Dyslipidemia is a major risk factor for development of atherosclerosis and cardiovascular disease (CVD). Effective lipid-lowering therapies has led to CVD risk reduction. This study evaluated the possible pharmacokinetic interactions between fenofibrate, a peroxisome proliferators-activated receptors α agonist, and pitavastatin, a 3-hydoxy-3-methylglutaryl-coenzyme A reductase inhibitor, in healthy Korean subjects. The study design was an open-label, randomized, multiple-dose, three-period, and six-sequence crossover study with a 10-day washout in 24 healthy volunteers. It had three treatments: 160 mg of micronized fenofibrate once daily for 5 days; 2 mg of pitavastatin once daily for 5 days; and 160 mg of micronized fenofibrate with 2 mg of pitavastatin for 5 days. Serial blood samples were collected at scheduled intervals for up to 48 h after the last dose in each period to determine the steady-state pharmacokinetics of both drugs. Plasma concentrations of fenofibric acid and pitavastatin were measured using a validated high-performance liquid chromatography with the tandem mass spectrometry method. A total of 24 subjects completed the study. Pitavastatin, when co-administered with micronized fenofibrate, had no effect on the C_max,ss and AUC_τ,ss of fenofibric acid. The C_max,ss and AUC_τ,ss of pitavastatin were increased by 36% and 12%, respectively, when co-administered with fenofibrate. Combined treatment with pitavastatin and micronized fenofibrate was generally well tolerated without serious adverse events. Our results demonstrated no clinically significant pharmacokinetic interactions between micronized fenofibrate and pitavastatin when 160 mg of micronized fenofibrate and 2 mg of pitavastatin are co-administered. The treatments were well tolerated during the study, with no serious adverse events.

Objective: Fimasartan, an angiotensin II type 1 receptor blocker, and linagliptin, a dipeptidyl-peptidase-4 inhibitor, are frequently coadministered to treat patients with hypertension and diabetes, respectively. This study sought to evaluate the pharmacokinetic interactions between fimasartan and linagliptin after co-administration in healthy Korean subjects. Methods: The overall study was divided into two separate parts, with each part designed as an open-label, multiple-dose, two-period, and single-sequence study. In Part A, to investigate the effect of linagliptin on fimasartan, 25 subjects received 120 mg fimasartan alone once daily for seven days during Period I, and 120 mg fimasartan with 20 mg linagliptin for seven days during Period II. In Part B, to examine the effect of fimasartan on linagliptin, 12 subjects received only linagliptin once daily for seven days during Period I, followed by concomitant administration of fimasartan for seven days during Period II, at the same doses used in Part A. Serial blood samples were collected at scheduled intervals for up to 24 h after the last dose to determine the steady-state pharmacokinetics of both drugs. Results: Thirty-six subjects completed the study. The geometric mean ratio and 90% confidence intervals for maximum plasma concentration at steady state (C_max,ss) and area under the concentration–time curve at steady state (AUC_τ,ss) of fimasartan with or without linagliptin were 1.2633 (0.9175– 1.7396) and 1.1740 (1.0499– 1.3126), respectively. The corresponding values for C_max,ss and AUC_τ,ss of linagliptin with or without fimasartan were 0.9804 (0.8480– 1.1336) and 0.9950 (0.9322– 1.0619), respectively. A total of eight adverse events (AEs) were reported and the incidence of AEs did not increase significantly with co-administration of the drugs. Conclusion: Our results suggest that there are no clinically significant pharmacokinetic interactions between fimasartan and linagliptin when co-administered. Treatments were well tolerated during the study, with no serious adverse effects. Clinical Trial Registry: http://clinicaltrials.gov, NCT03250052.

Background: YYD601 was developed as a novel dual delayed release (DDR) formulation of esomeprazole to prolong the plasma esomeprazole concentration and extend the duration of acid suppression. Purpose: The pharmacokinetic (PK) and pharmacodynamics (PD) characteristics of YYD601 after single and multiple oral administrations were investigated in healthy Korean adults under fasting and fed conditions, and compared with the original esomeprazole capsule. Methods: In the single-center, randomized, open-label, parallel-design, two-period study, thirty two volunteers were enrolled into four dosing groups, including esomeprazole 40-mg (group A), YYD60130-mg (group B), YYD601 40-mg (group C), and YYD601 60-mg (group D) once daily for 5 days. Blood samples were collected for PK analysis, before and up to 24 h after dosing. For PD characteristics of YYD601, the percentages of time with intragastric pH > 4 over a 24-h period and during night-time following multiple oral administrations were evaluated. Results: A total of 27 subjects completed the study. YYD601 showed a dual-peak PK profile under fasting condition, with delayed T_max, compared with conventional formulation. There were no significant differences in the AUC values adjusted for dose between the three YYD601 dosage groups and the conventional esomeprazole 40 mg. The esomeprazole AUC following single and multiple administration decreased with food intake by approximately 33%. YYD601 showed a linear pharmacokinetic profile in the dose range studied. There was no statistically significant difference in increase in mean percentage of time with intragastric pH > 4 for 24-hour and during night-time between the three different doses of YYD601 and the conventional formulation. The treatments were well-tolerated during the study and no serious adverse events were observed. Conclusion: YYD601 30 mg has a comparable effect on gastric acid inhibition as conventional esomeprazole 40 mg following once daily oral administration. Single and multiple oral dosing of YYD601 up to 60 mg were safe and well-tolerated throughout the study. Clinical Trial Registry: http://clinicaltrials.gov, NCT03558477 (date of registration: June 15, 2018; study period: between October 2017 and February 2018).

Fexuprazan, a potassium‐competitive acid blocker, is increasingly used for the treatment of gastroesophageal reflux disease in South Korea. While generally well tolerated, data regarding its hepatotoxic potential are scarce. We report a case of idiosyncratic drug‐induced liver injury in a 61‐year‐old woman following 2 months of fexuprazan therapy. She presented with fatigue and elevated liver enzymes, and liver biopsy demonstrated single‐cell necrosis, interface hepatitis and eosinophilic infiltration—features consistent with drug‐induced liver injury. Her liver function normalized after drug discontinuation. However, approximately 20 months later, the patient experienced a recurrence of liver injury after unintentionally being prescribed fexuprazan again. The second episode showed similar biochemical and histological features, fulfilling Hy's law criteria and increasing the RUCAM score from probable to highly probable . Pharmacokinetic analysis during the first episode revealed a prolonged elimination half‐life, suggestive of impaired metabolism during active hepatic injury. Pharmacogenetic testing revealed a cytochrome P450 enzyme 2C19 poor metabolizer genotype, although its clinical relevance was limited in this case. This report highlights a rare but reproducible adverse drug reaction to fexuprazan and emphasizes the importance of thorough drug history and postmarketing surveillance. To our knowledge, this is the first report of recurrent fexuprazan‐induced liver injury confirmed by unintentional re‐exposure.

This study compared the pharmacokinetics of a fixed-dose combination (FDC) of candesartan (16 mg) and amlodipine (10 mg) versus coadministration of individual formulations to clarify the bioequivalence of the FDC. In this randomized, open-label, single-dose, 2-treatment, 2-way crossover study, healthy Korean volunteers received a single dose of candesartan (16 mg) with amlodipine (10 mg) as either an FDC or single agents concomitantly administered, with a 2-week washout period. Serial blood samples were collected up to 72 hours after dosing for each treatment period, and plasma concentrations of candesartan and amlodipine were measured using a validated liquid chromatographytandem mass spectrometry method. A total of 39 subjects completed the study. The geometric mean ratios (GMRs) and 90% confidence intervals (Cis) for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC(0-t)) and the peak plasma concentration (C-max) for candesartan were 1.0182 (0.9562-1.0841) and 0.9492 (0.8726-1.0324), respectively. The GMR and 90% CI for the AUC(0-t) and C-max for amlodipine were 1.0552 (1.0255-1.0857) and 1.0668 (1.0259-1.1094), respectively. In conclusion, the new FDC formulation of candesartan (16 mg) and amlodipine (10 mg) was bioequivalent to the concomitant administration of single agents. A single dose of candesartan/amlodipine as the FDC or as single agents was well tolerated.