Tegoprazan is a novel potassium-competitive acid blocker that treats gastric acid-related diseases. Clarithromycin was widely used as one of various regimens for eradicating Helicobacter pylori. This study compared the pharmacokinetic and safety profile of tegoprazan and clarithromycin between combination therapy and monotherapy to evaluate the potential drug-drug interaction. An open-label, randomized, 6-sequence, 3-period crossover study was conducted in 24 healthy subjects. According to the assigned sequence, the subject was administered the assigned treatment during 5 days in each period. PK parameters of tegoprazan and clarithromycin administered in combination were compared with those of the respective monotherapies. The co-administration of tegoprazan with clarithromycin increased maximum steady-state plasma concentration (C ss,max ) and area under the plasma concentration-time curve in dosing interval at steady-state (AUC ss,tau ) of tegoprazan (1.6-fold in C ss,max and 2.5-fold in AUC ss,tau ) and M1 (2.0-fold in C ss,max , 2.5-fold in AUC ss,tau ) than tegoprazan alone. The C ss,max and AUC sss,tau of 14-hydroxyclarithromycin increased 1.8- and 2.0-fold in co-administration, respectively. The AUC ss.tau of clarithromycin was slightly increased in co-administration, but C ss,max was not changed. Combination of tegoprazan and clarithromycin and those of the respective monotherapies were tolerated in 24 healthy subjects. There may exist drug interaction that lead to reciprocal increase in plasma drug concentrations when tegoprazan and clarithromycin were administrated in combination and no safety concerns were raised. It is suggested that an in-depth analysis of the concentrationresponse relationship is necessary to determine whether these concentration changes warrant clinical action.

Clinical trials are essential for medical research, but they often face challenges in matching patients to trials and planning. Large language models (LLMs) offer a promising solution, signaling a transformative shift in the field of clinical trials. This review explores the multifaceted applications of LLMs within clinical trials, focusing on five main areas expected to be implemented in the near future: enhancing patient-trial matching, streamlining clinical trial planning, analyzing free text narratives for coding and classification, assisting in technical writing tasks, and providing cognizant consent via LLM-powered chatbots. While the application of LLMs is promising, it poses challenges such as accuracy validation and legal concerns. The convergence of LLMs with clinical trials has the potential to revolutionize the efficiency of clinical trials, paving the way for innovative methodologies and enhancing patient engagement. However, this development requires careful consideration and investment to overcome potential hurdles.

A common cause of drug hypersensitivity reactions is iodinated contrast media (ICM). ICM-induced hypersensitivity had been considered to be a non-immunological reaction, but evidence for an immunological mechanism has increased recently. Thus, we evaluated whether HLA-A, -B, and -C alleles were associated with ICM-induced hypersensitivity. In total, 126 patients who underwent contrast-enhanced computed tomography studies through outpatient clinics at a tertiary referral hospital between 2008 and 2012 were assessed. Sixty-one patients experienced ICM-induced hypersensitivity and the remainder, 65, were ICM-tolerant patients (control). ICM-induced hypersensitivity patients showed 51 with immediate, 7 with non-immediate, 3 with both or mixed type. HLA-A, -B, and -C genotyping was performed using a PCR sequence-based typing method. Four kinds of ICM were used: iopromide, iohexol, iobitridol, and iodixanol. The most used ICM among the hypersensitivity patients was iopromide. Significant difference in the frequency of HLA-B*58:01 (odds ratios [OR], 3.90; p = 0.0200, 95% confidence interval [CI], 1.16–13.07) was observed between ICM-induced immediate hypersensitivity and control. There were statistically significant differences in the frequencies of the HLA-B*38:02 (OR, 10.24; p = 0.0145; 95% CI, 1.09–96.14) and HLA-B*58:01 (OR, 3.98; p = 0.0348; 95% CI, 1.03–15.39) between iopromide-induced immediate hypersensitivity and control. The mechanism of ICM-induced hypersensitivity remains unknown, but this study showed associations, although weak, with HLA-B*58:01 alleles for ICM-induced immediate hypersensitivity and HLA-B*38:02 and HLA-B*58:01 for iopromideinduced immediate hypersensitivity as risk predictors. Further studies are needed to validate the associations in larger samples and to identify the functional mechanism behind these results.

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40–66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A,
Alleles ; Anticonvulsants ; Carbamazepine ; Cicatrix ; Drug Hypersensitivity Syndrome ; Female ; HLA-A Antigens ; Humans ; Long-Acting Thyroid Stimulator ; Lymphocyte Activation ; Lymphocytes ; Male ; Methods ; Phenytoin ; Seizures ; Stevens-Johnson Syndrome ; Valproic Acid

Two separate studies were conducted to establish bioequivalence (BE) for two doses of atorvastatin/metformin sustained-release (SR) fixed dose combination (FDC) versus the same dosage of the individual component (IC) tablets in healthy male subjects under fed conditions (study 1, BE of atorvastatin/metformin SR 20/500 mg FDC; study 2, BE of atorvastatin/metformin SR 20/750 mg FDC). Each study was a randomized, open-label, single oral dose, two-way crossover design. Serial blood samples were collected pre-dose and up to 36 hours post-dose for atorvastatin and 24 hours for metformin. Plasma concentrations of atorvastatin, 2-OH atorvastatin and metformin were analyzed using a validated liquid chromatography tandem mass-spectrometry. A non-compartmental analysis was used to calculate pharmacokinetic (PK) variables and analysis of variance was performed on the lognormal-transformed PK variables. A total of 75 subjects completed the study 1 (36 subjects) and study 2 (39 subjects). The 90% confidence intervals for the adjusted geometric mean ratio of Cmax and the AUC0-t were within the predefined 0.80 to 1.25 range. The number of subjects reporting at least one adverse event following FDC treatments was comparable to that following IC treatments. The two treatments were well tolerated. Therefore, atorvastatin/metformin SR 20/500 mg and 20/750 mg FDC tablets are expected to be used as alternatives to IC tablets to decrease the pill burden and increase patient compliance.
Atorvastatin Calcium* ; Chromatography, Liquid ; Cross-Over Studies* ; Humans ; Male* ; Metformin* ; Patient Compliance ; Pharmacokinetics* ; Plasma ; Tablets* ; Therapeutic Equivalency

Oseltamivir is a substrate of P-glycoprotein, an efflux drug transporter encoded by ABCB1. The objective of this study was to assess the role of ABCB1 (c.1236C>T, c.2677G>T/A, and c.3435C>T) polymorphisms in the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate in humans. Nineteen healthy male subjects were enrolled, and their ABCB1 polymorphisms were evaluated. After the oral administration of 75 mg oseltamivir, the plasma concentrations of oseltamivir and oseltamivir carboxylate were measured. Pharmacokinetic analysis was carried out. Systemic exposure to oseltamivir and oseltamivir carboxylate was higher in the mutant group than in the wild-type and heterozygous groups. We suggest that ABCB1 polymorphisms affect the pharmacokinetics of oseltamivir in humans. Further studies in a large population are necessary to validate the results of this preliminary study (Clinical Trial Registration Information [CRIS] registry: http://cris.nih.go.kr, No. KCT0001903).
Administration, Oral ; Humans* ; Male ; Oseltamivir* ; P-Glycoprotein ; Pharmacokinetics* ; Plasma

Simvastatin is a lipid-lowering drug that is metabolized to its active metabolite simvastatin acid (SA). We developed and validated a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to quantitate SA in human plasma using a liquid-liquid extraction method with methanol. The protonated analytes generated in negative ion mode were monitored by multiple reaction monitoring. Using 500-mL plasma aliquots, SA was quantified in the range of 0.1-100 ng/mL. Calibration was performed by internal standardization with lovastatin acid, and regression curves were generated using a weighting factor of 1/χ2. The linearity, precision, and accuracy of this assay for each compound were validated using quality control samples consisting of mixtures of SA (0.1, 0.5, 5, and 50 ng/mL) and plasma. The intra-batch accuracy was 95.3-107.8%, precision was -2.2% to -3.7%, and linearity (r2) was over 0.998 in the standard calibration range. The chromatographic running time was 3.0 min. This method sensitively and reliably measured SA concentrations in human plasma and was successfully used in clinical pharmacokinetic studies of simvastatin in healthy Korean adult male volunteers.
Adult ; Calibration ; Humans* ; Liquid-Liquid Extraction ; Lovastatin ; Male ; Mass Spectrometry* ; Methanol ; Plasma* ; Protons ; Quality Control ; Running ; Simvastatin* ; Volunteers

While phosphodiesterase type 5 inhibitors have been used for erectile dysfunction with acceptable safety profile, they can induce orthostatic hypotension in patients taking antihypertensive drugs with blood pressure lowering effect. This study evaluated the hemodynamic effects of 100 mg mirodenafil in hypertensive patients taking an amlodipine. Thirteen hypertensive patients who were taking 5 or 10 mg of amlodipine once daily participated in a randomized, double-blind, placebo-controlled, crossover study. A single oral dose of mirodenafil 100 mg or placebo was administered at 4.5 hour after administration of amlodipine. The maximal change in systolic and diastolic blood pressure (ΔmaxSBP and ΔmaxDBP) and pulse rate (ΔmaxPR) were compared between mirodenafil and placebo periods. Twelve patients completed this study and were included analysis. The values of ΔmaxPR in standing and supine position were significantly greater in the mirodenafil period (13.25±7.12 and 11.17±4.86 beats/minute) when compared to the placebo (8.50±4.72 and 6.58±3.90 beats/minute). The ΔmaxSBP and ΔmaxDBP in standing position appeared to be lower in the mirodenafil period, but they were not statistically different from those in the placebo period (ΔmaxSBP = -7.42±5.6 vs -4.42±5.37 mmHg and ΔmaxDBP = -7.17±5.72 vs -3.50±3.37 mmHg). Both ΔmaxSBP and ΔmaxDBP in standing and supine position were not significantly different between mirodenafil and placebo. This study demonstrated that mirodenafil exerted minimal hemodynamic effects in the patients taking amlodipine, that is unlikely associated with a clinically significant hypotensive event.
Amlodipine* ; Antihypertensive Agents ; Blood Pressure ; Cross-Over Studies ; Erectile Dysfunction ; Heart Rate ; Hemodynamics* ; Humans ; Hypotension, Orthostatic ; Male ; Phosphodiesterase 5 Inhibitors ; Posture ; Supine Position

The Vietnamese-Koreans, especially offspring between a Vietnamese mother and a Korean father constituted the highest proportion (64.2%) of total Kosian population according to a census in 2014. To evaluate genetic characteristics in the Vietnamese-Koreans, a total of 25 alleles from CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were genotyped using SNaPshot method with DNA samples of 127 Vietnamese-Koreans. The previous reports on the CYPs of Korean and Vietnamese populations were also analyzed for the comparative studies for the frequencies of CYP alleles. The statistical significances in allele and genotype frequencies among the ethnics were analyzed by Chi-square or Fisher's exact probability test. Although most of variants analyzed in 5 CYPs did not reach the statistically significant difference between the Vietnamese-Koreans and Vietnamese, some alleles were only found in Vietnamese-Koreans. Compared with Korean population, frequencies of CYP2D6*1 and CYP2D6*10B were statistically different from Vietnamese-Koreans (p<0.05). This is the first report to describe the CYP genotype profiles of Vietnamese-Koreans, which may provide important insight for the genotype based prediction of CYP activities of this admixture of Korean and Vietnamese.
Alleles ; Asian Continental Ancestry Group ; Censuses ; Cytochrome P-450 CYP2D6* ; Cytochrome P-450 Enzyme System ; DNA ; Fathers ; Genotype ; Humans ; Mothers ; Polymorphism, Genetic*

BACKGROUND: Amlodipine is a third-generation dihydropyridine calcium channel blocker, which has proven to be a useful drug against hypertension or angina. METHODS: This randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in twenty healthy male volunteers. Subjects were administered 5 mg of the test or reference formulation. After 2-week washout period, the other formulation was administered. Blood samples were collected up to 144 hours after drug administration, and plasma amlodipine concentrations were determined by validated liquid chromatography-tandem mass spectrometry. Drug safety was assessed using measurement of vital signs, physical examinations, laboratory test, electrocardiograms, and adverse event monitoring. RESULTS: All subjects were completed this study. The geometric mean ratios of Cmax and AUClast were 1.078 (90 % CI, 0.968 - 1.200) and 1.095 (90 % CI, 1.011 - 1.186), respectively. There were no serious adverse events were reported by both formulations. CONCLUSION: This study showed the test and reference formulations had similar pharmacokinetics and safety profiles.
Amlodipine ; Calcium Channels ; Cross-Over Studies ; Electrocardiography ; Healthy Volunteers ; Humans ; Hypertension ; Male* ; Mass Spectrometry ; Pharmacokinetics ; Physical Examination ; Plasma ; Vital Signs