We aimed to develop a sensitive method for detecting 13 ginsenosides using liquid chromatography–tandem mass spectrometry and to apply this method to pharmacokinetic studies in human following repeated oral administration of red ginseng extract. The chromatograms of Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT) in human plasma were well separated. The calibration curve range for 13 ginsenosides was 0.5–200 ng/mL and the lower limit of quantitation was 0.5 ng/mL for all ginsenosides. The inter- and intra-day accuracy, precision, and stability were less than 15%. Among the 13 ginsenosides tested, nine ginsenosides (Rb1, Rb2, Rc, Rd, Rg3, CK, Rh2, PPD, and PPT) were detected in the human plasma samples. The plasma concentrations of Rb1, Rb2, Rc, Rd, and Rg3 were correlated with the content in red ginseng extract; however, CK, Rh2, PPD, and PPT were detected although they are not present in red ginseng extract, suggesting the formation of these ginsenosides through the human metabolism. In conclusion, our analytical method could be effectively used to evaluate pharmacokinetic properties of ginsenosides, which would be useful for establishing the pharmacokinetic–pharmacodymic relationship of ginsenosides as well as ginsenoside metabolism in humans.

We investigated the tolerability and pharmacokinetic properties of various ginsenosides, including Rb1, Rb2, Rc, Rd, and compound K, after single or multiple administrations of red ginseng extract in human beings. Red ginseng extract (dried ginseng > 60%) was administered once and repeatedly for 15 days to 15 healthy Korean people. After single and repeated administration of red ginsengextract, blood sample collection, measurement of blood pressure and body temperature, and routine laboratory test were conducted over 48-h test periods. Repeated administration of high-dose red ginseng for 15 days was well tolerated and did not produce significant changes in body temperature or blood pressure. The plasma concentrations of Rb1, Rb2, and Rc were stable and showed similar area under the plasma concentration-time curve (AUC) values after 15 days of repeated administration. Their AUC values after repeated administration of red ginseng extract for 15 days accumulated 4.5- to 6.7-fold compared with single-dose AUC. However, the plasma concentrations of Rd and compound K showed large interindividual variations but correlated well between AUC of Rd and compound K. Compound K did not accumulate after 15 days of repeated administration of red ginseng extract. A good correlation between the AUC values of Rd and compound K might be the result of intestinal biotransformation of Rb1, Rb2, and Rc to Rd and subsequently to compound K, rather than the intestinal permeability of these ginsenosides. A strategy to increase biotransformation or reduce metabolic intersubject variability may increase the plasma concentrations of Rd and compound K.

Purpose: A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance. Methods: The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography–tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period. Results: Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (C_max) and the area under the plasma concentration–time curve from time 0 to the last measurement (AUC_0–t) values of telmisartan were 522.29 ng/mL and 2,475.16 ng⋅h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng⋅h/mL for the individual agents concomitantly administered, respectively. The mean C_max and AUC_0–t values of S-amlodipine were 2.71 ng/mL and 130.69 ng⋅h/mL for the FDC, and 2.74 ng/mL and 129.81 ng⋅h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan C_max and AUC_0–t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353–0.9846) and 0.9431 (0.8698–1.0226), respectively. The GMR and 90% CI for the S-amlodipine C_max and AUC_0–t (FDC/concomitant administration) were 0.9829 (0.9143–1.0567) and 0.9632 (0.8798–1.0546), respectively. As the intrasubject variability of the C_max for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study. Conclusion: CKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.

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.

Purpose: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. Methods: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. Results: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. Conclusion: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects. Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.