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Background: Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA). Methods: An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study. Results: Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (µg/L) and the area under the plasma concentration-time curve (h·µg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765-1.2017) and 0.9359 (0.7847-1.1163); free ezetimibe, 1.5713 (1.2821-1.9257) and 0.9941 (0.8384-1.1788); rosuvastatin, 2.1673 (1.7807-2.6379) and 1.1714 (0.9992-1.3733); telmisartan, 1.0745 (0.8139-1.4186) and 1.1057 (0.8379-1.4591); and amlodipine, 0.9421 (0.8764-1.0126) and 0.9603 (0.8862-1.0405). Both combination therapy and monotherapy were well tolerated by the subjects. Conclusion: The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.
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Amlodipino , Estudios Cruzados , Combinación de Medicamentos , Ezetimiba , Voluntarios Sanos , Rosuvastatina Cálcica , Telmisartán , Humanos , Telmisartán/administración & dosificación , Telmisartán/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Amlodipino/farmacocinética , Amlodipino/administración & dosificación , Masculino , Ezetimiba/administración & dosificación , Ezetimiba/farmacocinética , Adulto , Adulto Joven , Benzoatos/farmacocinética , Benzoatos/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/administración & dosificación , Relación Dosis-Respuesta a Droga , Interacciones FarmacológicasRESUMEN
BACKGROUND: Coinfection of tuberculosis or nontuberculous mycobacteria and Aspergillus presents a challenge in medication selection because of the pharmacokinetic interactions between rifampin and voriconazole. Some researchers have suggested the use of rifabutin as an alternative to rifampin because of its lower hepatic cytochrome P450 enzyme induction potency despite its contraindication to drug labels. This study presents clinical cases of voriconazole and rifabutin coadministration and their potential risks. METHODS: This retrospective study was conducted using clinical data from patients who met the following criteria: (1) admitted to Seoul National University Hospital between July 2014 and August 2023 and (2) concurrently administered rifabutin and voriconazole for more than 5 days. RESULTS: Among the 6 patients analyzed, 4 experienced adverse drug reactions (ADRs). Three patients experienced visual and auditory hallucinations, lower extremity numbness, or delirious behavior. Two patients had prolonged the time from the start of the Q wave to the end of the T wave intervals, and 1 had elevated aspartate aminotransferase and alanine aminotransferase levels. In addition, 2 patients experienced severe nausea, poor oral intake, and weight loss. Despite receiving 1.81-fold the recommended voriconazole dosage, a therapeutic concentration (1.0-5.5 mg/L) was not achieved because of cytochrome P450 induction by rifabutin. However, during septic shock, the voriconazole concentration increased by 13.7- to 36-fold. CONCLUSIONS: Concurrent use of rifabutin and voriconazole was associated with ADRs, including the time from the start of the Q wave to the end of the T wave prolongation, hallucinations, and severe nausea. Moreover, initially, there was a significant decrease in voriconazole concentrations; however, these concentrations substantially increased during septic shock. Therefore, it is essential to monitor drug concentrations and ADRs during concurrent use of voriconazole and rifabutin.
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Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (Cmax,ss) and area under plasma concentration-time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in Cmax, 19% in AUCτ,ss) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for Cmax,ss and AUCτ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.
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Antiinflamatorios no Esteroideos , Estudios Cruzados , Interacciones Farmacológicas , Humanos , Masculino , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/administración & dosificación , Adulto , Adulto Joven , Voluntarios Sanos , Área Bajo la Curva , Meloxicam/farmacocinética , Meloxicam/administración & dosificación , Naproxeno/farmacocinética , Naproxeno/administración & dosificación , Celecoxib/farmacocinética , Celecoxib/administración & dosificación , Persona de Mediana EdadRESUMEN
Vutiglabridin, which affects the pharmacokinetics (PKs) of food, is currently under clinical development for the treatment of obesity. This study aimed to evaluate the effects of low- and high-fat meals on PKs of vutiglabridin in healthy male subjects. A randomized, open-label, single-dose, three-period, six-sequence crossover study was conducted. The subjects received a single oral dose of vutiglabridin 480 mg in a fasted state, 30 min after the intake of a low-fat meal (total 500-600 kcal, fat content 100-125 kcal) and high-fat meal (total 800-1000 kcal, fat content 500-600 kcal), with a 21-day washout period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve to the last measurable timepoint (AUClast ) were calculated. After intake of low- and high-fat meals, systemic exposure to vutiglabridin was increased, and the time to reach Cmax (Tmax ) was delayed compared to that in the fasted state. The GMRs (90% CIs) of low-fat meal to fasted state for Cmax and AUClast were 2.14 (1.76-2.60) and 2.15 (1.92-2.42), respectively, and those of high-fat meal to fasted state were 3.07 (2.53-3.72) and 3.00 (2.67-3.37), respectively. The median Tmax was delayed by 1.5 h in both fed states compared with that in the fasted state. The study drug was well-tolerated after administration in both the fed and fasted states. Food ingestion substantially increased the extent of oral vutiglabridin absorption in healthy subjects, and this enhancement increased with the fat content of the meal.
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Fármacos Antiobesidad , Masculino , Humanos , Disponibilidad Biológica , Fármacos Antiobesidad/efectos adversos , Estudios Cruzados , Voluntarios Sanos , ComidasRESUMEN
Genetic variants affect drug responses, making pre-emptive genotyping crucial for averting serious adverse events (SAEs) and treatment failure. However, assessing the benefits of pre-emptive genotyping based on genetic distribution, drug exposure, and demographics is challenging. This study aimed to estimate the population-level benefits of pre-emptive genotyping in the Korean population using nationwide cohort data. We reviewed actionable gene-drug combinations recommended by both the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) as of February 2022, identifying high-risk phenotypes. We collected reported risk reduction from genotyping and standardized it into population attributable risks. Healthcare reimbursement costs for SAEs and treatment failures were obtained from the Health Insurance Review and Assessment Service Statistics in 2021. The benefits of pre-emptive genotyping for a specific group were determined by multiplying drug exposure from nationwide cohort data by individual genotyping benefits. We identified 31 gene-drug-event pairs, with CYP2D6 and CYP2C19 demonstrating the greatest benefits for both male and female patients. Individuals aged 65-70 years had the highest individual benefit from pre-emptive genotyping, with $84.40 for men and $100.90 for women. Pre-emptive genotyping, particularly for CYP2D6 and CYP2C19, can provide substantial benefits.
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Citocromo P-450 CYP2D6 , Farmacogenética , Femenino , Humanos , Masculino , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Genotipo , Fenotipo , AncianoRESUMEN
Purpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects. Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters. Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054-1.1883) and 0.9885 (0.9588-1.0192) for atorvastatin, 0.9607 (0.9068-1.0178) and 0.9770 (0.9239-1.0331) for EPA, and 0.9961 (0.9127-1.0871) and 0.9634 (0.8830-1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated. Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia.
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Dislipidemias , Ácido Eicosapentaenoico , Humanos , Masculino , Atorvastatina , Ácido Eicosapentaenoico/farmacocinética , Voluntarios Sanos , Estudios Cruzados , Ácidos Docosahexaenoicos , República de Corea , Combinación de Medicamentos , Área Bajo la CurvaRESUMEN
Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5-13.2], P = 7.2 × 10-6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5-1423], P = 7.5 × 10-6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility. Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.
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Arilamina N-Acetiltransferasa , Enfermedad Hepática Inducida por Sustancias y Drogas , Enfermedades Mitocondriales , Tuberculosis , Humanos , Antituberculosos/efectos adversos , Antituberculosos/toxicidad , Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Cobre/toxicidad , Genotipo , Isoniazida/toxicidad , Tuberculosis/tratamiento farmacológico , Tuberculosis/genéticaRESUMEN
OBJECTIVE: Despite the suggested topiramate serum level of 5-20 mg/L, numerous institutions have observed substantial drug response at lower levels. We aim to investigate the correlation between topiramate serum levels, drug responsiveness, and adverse events to establish a more accurate and tailored therapeutic range. METHODS: We retrospectively analyzed clinical data collected between January 2017 and January 2022 at Seoul National University Hospital. Drug responses to topiramate were categorized as "insufficient" or "sufficient" by reduction in seizure frequency ≥ 50%. A population pharmacokinetic model estimated serum levels from spot measurements. ROC curve analysis determined the optimal cutoff values. RESULTS: A total of 389 epilepsy patients were reviewed having a mean dose of 178.4 ± 117.9 mg/day and the serum level, 3.9 ± 2.8 mg/L. Only 5.6% samples exhibited insufficient response, with a mean serum level of 3.6 ± 2.5 mg/L while 94.4% demonstrated sufficient response, with a mean 4.0 ± 2.8 mg/L, having no statistical significance. Among the 69 reported adverse events, logistic regression analysis identified a significant association between ataxia and serum concentration (p = 0.04), with an optimal cutoff value of 6.5 mg/L. INTERPRETATION: This study proposed an optimal therapeutic concentration for topiramate based on patients' responsiveness to the drug and the incidence of adverse effects. We recommended serum levels below 6.5 mg/L to mitigate the risk of ataxia-related side effects while dose elevation was found unnecessary for suboptimal responders, as the drug's effectiveness plateaus at minimal doses.
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Anticonvulsivantes , Fructosa , Humanos , Topiramato , Estudios Retrospectivos , Fructosa/efectos adversos , AtaxiaRESUMEN
Velufenacin (DA-8010) is a new muscarinic receptor antagonist under development for the treatment of overactive bladder. This study aimed to evaluate the effect of food on the pharmacokinetics (PK) and safety of velufenacin in healthy subjects. A randomized, open-label, single-dose, 4-sequence, 4-treatment, 4-period crossover study was conducted. Subjects received a single oral dose of velufenacin 2.5 or 5 mg in a fasted or fed (high-fat meal) state in each period with a 7-day washout. PK parameters including maximum plasma concentration (Cmax ) and area under the concentration-time curve from time 0 to the last measurable point were compared between the fed and fasted states. Twenty-seven subjects completed the study. The mean area under the concentration-time curve from time 0 to the last measurable point of the velufenacin 2.5 and 5 mg doses under the fed condition showed a 1.5- and 1.3-fold increase, respectively, compared to the fasted condition. The corresponding values for Cmax were a 2.3- and 2.0-fold increase, respectively. The time to reach Cmax was comparable regardless of the dose or food intake, showing median values of 4.5-5.0 hours. These results suggest a modest increase of velufenacin absorption by food intake. Velufenacin was generally safe and well tolerated at the 2.5 and 5 mg doses regardless of food.
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Comidas , Antagonistas Muscarínicos , Humanos , Voluntarios Sanos , Estudios Cruzados , Administración Oral , Antagonistas Muscarínicos/efectos adversos , Receptores MuscarínicosRESUMEN
AIM: Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects. METHODS: In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing. RESULTS: Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated. CONCLUSION: The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.
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Etnicidad , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Masculino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Estudios Cruzados , Área Bajo la Curva , Interacciones Alimento-Droga , Voluntarios Sanos , Administración Oral , República de Corea , ChinaRESUMEN
Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18-64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68-14.32) also satisfied the non-inferiority criterion (95% CI lower limit > -5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.
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Tripegfilgrastim is a long-acting granulocyte colony-stimulating factor (G-CSF) that has been used to prevent chemotherapy-induced neutropenia in adults. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to explore the impact of chemotherapy and tripegfilgrastim on absolute neutrophil counts (ANCs) and to further propose a fixed-dose regimen in pediatric patients. Because neutrophils affect the clearance of tripegfilgrastim, the semimechanistic PK-PD model was developed simultaneously by using data from 40 healthy adults and 27 pediatric patients with solid tumors. Tripegfilgrastim PK and ANC dynamics were described with a pharmacodynamics-mediated drug disposition model assuming quasi-equilibrium with five transit compartments mimicking neutrophil granulopoiesis. The effect of chemotherapy on neutrophils was included by stimulating the elimination of the G-CSF receptor at the mitotic cells. Healthy adult and pediatric patients showed significantly different value for dissociation constant of the tripegfilgrastim-G-CSF receptor complex (Kd ) and apparent volume of distribution (Vd /F). Patients treated with chemotherapy had a higher Vd /F and 62% lower Kd than healthy adults. As the age increased, the absorption rate of tripegfilgrastim was decreased. Body weight affected the G-CSF receptor-mediated internalization of tripegfilgrastim, and the baseline ANC value impacted the production rate of G-CSF receptors. Simulations from the developed model suggested that 1.5, 2.5, 4, and 6 mg single subcutaneous tripegfilgrastim doses for the respective weight groups of 10-20, 21-30, 31-44, and more than 45 kg significantly reduced the duration of Grade 4 neutropenia similar to tripegfilgrastim weight-based treatment with 100 µg/kg.
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Neutropenia , Receptores de Factor Estimulante de Colonias de Granulocito , Adulto , Humanos , Niño , Receptores de Factor Estimulante de Colonias de Granulocito/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Recuento de Leucocitos , Neutropenia/inducido químicamente , Neutropenia/prevención & control , NeutrófilosRESUMEN
AIMS: The new modified-release formulation of tegoprazan, a novel potassium-competitive acid blocker, is expected to improve the management of acid-related disease, including nocturnal acid breakthrough, by prolonging the duration of acid suppression. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of various combinations of tegoprazan with immediate-release (IR) and delayed-release (DR) formulations. METHODS: A three-cohort, open-label, randomized, single-dose, three-treatment, six-sequence, three-period crossover study was conducted. Various combinations of tegoprazan IR and DR formulations (50, 75 or 100 mg) were administered orally once per period. The 24-h intragastric pH was monitored before and after each administration. PK blood samples were collected for up to 48 h. PK and PD were compared among treatments. RESULTS: Eighteen healthy Korean subjects completed the study. All treatment groups showed intragastric pH above 4 approximately 1 h following tegoprazan administration. Among the various combinations, the IR and DR combination at a 1:1 ratio induced greater gastric acid suppression (%Time pH ≥ 4) than IR alone in each dose group, both for 24 h (50 mg; 59% vs. 52%, P = .2188, 95% confidence interval [CI] -6.92-22.27, 100 mg; 85% vs. 70%, P < .05, 95% CI 8.92-22.19) and at night (50 mg; 27% vs. 16%, P = .1563, 95% CI -11.79-37.71, 100 mg; 77% vs. 49%, P < .05, 95% CI 16.14-42.98), with similar systemic exposure. CONCLUSIONS: The combinatorial tegoprazan in the IR and DR 1:1 ratio formulation was found to induce stronger gastric acid suppression throughout the day and at night, compared to the conventional IR formulation.
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Background: Dapagliflozin formate (DAP-FOR, DA-2811), an ester prodrug of dapagliflozin, was developed to improve the stability and pharmaceutical manufacturing process of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor. Purpose: This study aimed to evaluate the pharmacokinetics (PKs) and safety of dapagliflozin for DAP-FOR compared to those for dapagliflozin propanediol monohydrate (DAP-PDH, Forxiga) in healthy subjects. Methods: This was an open-label, randomized, single-dose, two-period, two-sequence crossover study. The subjects received a single dose of DAP-FOR or DAP-PDH 10 mg in each period, with a 7-day washout. Serial blood samples for PK analysis were collected up to 48 hours after a single administration to determine plasma concentrations of DAP-FOR and dapagliflozin. PK parameters were calculated using a non-compartmental method and compared between the two drugs. Results: In total, 28 subjects completed the study. DAP-FOR plasma concentrations were not detected in all of the blood sampling time points except for one time point in one subject, and the corresponding DAP-FOR plasma concentration in the subject was close to the lower limit of quantification. The mean plasma concentration-time profiles of dapagliflozin were comparable between the two drugs. The geometric mean ratios and its 90% confidence intervals of the maximum plasma concentration and area under the plasma concentration-time curve of dapagliflozin for DAP-FOR to DAP-PDH were within the conventional bioequivalence range of 0.80-1.25. Both drugs were well-tolerated, with a similar incidence of adverse drug reactions. Conclusion: The rapid conversion of DAP-FOR into dapagliflozin led to the extremely low exposure of DAP-FOR and comparable PK profiles of dapagliflozin between DAP-FOR and DAP-PDH. The safety profiles were also similar between the two drugs. These results suggest that DAP-FOR can be used as an alternative to DAP-PDH.
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Diabetes Mellitus Tipo 2 , Profármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Hipoglucemiantes/farmacocinética , Profármacos/efectos adversos , Diabetes Mellitus Tipo 2/inducido químicamente , Voluntarios Sanos , Estudios Cruzados , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Equivalencia Terapéutica , Formiatos , Glicoles de Propileno , Área Bajo la CurvaRESUMEN
Background: Esomeprazole, a proton pump inhibitor (PPI), is widely used to treat acid-related disorders, but it has short plasma half-life which can cause insufficient gastric acid suppression, such as nocturnal acid breakthrough. A new dual delayed-release (DR) formulation of esomeprazole (Esomezol DR), was developed to extend the duration of gastric acid suppression. Purpose: This study aimed to evaluate the pharmacokinetics (PKs) and pharmacodynamics (PDs) of esomeprazole for the DR formulation compared to a conventional enteric-coated (EC) formulation (Nexium) in healthy male subjects. Methods: Two randomized, open-label, multiple-dose, two-way crossover studies with esomeprazole 20 mg and 40 mg were conducted. Subjects received the DR formulation or the EC formulation once daily for 7 days in each period with a 7-day washout. Serial blood samples were collected up to 24 hours after the 1st dose, and 24-hour intragastric pH was continuously monitored before the 1st dose as baseline and after the 1st and the 7th dose. Results: In 20 mg and 40 mg dose groups, 38 and 44 subjects completed the study, respectively. The DR formulation exhibited the dual-release pattern of esomeprazole, resulting in more sustained plasma concentration-time profiles compared to the EC formulation. The systemic exposure of esomeprazole for the DR formulation was comparable to that for the EC formulation, showing the similar area under the plasma concentration-time curve. The 24-hour gastric acid suppression was also similar between the two formulations, while the inhibition during night-time (22:00-06:00) showed a better tendency in the DR formulation. Conclusion: The sustained exposure of esomeprazole in the DR formulation led to well-maintained and higher acid inhibition compared to the EC formulation, especially during the night-time. These results suggest that the DR formulation can be an alternative formulation to the conventional EC formulation, expecting the potential of relieving nocturnal acid-related symptoms.
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Antiulcerosos , Esomeprazol , Humanos , Masculino , Antiulcerosos/farmacología , Estudios Cruzados , Ácido Gástrico , Voluntarios Sanos , Concentración de Iones de Hidrógeno , Inhibidores de la Bomba de Protones/farmacologíaRESUMEN
Bersiporocin, a novel first-in-class prolyl-tRNA synthetase (PRS) inhibitor currently under clinical development, was shown to exert an antifibrotic effect through the downregulation of collagen synthesis in various pulmonary fibrosis models. The aim of this first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-dose, dose-escalation study was to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bersiporocin in healthy adults. A total of 40 and 32 subjects were included in a single- (SAD) and multiple-ascending dose (MAD) study, respectively. No severe or serious adverse events were observed after a single oral dose up to 600 mg and multiple oral doses up to 200 mg twice daily for 14 days. The most common treatment-emergent adverse events were gastrointestinal adverse events. To improve the tolerability, initial bersiporocin solution was changed to the enteric-coated formulation. Afterward, the enteric-coated tablet was used in the last cohort of SAD and in the MAD study. Bersiporocin showed dose-proportional PK characteristics after a single dose up to 600 mg and multiple doses up to 200 mg. Upon reviewing the safety and PK data, the final SAD cohort (800 mg enteric-coated tablet) was canceled by the Safety Review Committee. The levels of pro-peptide of type 3 procollagen were lower after treatment with bersiporocin than after the placebo in the MAD study, whereas no significant change was observed in other idiopathic pulmonary fibrosis (IPF) biomarkers. In conclusion, the safety, PK, and PD profile of bersiporocin supported its further investigation in patients with IPF.
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Comprimidos Recubiertos , Adulto , Humanos , Voluntarios Sanos , Área Bajo la Curva , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND AND OBJECTIVE: CYP2C19-mediated drug interactions of acid-reducing agents are clinically important given the high possibility of concomitant administration with CYP2C19 substrates. This study aimed to evaluate the effect of tegoprazan on the pharmacokinetics (PK) of a CYP2C19 substrate, proguanil, compared with vonoprazan or esomeprazole. METHODS: A two-part, randomized, open-label, two-sequence, three-period crossover study was conducted in 16 healthy CYP2C19 extensive metabolizers (eight subjects per part). In each period, a single oral dose of atovaquone/proguanil 250/100 mg was administered alone or co-administered with tegoprazan 50 mg, esomeprazole 40 mg (Part 1 only) or vonoprazan 20 mg (Part 2 only). The plasma and urine concentrations of proguanil and its metabolite, cycloguanil, were measured up to 48 h post-dose. PK parameters were calculated using a non-compartmental method and compared between administered alone and co-administered with tegoprazan, vonoprazan or esomeprazole. RESULTS: Co-administration of tegoprazan did not significantly affect the systemic exposure of proguanil and cycloguanil. In contrast, co-administration of vonoprazan or esomeprazole increased proguanil systemic exposure and decreased cycloguanil systemic exposure, and the magnitude of the corresponding change was greater with esomeprazole co-administration than vonoprazan co-administration. CONCLUSION: Tegoprazan, unlike vonoprazan and esomeprazole, exhibited negligible CYP2C19-mediated PK interaction. It suggests that as an alternative to other acid-reducing agents, tegoprazan can be used concomitantly with CYP2C19 substrates in clinical settings. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04568772 (Registered on September 29, 2020).
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Esomeprazol , Proguanil , Humanos , Atovacuona , Estudios Cruzados , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Interacciones Farmacológicas , Esomeprazol/farmacología , Proguanil/farmacocinética , Sustancias ReductorasRESUMEN
A novel dual delayed-release formulation (DR) of esomeprazole was developed to prolong the effect of esomeprazole inhibiting gastric acid secretion. This study investigated the effect of food on the pharmacokinetics (PK) and pharmacodynamics (PD) of DR esomeprazole. A randomized, open-label, single-dose, 2-period, 2-sequence crossover study was conducted in healthy Korean subjects. Subjects were orally administered a single dose of 40- mg DR esomeprazole in fasted and fed states in each period. PK and PD characteristics evaluated through continuous 24-hour intragastric pH monitoring in fasted and fed states were compared between the 2 conditions. A total of 23 subjects completed the study and were included in the PK analysis. PD analysis was conducted in 21 subjects, excluding 2 subjects, because of inappropriate pH profiles. The systemic exposure of esomeprazole after a single dose of DR esomeprazole in the fed state decreased compared to that in the fasted state. However, the percentage decrease from baseline in integrated gastric acidity and the percentage of time at pH ≥4 were not significantly different between the 2 conditions. In conclusion, although the systemic exposure of esomeprazole decreased when DR esomeprazole was administered in the fed state compared to that in the fasted state, the degree of gastric acid secretion inhibition was not clinically different, regardless of food intake.
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Antiulcerosos , Esomeprazol , Humanos , Antiulcerosos/farmacología , Estudios Cruzados , Voluntarios Sanos , AlimentosRESUMEN
Acid-reducing agents are commonly used for the prevention of aspirin-induced gastrointestinal complications such as peptic ulcers. As a novel potassium-competitive acid blocker, fexuprazan is expected to prevent aspirin-induced gastrointestinal complications. This randomized, open-label study aimed to evaluate the pharmacodynamic and pharmacokinetic interactions between aspirin and fexuprazan in healthy Koreans. Subjects randomized to the aspirin group received 500 mg aspirin in combination with 80 mg fexuprazan. For the fexuprazan group, fexuprazan 80 mg was administered alone and then in combination with aspirin 500 mg. Platelet aggregation inhibited by aspirin and the pharmacokinetic parameters of aspirin and fexuprazan were compared between monotherapy and combination therapy. A total of 22 subjects completed the study. The platelet aggregation-inhibitory activity and systemic exposure to aspirin were not significantly affected by fexuprazan coadministration. The systemic exposure of fexuprazan was decreased up to 20% by aspirin coadministration, which was not regarded as clinically meaningful considering the previously reported exposure-response relationship. In conclusion, there were no clinically relevant pharmacodynamic or pharmacokinetic interactions between aspirin and fexuprazan. This finding suggests the potential of fexuprazan for the prevention of aspirin-induced gastrointestinal complications, serving as a baseline for optimizing its therapeutic application with aspirin.
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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.