability was assessed by physical examinations, vital signs, clinical laboratory test results, and electrocardiograms. FINDINGS: Thirty-eight healthy volunteers completed the study. The geometric mean ratios of the AUC(last) and C(max) for test 1/reference were 0.88 (90% CI, 0.84-0.92) and 1.07 (90% CI, 0.99-1.15), respectively. The geometric mean ratios of the AUC(last) and C(max) for test 2/reference were 0.88 (90% CI, 0.84-0.93) and1.03 (90% CI, 0.96-1.10), respectively. All formulations were well tolerated. IMPLICATIONS: The pharmacokinetic characteristics and tolerability of the 2 megestrol acetate formulations are similar in fed volunteers and suggest no relevant difference in tolerability. ClinicalTrials.gov identifier: NCT01342055.

Asunto(s)

Estimulantes del Apetito/efectos adversos , Estimulantes del Apetito/farmacocinética , Acetato de Megestrol/efectos adversos , Acetato de Megestrol/farmacocinética , Adulto , Estimulantes del Apetito/administración & dosificación , Área Bajo la Curva , Pueblo Asiatico , Química Farmacéutica , Cromatografía Liquida , Estudios Cruzados , Voluntarios Sanos , Humanos , Masculino , Acetato de Megestrol/administración & dosificación , Nanopartículas/administración & dosificación , Nanopartículas/metabolismo , Espectrometría de Masas en Tándem , Equivalencia Terapéutica , Adulto Joven

RESUMEN

BACKGROUND: CG100649 is a novel anti-inflammatory drug that is currently under development. CG100649 demonstrates a dual mechanism of action on cyclooxygenase-2 and carbonic anhydrase that may result in favorable treatment effects and few adverse gastrointestinal and cardiovascular events. OBJECTIVE: The objective of this study was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of administering multiple oral doses of CG100649 to healthy Korean volunteers. METHODS: This was a randomized, double-blind, placebo-controlled, multiple ascending oral dose study that was performed on 8 male and 8 female subjects per dose cohort. Each subject was randomly selected to receive either a single loading dose followed by 6 days of once-daily placebo (n = 4; 2 male and 2 female subjects) or CG100649 (n = 12; 6 male and 6 female subjects). Each subject was administered 1 of 3 sequential dose levels (8-mg loading dose + 2 mg/d, 10-mg loading dose + 4 mg/d, or 12-mg loading dose + 8 mg/d). Blood samples for pharmacokinetic analysis were obtained ≤480 hours after the last dose. Blood samples for measuring serum thromboxane B2 (TXB2) and ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2) (markers of cyclooxygenase-1 and cyclooxygenase-2 activity, respectively) and urine samples for measuring prostanoid metabolites were collected ≤21 days after the last dose. RESULTS: During steady state, the median Tmax in blood and plasma after the last dose ranged from 3 to 10 hours and 3.5 to 7.3 hours, respectively. Mean terminal t½ values in blood and plasma ranged from 121 to 203 hours and 100 to 167 hours, respectively. Whole blood concentrations were 50 to 70 times higher than plasma concentrations in all 3 dose cohorts in both male and female subjects. Compared with baseline, serum TXB2 diminished by 68% to 91% at 8 hours after the administration of the last dose in all 3 cohorts (P < 0.001). Ex vivo lipopolysaccharide-stimulated PGE2 was maximally inhibited (89%-96%; P < 0.001) by all 3 dose levels on day 7. Urinary prostacyclin metabolite was inhibited by 64% (P < 0.001) on day 7 (12-24 hours) but only by the highest CG100649 dose. There were no clinically significant drug-related changes in blood pressure between treatment groups. The most frequently encountered adverse events were aphthous stomatitis and dyspepsia. CONCLUSIONS: CG100649 was well tolerated and demonstrated a whole blood concentration that is ~50 to 70 times higher than in plasma in these healthy subjects. CG100649 suppressed TXB2 and PGE2 at all 3 doses, and only the highest dose suppressed the urinary excretion of the urinary prostacyclin metabolite.

Asunto(s)

Inhibidores de la Ciclooxigenasa 2/farmacología , Furanos/farmacología , Sulfonamidas/farmacología , Administración Oral , Adulto , Pueblo Asiatico , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Método Doble Ciego , Femenino , Furanos/efectos adversos , Furanos/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Adulto Joven

RESUMEN

PURPOSE: Gemigliptin is approved for the treatment of type II diabetes mellitus. Sulfonylureas are commonly used in combination with other antidiabetic drugs to improve glycemic control. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of gemigliptin and glimepiride combination therapy compared with those of monotherapies. METHODS: A randomized, open-label, crossover study was performed on healthy Korean male volunteers. Each subject received the following treatments (A and B) with a 7-day washout period: treatment A consisted of gemigliptin 50 mg once daily administered orally for 6 days, followed by concomitant oral dosing of glimepiride 4 mg and gemigliptin 50 mg on day 7; treatment B consisted of a single dose of glimepiride 4 mg. Blood samples were collected up to 24-h postdose on day 6 (gemigliptin) and day 7 (gemigliptin and glimepiride) following treatment A, and on day 1 (glimepiride) following treatment B. Concentrations of gemigliptin, glimepiride, and metabolites were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Safety assessments were performed throughout the study. RESULTS: Twenty-three subjects completed the study. The geometric mean ratios (GMRs) of C max,ss and AUC τ,ss for gemigliptin were 1.0097 [90 % confidence interval (CI) 0.924-1.103] and 0.9997 (90 % CI 0.976-1.024), respectively. For glimepiride, the GMRs of C max and AUClast were 1.031 (90 % CI 0.908-1.172) and 0.995 (90 % CI 0.902-1.097), respectively. Both combination and monotherapy were well tolerated, and no serious adverse events were reported. CONCLUSION: Gemigliptin and glimepiride did not alter the pharmacokinetic properties of each other when they were co-administered in healthy volunteers, and were generally tolerated.

Asunto(s)

Hipoglucemiantes/farmacocinética , Piperidonas/farmacocinética , Pirimidinas/farmacocinética , Compuestos de Sulfonilurea/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Pueblo Asiatico , Cromatografía Liquida/métodos , Estudios Cruzados , Interacciones Farmacológicas , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Masculino , Piperidonas/efectos adversos , Piperidonas/farmacología , Pirimidinas/efectos adversos , Pirimidinas/farmacología , República de Corea , Compuestos de Sulfonilurea/efectos adversos , Compuestos de Sulfonilurea/farmacología , Espectrometría de Masas en Tándem , Adulto Joven

RESUMEN

OBJECTIVES: For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. MATERIALS AND METHODS: This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. RESULTS: Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. CONCLUSION: The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.

Asunto(s)

Interacciones Alimento-Droga , Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Piperidonas/farmacocinética , Pirimidinas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Estudios Cruzados , Preparaciones de Acción Retardada , Esquema de Medicación , Combinación de Medicamentos , Ayuno/sangre , Semivida , Voluntarios Sanos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/sangre , Masculino , Tasa de Depuración Metabólica , Metformina/administración & dosificación , Metformina/efectos adversos , Metformina/sangre , Piperidonas/administración & dosificación , Piperidonas/efectos adversos , Piperidonas/sangre , Periodo Posprandial , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/sangre , República de Corea , Factores Sexuales , Comprimidos , Adulto Joven

RESUMEN

BACKGROUND: Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent, which has potent activity against most Gram-negative and Gram-positive organisms. It is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. OBJECTIVE: The aim of this study was to assess the clinical potential of a new gemifloxacin 200 mg intravenous formulation by comparing its pharmacokinetic characteristics with those of the branded Factive(®) gemifloxacin tablet. METHODS: A single-dose, open-label, randomized-sequence, two-period crossover study was performed with 17 healthy male volunteers. The two treatment periods were separated by a 1-week washout period. Blood samples were taken for up to 48 h post-dose. Plasma gemifloxacin concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. To calculate the pharmacokinetic parameters, noncompartmental analysis was performed. The two formulations were considered to be pharmacokinetically equivalent if the 90 % confidence intervals (CIs) of the log-transformed ratios (intravenous/oral formulations) of the area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) and the AUC from time zero to infinity (AUC∞) were within the standard bioequivalence range (0.8-1.25). Safety and tolerability were evaluated on the basis of physical examinations, vital signs, electrocardiograms, clinical laboratory tests and adverse event monitoring. RESULTS: Seventeen subjects were enrolled, and 15 subjects completed the study. Sixteen subjects received intravenous 200 mg gemifloxacin and 15 received oral 320 mg gemifloxacin. The 15 subjects in the pharmacokinetic analysis set had a mean (standard deviation [SD]) age, height and weight of 27.2 (5.3) years, 173.5 (4.4) cm and 67.3 (7.4) kg, respectively. Both formulations had similar pharmacokinetic profiles. For the intravenous formulation, the mean (SD) AUClast, AUC∞ and maximum plasma concentration (C max) values were 9.12 (4.03) µg·h/mL, 9.26 (4.07) µg·h/mL and 2.90 (1.65) µg/mL, respectively, while these values for the oral formulation were 9.44 (3.34) µg·h/mL, 9.60 (3.49) µg·h/mL and 2.03 (0.95) µg/mL, respectively. For the intravenous and oral formulations, the median (range) time to reach C max (t max) values were 0.9 (0.7-1.0) and 1.0 (0.5-2.0) h, respectively. The mean relative bioavailability was 68.99 %. The 90 % CI of the ratios of the log-transformed values of AUClast and AUC∞ was 0.82-1.07. There were no serious adverse events. The intravenous and oral formulations were associated with treatment-emergent adverse event incidences of 63 % (10/16) and 13 % (2/15), respectively. After the intravenous formulation was administered, application site pain and paraesthesia were the most frequently reported adverse events (31 and 25 %, respectively). All adverse events resolved spontaneously without treatment. CONCLUSION: Intravenous 200 mg and oral 320 mg formulations of gemifloxacin are equivalent in terms of AUC following a single dose in healthy male subjects.

Asunto(s)

Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacocinética , Naftiridinas/administración & dosificación , Naftiridinas/farmacocinética , Administración Oral , Adulto , Disponibilidad Biológica , Química Farmacéutica , Estudios Cruzados , Gemifloxacina , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

BACKGROUND AND OBJECTIVE: Valsartan, an angiotensin receptor blocker, is often used with calcium channel blockers (CCBs) such as amlodipine to control hypertension. Recently, the fixed-dose combination (FDC) of amlodipine 10 mg/valsartan 160 mg (Exforge) was approved. Amlodipine is a racemic mixture of CCB; S-amlodipine has higher activity than R-form. Therefore, AGSAV301, the FDC of S-amlodipine 5 mg/valsartan 160 mg was recently developed. The objective of this study was to compare the pharmacokinetic (PK) characteristics of S-amlodipine and valsartan when administered as one tablet each of Exforge and AGSAV301 to healthy male subjects. METHODS: This was a single-dose, randomized, open-label, two-way, two-period crossover study. Each subject received a single dose of AGSAV301 and Exforge, separated by a 3-week washout period. Plasma samples for the PK analysis of valsartan and S-amlodipine were collected at predose (0) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 168 h after administration. Tolerability was also evaluated. RESULTS: A total of 29 subjects were enrolled; 24 completed this study. The S-amlodipine maximum plasma concentration (C max) geometric mean ratio (GMR) between AGSAV301 and Exforge was 0.951 (90 % CI 0.983-1.014), and area under the concentration-time curve from time 0 to last measured time point (AUClast) was 0.917 (90 % CI 0.861-0.976). The GMR of valsartan C max was 0.994 (90 % CI 0.918-1.076), and the AUClast was 0.927 (90 % CI 0.821-1.047). All adverse events (AEs) were resolved without sequelae; no serious AEs were reported. Two drugs showed similar tendencies to lower blood pressure in healthy subjects. CONCLUSIONS: The PK profiles of AGSAV301 and Exforge were bioequivalent. Both drugs were also well tolerated, with comparable AE profiles and similar blood pressure-lowering tendencies in healthy volunteers, suggesting equivalent therapeutic indications.

Asunto(s)

Amlodipino/administración & dosificación , Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Tetrazoles/administración & dosificación , Administración Oral , Adulto , Amlodipino/efectos adversos , Amlodipino/farmacocinética , Combinación Amlodipino y Valsartán , Antihipertensivos/efectos adversos , Antihipertensivos/farmacocinética , Área Bajo la Curva , Estudios Cruzados , Combinación de Medicamentos , Estudios de Seguimiento , Humanos , Masculino , Estereoisomerismo , Comprimidos , Tetrazoles/efectos adversos , Tetrazoles/farmacocinética , Equivalencia Terapéutica , Factores de Tiempo , Adulto Joven

RESUMEN

BACKGROUND: Eperisone hydrochloride, a centrally acting muscle relaxant, is a calcium antagonist that causes vasodilation and antispastic actions. Aceclofenac, an anti-inflammatory analgesic and antipyretic drug, has similar efficacy and improved gastrointestinal tolerance compared with other nonsteroidal anti-inflammatory drugs, such as diclofenac. Although eperisone hydrochloride and aceclofenac are frequently coadministered, no published studies have reported on the pharmacokinetic interactions between these 2 drugs. OBJECTIVE: The aim of this study was to investigate any pharmacokinetic interactions between eperisone hydrochloride and aceclofenac in healthy Korean men. METHODS: This was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and received eperisone hydrochloride (3 doses of 50 mg each), aceclofenac (2 doses of 100 mg each), or both as a single dose with a 7-day washout period between each dose. Blood samples were collected ≤ 24 hours after dosing, and plasma eperisone hydrochloride and aceclofenac concentrations were determined using validated LC/MS-MS. Pharmacokinetic analyses were conducted using noncompartmental methods. A safety profile was determined using the measurement of vital signs, ECG, and clinical laboratory tests. RESULTS: A total 24 of men were enrolled, and all completed the study. The geometric mean ratios (90% CIs) of the Cmax and AUC0-∞ values for eperisone were 1.18 (0.828-1.673) and 1.12 (0.836-1.507), respectively. The geometric mean ratios (90% CIs) of the Cmax and AUC0-∞ for aceclofenac were 0.93 (0.847-1.022) and 1.01 (0.979-1.036), respectively. A total of 7 adverse events were reported in 7 men. All adverse events were mild, and no significant differences were found between treatment groups. CONCLUSION: No clinically significant pharmacokinetic differences exist between 150 mg eperisone hydrochloride and 200 mg aceclofenac when administrated as a monotherapy or in combination.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacocinética , Bloqueadores de los Canales de Calcio/farmacocinética , Diclofenaco/análogos & derivados , Relajantes Musculares Centrales/farmacocinética , Propiofenonas/farmacocinética , Administración Oral , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Estudios Cruzados , Diclofenaco/administración & dosificación , Diclofenaco/farmacocinética , Interacciones Farmacológicas , Quimioterapia Combinada , Voluntarios Sanos , Humanos , Masculino , Relajantes Musculares Centrales/administración & dosificación , Propiofenonas/administración & dosificación , República de Corea , Equivalencia Terapéutica , Adulto Joven

RESUMEN

OBJECTIVE: To evaluate and compare the pharmacokinetics and tolerability of a single oral dose of mirodenafil in volunteer patients with severe renal impairment and healthy volunteers. METHODS AND MATERIALS: This open-label, single-dose, parallel group clinical study enrolled a total 12 volunteers (6 healthy volunteers and 6 volunteer patients with severe renal impairment). Each volunteer was orally administered 50 mg mirodenafil and serial blood samples were obtained after drug administration to determine the plasma concentration of mirodenafil using LC-MS/MS. The measured individual plasma concentrations were used to calculate the pharmacokinetic parameters using noncompartmental methods. Tolerability was also assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: All of the volunteers completed the study with no serious adverse events (AEs). A total of 4 AEs were reported, but all were of mild or moderate intensity and not considered to be related to the study drug. The geometric mean (95% CI) of the terminal half-life (t1/2ß) and the apparent clearance (CL/F) values of mirodenafil were 2.2 (1.4 - 3.4) h and 127.2 (95.1 - 170.2) l/h in the volunteer patients, and 3.0 (2.1 - 4.4) h and 136.1 (74.4 - 249.2) l/h in the healthy volunteers, respectively. The geometric mean of the AUC0-t of the volunteer patients was 8% higher and the geometric mean for clearance was 7% lower compared with the healthy volunteers. However, the geometric mean of the Cmax of the volunteer patients was 38% higher than that of the healthy volunteers. CONCLUSIONS: A single oral 50-mg dose of mirodenafil was well tolerated. Exposure (AUC0-t) to mirodenafil was similar in both healthy volunteers and volunteer patients with severe renal impairment and healthy volunteers.

Asunto(s)

Inhibidores de Fosfodiesterasa 5/farmacocinética , Pirimidinonas/farmacocinética , Insuficiencia Renal/metabolismo , Sulfonamidas/farmacocinética , Adulto , Cromatografía Liquida , Humanos , Masculino , Persona de Mediana Edad , Pirimidinonas/efectos adversos , Sulfonamidas/efectos adversos , Espectrometría de Masas en Tándem

RESUMEN

BACKGROUND: To date, no definitive treatment of functional dyspepsia (FD) has been proven to be effective and reasonably well-tolerated. Proton pump inhibitors (PPIs) combined with prokinetic agents are considered an effective option. Revaprazan is a selective potassium-competitive acid blocker that reversibly inhibits gastric H(+)/K(+)-ATPase and shows effective acid suppression comparable to PPIs. Itopride is a prokinetic agent that has anticholinesterase activity as well as dopamine D(2) receptor antagonistic activity. For this reason, revaprazan and itopride have been prescribed for FD; however, no available studies have reported the pharmacokinetic interactions of these 2 drugs. OBJECTIVE: The objective of this study was to compare the bioavailability and tolerability of revaprazan and itopride combination therapy to those of equally dosed monotherapies to acquire basic drug-drug interaction information about revaprazan. METHODS: This multiple-dose, randomized crossover study was conducted in healthy male Korean subjects. Subjects received, in randomized sequence, a 7-day oral dose of revaprazan 200 mg once daily, itopride 50 mg TID, or both. Each treatment period was separated by a 7-day washout period. Blood samples were collected for up to 24 hours following the last dose at steady state, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, clinical chemistry testing, and interviews. RESULTS: A total of 30 subjects were enrolled in the study. Among them, 28 subjects completed revaprazan treatment, and 27 completed the study (3 subjects were withdrawn). The geometric mean ratios (GMRs) (90% CI) of C(max,ss), and AUC(τ,ss) with revaprazan were 0.92 (0.84-1.00) and 0.96 (0.89-1.03), respectively. The GMRs of C(max,ss) and AUC(τ,ss) with itopride were 1.07 (0.96-1.20) and 1.12 (1.06-1.18), respectively. A total of 15 adverse events (AEs) were reported in 8 subjects. All AEs were considered to be mild, and there were no clinically significant differences between treatment groups. CONCLUSION: The findings from this study suggest bioequivalence between revaprazan given as monotherapy and in combination with itopride in these healthy Korean male volunteers, with no clinical significant drug-drug interaction. All treatments in this study was generally well tolerated. ClinicalTrials.gov identifier: NCT0133289.

Asunto(s)

Benzamidas/farmacocinética , Compuestos de Bencilo/farmacocinética , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Bomba de Protones/farmacocinética , Pirimidinonas/farmacocinética , Tetrahidroisoquinolinas/farmacocinética , Adulto , Área Bajo la Curva , Benzamidas/efectos adversos , Benzamidas/farmacología , Compuestos de Bencilo/efectos adversos , Compuestos de Bencilo/farmacología , Disponibilidad Biológica , Inhibidores de la Colinesterasa/efectos adversos , Inhibidores de la Colinesterasa/farmacología , Cromatografía Liquida , Estudios Cruzados , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Masculino , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacología , Pirimidinonas/efectos adversos , Pirimidinonas/farmacología , República de Corea , Espectrometría de Masas en Tándem , Tetrahidroisoquinolinas/efectos adversos , Tetrahidroisoquinolinas/farmacología , Adulto Joven

RESUMEN

OBJECTIVE: To compare pharmacokinetics and pharmacodynamics of two formulations of metformin in healthy male volunteers under fasting conditions. METHODS AND MATERIALS: This was a randomized, 3-treatment, 6-sequence, 3-period, crossover study in healthy Korean volunteers. Subjects received a placebo or a single oral dose of reference formulation (500-mg metformin hydrochloride) or a test formulation (571-mg metformin acetate). The pharmacodynamic profile was assessed according to the blood glucose level. RESULTS: A total of 30 healthy male volunteers were included, although 2 of them withdrew consent before drug administration. For the test formulation, the mean (SD) pharmacokinetic parameters of Cmax and AUC(0-24) were 1,691 (476.7) µg/ ml and 11,081 (2,804.5) mg×h/ml, respectively. For the reference formulation, the mean (SD) pharmacokinetic parameters of C(max) and AUC(0-24) were 1,749 (494.4) mg/ml and 11,814 (3,344.2) mg×h/ml, respectively. The 90% CIs for the test:reference ratio were 86.6 - 103.5 for logarithm-transformed AUClast and 87.9 - 107.4 for logarithm-transformed C(max), respectively. In pharmacodynamic analysis, the average blood glucose levels were obtained in the first 4 hours and 5 - 8 hours after drug administration. The 90% CIs for the test:reference ratio of the average blood glucose level were 96.5 - 101.8 for the intervals up to 4 hours during continued fasting and 99.3 - 106.8 for 5 - 8 hours after drug administration, respectively. CONCLUSION: The data suggests that the test and reference formulations meet the regulatory criteria for the pharmacokinetic equivalence in fasting healthy Korean male volunteers. The pharmacodynamic profile was similar between the test and reference formulations. Both metformin formulations appeared to be generally well-tolerated.

Asunto(s)

Hipoglucemiantes/farmacología , Hipoglucemiantes/farmacocinética , Metformina/farmacología , Metformina/farmacocinética , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Glucemia/efectos de los fármacos , Química Farmacéutica , Estudios Cruzados , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , Equivalencia Terapéutica

RESUMEN

BACKGROUND: Telmisartan belongs to a class of orally active angiotensin II receptor blockers (ARBs), and S-amlodipine is an enantiomer of amlodipine. Amlodipine is a racemic mixture and the calcium channel blocking (CCB) effect is confined to S-amlodipine, whereas R-amlodipine has a 1000-fold lower activity and no racemization occurs in vivo in human plasma. Combination therapy of ARBs with CCBs provides advantages for blood pressure control and vascular protection over monotherapy. OBJECTIVE: To investigate the effects of coadministration of telmisartan and S-amlodipine on the steady-state pharmacokinetic properties of each drug as a drug-drug interaction study required before developing the fixed-dose combination agent. METHODS: This study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-sequence, 2-period, crossover study in healthy male Korean volunteers. In part A, volunteers were administered 80 mg of telmisartan, either alone or with 5 mg of S-amlodipine. In part B, volunteers were administered 5 mg of S-amlodipine, either alone or with 80 mg of telmisartan. Blood samples were taken on days 9 and 37, following the final dose of each treatment, and at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration in part A, and were taken at 0 (predose), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, and 24 hours after administration in part B. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic properties of each drug after coadministration of telmisartan and S-amlodipine were compared with those of each drug administered alone. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: Fifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B). The geometric mean ratios (GMRs) (90% CI) for the C(max,ss) and AUC(τ,ss) of telmisartan (with or without S-amlodipine) were 1.039 (0.881-1.226) and 1.003 (0.926-1.087), respectively. The GMRs (90% CI) for C(max,ss) and AUC(τ,ss) of S-amlodipine (with or without telmisartan) were 0.973 (0.880-1.076) and 0.987 (0.897-1.085). Total 11 adverse events (AEs) were reported in 7 volunteers (21.9%) in part A. A total of 9 AEs were reported in 6 volunteers (25.0%) in part B. Statistical analysis confirmed that the 90% CIs for these pharmacokinetic parameters were within the commonly accepted bioequivalence range of 0.8 to 1.25, indicating that the extent of bioavailability of S-amlodipine was not affected by telmisartan. The intensity of all AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations. CONCLUSIONS: Following multiple-dose coadministration of high doses of telmisartan and S-amlodipine, the steady-state pharmacokinetic properties of telmisartan were not significantly affected, and telmisartan had no significant effect on the pharmacokinetic properties of S-amlodipine at steady state in these selected groups of healthy volunteers. Both formulations were generally well-tolerated.

Asunto(s)

Amlodipino/farmacocinética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Bencimidazoles/farmacocinética , Benzoatos/farmacocinética , Bloqueadores de los Canales de Calcio/farmacocinética , Adulto , Amlodipino/efectos adversos , Amlodipino/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Área Bajo la Curva , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Benzoatos/efectos adversos , Benzoatos/farmacología , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacología , Cromatografía Liquida , Estudios Cruzados , Interacciones Farmacológicas , Estudios de Seguimiento , Humanos , Masculino , República de Corea , Estereoisomerismo , Espectrometría de Masas en Tándem , Telmisartán , Factores de Tiempo , Adulto Joven

RESUMEN

BACKGROUND: Gemigliptin (LC15-0444) is a newly developed selective and competitive inhibitor of dipeptidyl peptidase (DPP)-4 and has potential for the treatment of type 2 diabetes mellitus. Gemigliptin is metabolized by the cytochrome P450 (CYP) 3A4 isozyme to yield the active major metabolite LC15-0636. OBJECTIVE: The effects of multiple oral doses of ketoconazole (a potent CYP3A4 inhibitor) and multiple oral doses of rifampicin (a potent CYP3A4 inducer) on the pharmacokinetic properties of a single oral dose of gemigliptin were evaluated in fasting healthy male Korean volunteers. METHODS: In this open-label, 2-part, 3-treatment, 1-sequence, 2-period crossover drug-drug interaction study, 1 group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions-once as monotherapy and again after pretreatment with 400 mg of oral ketoconazole once daily for 7 days. The other group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions-once without pretreatment and again after pretreatment with 600 mg of oral rifampicin once daily for 10 days. Blood samples were obtained at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 hours after gemigliptin dosing. Plasma concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: Twenty-four subjects were enrolled (12 per group). Concurrent administration of ketoconazole was associated with increased total gemigliptin plasma exposure (AUC(0-∞); 2.36-fold [90% CI, 2.19-2.54]) and decreased metabolism of gemigliptin until negligible concentrations of LC15-0636 were detected. Pretreatment with rifampicin was associated with decreased AUC(0-∞) of gemigliptin (by 80% [90% CI, 78%-82%]) and a 2.9-fold increase (mean [SD], 0.18 [0.08] to 0.52 [0.10]) in the metabolic ratio of gemigliptin to LC15-0636. The treatments were well-tolerated, with no severe adverse events reported. Six of the 24 subjects (25%) experienced AEs during the first period of gemigliptin monotherapy administration. Six of 12 subjects (50%) each experienced AEs during concurrent administration with ketoconazole and rifampicin. CONCLUSIONS: In this select group of healthy male Korean volunteers, concurrent administration of gemigliptin with ketoconazole or rifampicin was associated with significantly increased or decreased systemic exposure to gemigliptin, respectively. These findings suggest that gemigliptin may require a dose adjustment when concurrently administered with drugs that alter CYP3A4 activity. Concurrent administration of gemigliptin with ketoconazole or rifampicin was well tolerated. ClinicalTrials.gov identifier: NCT01426906.

Asunto(s)

Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Cetoconazol/farmacología , Compuestos Orgánicos/farmacocinética , Rifampin/farmacología , Administración Oral , Adulto , Área Bajo la Curva , Pueblo Asiatico , Cromatografía Liquida , Estudios Cruzados , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Esquema de Medicación , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Humanos , Cetoconazol/administración & dosificación , Cetoconazol/efectos adversos , Masculino , Compuestos Orgánicos/administración & dosificación , Compuestos Orgánicos/efectos adversos , Piperidonas/metabolismo , Pirimidinas/metabolismo , República de Corea , Rifampin/administración & dosificación , Rifampin/efectos adversos , Espectrometría de Masas en Tándem , Factores de Tiempo , Adulto Joven

RESUMEN

BACKGROUND: Pitavastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and valsartan, an angiotensin receptor blocker, are used concurrently in some patients who are both hyperlipidemic and hypertensive. However, to date, no published studies have explored whether there is an interaction between pitavastatin and valsartan. OBJECTIVE: The aim of this study was to investigate the potential pharmacokinetic interaction between pitavastatin and valsartan in healthy male volunteers in Korea. METHODS: A randomized, open-label crossover study was conducted in healthy male Korean volunteers. In varying sequences, each subject received pitavastatin 2 × 2 mg, valsartan 2 × 160 mg, and both treatments, once daily for 7 consecutive days, with a 7-day washout period between each treatment period. Plasma samples were obtained at steady state for the pharmacokinetic evaluation of pitavastatin and valsartan. Pharmacodynamic assessment included lipid profiles and vital sign measurements (systolic and diastolic blood pressure [SBP and DBP, respectively] and pulse rate [PR]). A safety profile assessment, which included vital sign measurements, ECG, and clinical laboratory testing, was performed in each subject. RESULTS: A total of 24 subjects were enrolled (mean age, 30.5 years [range, 23.0-45.0 years]; mean body weight, 71.2 kg [range, 56.1-86.0 kg]; and mean body mass index, 23.2 kg/m(2) [range, 19.2-25.8 kg/m(2)]). The 95% CIs of the geometric mean ratios of AUC(τ) and C(max,ss) of pitavastatin were 0.97 to 1.11 and 0.73 to 1.09, respectively. The 95% CIs of the geometric mean ratios of AUC(τ) and C(max,ss) of valsartan were 0.90 to 1.27 and 0.81 to 1.29. Pitavastatin administered as monotherapy and in combination with valsartan was associated with significantly lowered total cholesterol and LDL-C compared with valsartan monotherapy (both, P < 0.05). Differences in lipid-lowering effects were not statistically significant between pitavastatin monotherapy and pitavastatin combined with valsartan. Valsartan monotherapy and valsartan combined with pitavastatin were associated with significantly lower SBP and DBP compared with baseline (both, P < 0.05), although no significant changes in PR were observed. No significant differences in BP or PR changes were noted between concurrent administration of valsartan monotherapy compared with pitavastatin + valsartan. There were no serious AEs reported, and none of the subjects discontinued the study due to AEs. CONCLUSIONS: The pharmacokinetic profiles of pitavastatin and valsartan administered as monotherapy were comparable to combination treatment in these healthy male Korean volunteers, suggesting that individual pharmacokinetic properties are not significantly affected by concurrent administration. The concurrent administration of pitavastatin and valsartan was generally well tolerated. The findings from the present study provide a basis for a larger study in hypertensive patients with hyperlipidemia.

Asunto(s)

Antihipertensivos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Quinolinas/farmacocinética , Tetrazoles/farmacocinética , Valina/análogos & derivados , Adulto , Estudios Cruzados , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , República de Corea , Valina/farmacocinética , Valsartán

RESUMEN

PURPOSE: This study was designed to evaluate the effects of an educational program on pregnancy and delivery including pregnancy related knowledge, newborn care knowledge, and postpartum care self-efficacy for married immigrant women. METHODS: A nonequivalent control group quasi-experimental design was used. The educational program was developed by though an educational need assessment of married immigrant women and an expert opinion. The program was provided for 3 weeks, once a week for two hours. The data were analyzed with SPSS program using Kolmogorov-Smirnov, X(2)-test, Fisher's exact test, and t-test. RESULTS: The program significantly improved pregnancy related knowledge, newborn care knowledge, and postpartum care self-efficacy for the married immigrant women who participated in the program compared to the women who did not. CONCLUSION: The results indicate that the educational program has an affirmative effect on pregnancy related knowledge, knowledge of newborn care, and postpartum care self-efficacy in these women. It is suggested, therefore, that the educational program be used to every married immigrant woman at the public health centers or delivery clinics help them to adjust to the childbearing and childrearing experience and this will ultimately enhance the quality of family life of married immigrant women in Korea.

Asunto(s)

Emigrantes e Inmigrantes , Educación del Paciente como Asunto , Embarazo , Adulto , Femenino , Humanos , Matrimonio , Conducta Materna , Atención Posnatal , Atención Prenatal , Autoeficacia , Adulto Joven