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.

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.

Lee HW, et al. Transl Clin Pharmacol. 2022 Sep;30(3):136-144. https://doi.org/10.12793/tcp.2022.30.e13

Beta-Lapachone has been reported to have anticancer and various other therapeutic effects, but is limited in clinical applications by its low bioavailability. pH-Dependent isomerization can be suggested as one plausible factor influencing its low bioavailability. Since it is known that beta-lapachone is converted to its isomer, alpha-lapachone in hydrochloric acid (HCl) solution, isomerization in the human body may be driven by HCl in the gastric fluid. The purpose of this study was to evaluate the possibility of isomerization of beta-lapachone in the human body. Chemical reactions were conducted using simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.5) at 37 degrees C. beta-Lapachone was observed in SGF at 37 degrees C for 1 hour and SIF for 3 hours. In addition, biofluid analysis was performed on plasma samples 1 hour and 4 hours, and on urine sample 12 hours after oral administration of 100 mg MB12066, a synthetic beta-lapachone, in healthy adult male. All samples were analyzed using liquid chromatography-tandem mass spectrometry. Only beta-lapachone peaks existed in the spectra obtained from SGF and SIF. No isomerization of beta-lapachone was observed in the analysis of any of the human samples. In the current study, the possibility of pH-dependent isomerization of beta-lapachone in the human body was not confirmed.

Myocardial ischemia is a leading cause of cardiovascular morbidity and mortality; however, early and noninvasive diagnosis remains challenging. Conventional diagnostic methods, including electrocardiography, coronary angiography, and myocardial perfusion imaging have limitations in detecting early-stage ischemia. This study aimed to identify plasma metabolite biomarkers associated with early myocardial ischemia using liquid chromatography–quadrupole time-of-flight mass spectrometry (LC–QTOF/MS) based metabolomics. Eighty-nine patients with suspected myocardial ischemia hospitalized at Kyungpook National University Hospital were screened. After applying exclusion criteria, 43 patients were enrolled and divided into 2 groups: control (n = 24, no angiographic stenosis) and case (n = 19, >70% stenosis in vessels with a diameter of ≥2.5 mm). All participants underwent an exercise stress test based on the Bruce protocol. Plasma samples were collected before and 10 minutes after exercise. Untargeted LC–QTOF/MS profiling was performed, and multivariate analyses (principal component analysis and orthogonal partial least squares-discriminant analysis) were used to identify differential metabolites. Receiver operating characteristic analysis was conducted to evaluate diagnostic performance. Multivariate modeling revealed distinct metabolic differences between the groups. Thirteen metabolites were significantly altered in both groups, while 9 changed exclusively in the ischemia group following exercise. Notably, several phosphatidylcholine (PC) species – PC (O-18:5/2:0), PC (O-16:0/22:4), PC (O-18:4/18:2), and PC (20:4/20:4) – as well as 13Z-docosenamide, differed significantly between groups. Receiver operating characteristic analysis identified 3 key metabolites – 13Z-docosenamide, PC (16:0/22:5), and PC (18:1/20:4) – with excellent discriminative performance (area under the curve = 0.941; 95% confidence interval: 0.865–1.000; sensitivity, 92%; specificity, 93%). Pathway analysis indicated that exercise-induced ischemia was associated with alterations in phospholipid, sphingolipid, and fatty acid metabolism, reflecting hypoxia-mediated energy shifts and oxidative stress. LC–MS-based metabolomic profiling identified distinct lipid metabolic signatures associated with early myocardial ischemia. The metabolites 13Z-docosenamide, PC (16:0/22:5), and PC (18:1/20:4) demonstrated strong diagnostic potential and may serve as early biomarkers for the noninvasive detection of myocardial ischemia. Further validation in independent cohorts might be required to confirm their clinical applicability.