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Purpose: Current understanding of COVID-19 disease progression suggests a major role for the “cytokine storm” as an important contributor to COVID-19 mortality. To prevent an exaggerated immune response and improve COVID-19 patient endpoints, anti-inflammatory therapeutics have been proposed as clinically useful in severe patients with COVID-19. The purpose of this study was to propose a clinical trial design for the development of anti-inflammatory agents for the treatment of COVID-19, taking into account the physiological and immunological process of COVID-19 and the treatment mechanism of anti-inflammatory agents.Methods: We reviewed and analyzed the guidelines for the development of COVID-19 treatments and the treatment of COVID-19 by regulatory agencies and previously conducted clinical trials on anti-inflammatory drugs for COVID-19. Finally, after discussing with an advisory group, a synopsis was presented for an example protocol for a COVID-19 anti-inflammatory agent phase 2 or 3 study that considers the drug mechanism and the disease progression of COVID-19.Results: A randomized, placebo-controlled, double-blind parallel-group design was suggested as a phase 2 or 3 trial design for developing an anti-inflammatory agent as a COVID-19 treatment. A key item of the example protocol specific to anti-inflammatory agents was the inclusion and exclusion criteria, taking into account the immunosuppressive effects of the drug, clinical time course of COVID-19 disease, and treatment guidelines for COVID-19. Time to recovery is the primary endpoint associated with clinical efficacy and is generally well accepted by many experts.Conclusion: Through this suggested phase 2 or 3 study design of an anti-inflammatory drug for COVID-19, we provide a basis for a study design that can be utilized in clinical development by pharmaceutical companies which are developing a potential anti-inflammatory agent for COVID-19.

Obesity is a life-threatening metabolic disorder necessitating urgent development of safe and effective therapy. Currently, limited such therapeutic measures are available for obesity. The present study was designed to develop a novel, safe and effective herbal therapy for the management of obesity. A polyherbal formulation (18KHT01) was developed by homogeneously mixing a specific proportion of crude Quercus acutissima (acorn jelly powder), Camellia sinensis (dry leaf buds), and Geranium thunbergii (dry aerial part) along with Citrus limon (fruit juice). Synergistic antioxidant, antiadipogenic, and anti-obesity activities were evaluated by in vitro as well as in vivo studies. In vitro experiments revealed strong synergistic antioxidant and anti-adipogenic activities of 18KHT01. Molecular assessment of 18KHT01 showed significant down-regulation of vital adipogenic factors such as PPARγ, C/EBPα, aP2, SREBP-1c, FAS, and LPL. Based on the results of the preliminary toxicity study, 75 and 150 mg/kg, twice daily doses of 18KHT01 were administered to evaluate anti-obesity activity in diet-induced obese (DIO) C57BL/6J mice model. The major obesity-related parameters such as body weight, weight gain, food efficiency ratio, as well as serum lipid profile were significantly reduced by 18KHT01 with potential synergism. Also, the high-fat diet-induced insulin resistance was suggestively alleviated by the formulation, and thus ameliorated fasting blood glucose. Histological evaluation of liver and white adipose tissue revealed that the significant reduction of fat depositions and thus reduction of these tissue weights. Synergy evaluation experiments exhibited that the 18KHT01 offered strong synergism by improving efficacy and reducing the toxicity of its ingredients. Overall results evidenced the 18KHT01 as a safe and potent anti-obesity herbal therapy.

This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug–drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator® and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure.

Duloxetine (DLX) is a potent drug investigated for the treatment of depression and urinary incontinence. DLX is extensively metabolized in the liver by two P450 isozymes, CYP2D6 and CYP1A2. Propolis (PPL) is one of the popular functional foods known to have effects on activities of CYPs, including CYP1A2. Due to the high probability of using DLX and PPL simultaneously, the present study was designed to investigate the potent effect of PPL on pharmacokinetics (PKs) of DLX after co-administration in humans. A PK study was first conducted in 18 rats (n = 6/group), in which the plasma concentration of DLX and its major metabolite 4-hydroxy duloxetine (4-HD) with or without administration of PPL was recorded. Population PKs and potential effects of PPL were then analyzed using NONMEM software. Lastly, these results were extrapolated from rats to humans using the allometric scaling and the liver blood flow method. PPL (15,000 mg/day) exerts a statistically significant increase in DLX exposures at steady state, with a 20.2% and 24.6% increase in DLX C m a x , s s and the same 28.0% increase in DLX A U C s s when DLX (40 or 60 mg) was administered once or twice daily, respectively. In conclusion, safety issues are required to be attended to when individuals simultaneously use DLX and PPL at high doses, and the possibility of interactions between DLX and PPL might be noted.

Aims This study was aimed at evaluating changes in CYP3A activity following and during pregnancy by analyzing metabolic markers for CYP3A activity, which can help avoid unnecessary drug exposure and invasive sampling. Methods Forty-eight pregnant women and 25 non-pregnant women were enrolled in this study. Plasma and urine samples were collected from the pregnant women during each trimester and from the non-pregnant women for evaluation of metabolic markers for CYP3A activity. Metabolic markers for CYP3A activity were measured using GC-MS. Results An increased 4β-hydroxycholesterol/cholesterol ratio, consistent with high CYP3A activity, was observed in pregnant women compared with that in non-pregnant women; however, no differences were observed among trimesters. No significant differences were observed in urinary markers. Conclusions We observed an increase in the activity of CYP3A following but not during pregnancy when measured using the 4β-hydroxycholesterol/cholesterol ratio. In addition, based on our results, we suggest that the plasma 4β-hydroxycholesterol/cholesterol ratio be used to measure CYP3A activity in pregnant women.

Jieon Lee, Su-jin Rhee, SeungHwan Lee, Kyung-Sang Yu Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea Objectives: As hypercholesterolemia is often accompanied by hypertension, statins are usually prescribed with angiotensin receptor blockers in clinical practice. This study was performed to evaluate the pharmacokinetics and safety of fimasartan and rosuvastatin when coadministered or administered alone as a single dose or as multiple doses to healthy Caucasians.Methods: Thirty-six subjects were enrolled into an open-labeled, randomized, 6-sequence, 3-period, 3-way crossover study, and randomly received fimasartan (120 mg), rosuvastatin (20 mg) or both. Blood samples for pharmacokinetics were collected up to 48 hours for fimasartan and 72 hours for rosuvastatin after the last dosing and plasma concentrations of study drugs were determined by liquid chromatography-tandem mass spectrometry. Maximum plasma concentration (Cmax), area under the concentration-time curve (AUC) from 0 to the last measurable time (AUClast), maximum plasma concentration at steady state (Cmax,ss) and AUC to the end of the dosing period at steady state (AUCτ,ss) were estimated using a non-compartmental method. Safety and tolerability were evaluated throughout the study.Results: Thirty subjects completed the study. After single dose administration, the geometric mean ratio (GMR) and 90% confidence intervals (CIs) of fimasartan with or without rosuvastatin were 0.95 (0.80–1.14) and 0.98 (0.91–1.07) for Cmax and AUClast, respectively. The corresponding values for rosuvastatin with or without fimasartan were 1.32 (1.16–1.50) and 0.97 (0.89–1.05), respectively. After administration of multiple doses, the GMRs (90% CIs) for Cmax,ss and AUCτ,ss of fimasartan with or without rosuvastatin were 0.94 (0.74–1.20) and 1.07 (0.90–1.16), respectively. The corresponding values for rosuvastatin with or without fimasartan were 1.16 (1.02–1.32) and 0.86 (0.79–0.94), respectively. A total of 74 adverse events (AEs) were reported and incidences of AEs did not increase significantly with co-administration.Conclusion: Co-administration of fimasartan and rosuvastatin did not result in clinically relevant changes in the systemic exposure of fimasartan or rosuvastatin after single and multiple administrations, and they were well tolerated. Keywords: fimasartan, rosuvastatin, drug interaction, clinical trial, angiotensin II receptor antagonist, healthy subjects&nbsp

Purpose This study aimed to assess and compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties following a single subcutaneous injection of epoetin alfa (Eporon®) with those of the comparator (Eprex®) in healthy male subjects. Subjects and methods A randomized, double-blind, two-sequence, crossover study was conducted. Subjects were randomly assigned to receive a single dose, that is, 4,000 IU, of the test or comparator epoetin alfa. After 4 weeks, all subjects received the alternative formulation. The primary PK parameters, maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUCinf), were calculated with the serum erythropoietin (EPO) concentrations from blood samples collected for 144 h after dosing. The reticulocyte, hematocrit, hemoglobin and red blood cell counts were measured up to 312 h as PD markers. The primary PD parameters, maximum observed effect (Emax) and area under the effect curve (AUEC), were obtained from the baseline-corrected reticulocyte count. The serum EPO concentration and the reticulocyte count were used to assess the concentration-response relationship. The tolerability and immunogenicity profiles were assessed together. Results Forty-two subjects completed the study. The mean EPO concentration-time profiles were comparable between the two formulations. The geometric mean ratios (90% CI) of the Cmax and AUCinf were 0.908 (0.843-0.978) and 1.049 (0.999-1.101), respectively, both of which were within the regulatory range of 0.80-1.25. Additionally, the PD and tolerability profiles were similar between the two formulations. The time-matched serum EPO concentration and PD markers presented a counterclockwise hysteresis, suggesting a time delay between the measured concentration and the response. Both formulations were well tolerated, and production of anti-drug antibodies was not observed. Conclusion The two epoetin alfa formulations had similar PK, PD and tolerability profiles. Furthermore, both formulations had a similar time-matched serum EPO concentration and erythropoietic response profile. Thus, the two formulations are expected to be used interchangeably in clinical settings.

Levetiracetam (LEV) is commonly used as a mono- or adjunctive therapy for treating patients with partial and generalized epilepsy. This study aimed to develop a population pharmacokinetic (PK) model of LEV, based on sparse data, and to explore LEV efficacy relative to its PK properties in patients with epilepsy. We included 483 LEV concentrations from 425 patients with epilepsy that received multiple oral LEV doses. We performed a population PK analysis, implemented in NONMEM (version 7.2). In addition, we explored the relationships between seizure control and PK variables (i.e., LEV dose, trough concentration, and the number of concomitant anti-epileptic drugs). LEV concentration-time profiles were adequately described with a one-compartment, open linear model, with first-order absorption, and additive residual error. The typical population estimates of the apparent clearance (CL/F) and the volume of distribution (V/F) were 3.9L/h and 65.3L, respectively. Body weight was a significant covariate for CL/F and V/F; the estimated glomerular filtration rate only significantly affected CL/F; and concomitant intake of other anti-epileptic drugs did not significantly affect either parameter. A cumulative percentage analysis revealed that over 95% of patients that remained seizure-free received LEV doses of 2000mg/day or lower. LEV trough concentrations were not significantly different between seizure-free and seizure groups, for each LEV dose. In conclusion, we successfully developed a population PK model of LEV, which enabled investigation of LEV efficacy, relative to its PK properties. The findings in this study can be utilized to optimize LEV dosing regimens in clinical practice.

Fluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen. A pharmacokinetic model was developed using 301 fluconazole concentrations from 75 preterm infants with a baseline body weight (WT) ranging from 0.5 to 1.5 kg and an estimated glomerular filtration rate (eGFR) ranging from 12.9 to 58.5 ml/min/1.73 m2. Eligible infants received an intravenous or oral dose of 3 mg/kg of body weight of fluconazole, twice weekly with a ≥72-h dose interval, for 4 weeks. The model was qualified with basic goodness-of-fit diagnostics, visual predictive checks, and bootstrapping. The fluconazole pharmacokinetics was well described with a one-compartment linear model with a proportional residual error. The population clearance (CL) and volume of distribution (V) were derived as 0.0197 × (WT/1.00)0.746 × (eGFR/25.0)0.463 × exp(η) and 1.04 × WT × exp(η), respectively. Such covariate analyses augment the awareness of the need for personalized dosing in preterm infants. (This study has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT01683760","term_id":"NCT01683760"}}NCT01683760.)

Highly variable and non-linear pharmacokinetics of voriconazole are mainly caused by CYP2C19 polymorphisms. This study aimed to develop a mechanistic population pharmacokinetic model including the CYP2C19 phenotype, and to assess the appropriateness of various dosing regimens based on the therapeutic target. A total of 1,828 concentrations from 193 subjects were included in the population pharmacokinetic analysis. A three-compartment model with an inhibition compartment appropriately described the voriconazole pharmacokinetics reflecting auto-inhibition. Voriconazole clearance in the CYP2C19 intermediate metabolizers (IMs) and poor metabolizers (PMs) decreased by 17% and 53% compared to that in the extensive metabolizers (EMs). There was a time-dependent inhibition of clearance to 16.2% of its original value in the CYP2C19 EMs, and the extent of inhibition differed according to the CYP2C19 phenotypes. The proposed CYP2C19 phenotype-guided initial dosing regimens are 400 mg twice daily (bid) for EMs, 200 mg bid for IMs, and 100 mg bid for PMs. This CYP2C19 phenotype-guided initial dosing regimen will provide a rationale for individualizing the optimal voriconazole therapy.

Physiologically based pharmacokinetic (PBPK) modelling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms and disease status on the PK, and evaluating the potential of drug-drug interactions. We developed a Korean-specific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S-warfarin, metoprolol, omeprazole, lorazepam and rosuvastatin) of five major drug metabolizing enzymes (DMEs) and two transporters. Forty-three parameters including the proportion of phenotypes in DMEs and transporters were incorporated into the Korean-specific virtual population. The simulated concentration-time profiles in Koreans were overlapped with most of the observed concentrations for the selected substrate drugs with a < 2-fold difference in clearance. Furthermore, we found some drug models within the SimCYP® library can be improved, e.g., the minor allele frequency of ABCG2 and the fraction metabolized by UGT2B15 should be incorporated for rosuvastatin and lorazepam, respectively. The Korean-specific population can be used to evaluate the impact of ethnicity on the PKs of a drug, particularly in various stages of drug development.

To build a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide, and to investigate the drug–drug interaction (DDI) potentials. The PBPK model of each drug was developed using Simcyp software (Version 15.0), based on the information obtained from literature sources and in vitro studies. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data collected from healthy subjects after multiple oral doses of fimasartan, amlodipine, and hydrochlorothiazide. The DDI potentials after co-administration of three drugs were simulated using the final model. The predicted-to-observed ratios of all the pharmacokinetic parameters met the acceptance criterion. The PBPK model predicted no significant DDI when fimasartan was co-administered with amlodipine or hydrochlorothiazide, which is consistent with the observed clinical data. In the simulation of DDI at steady-state after co-administration of three drugs, the model predicted that fimasartan exposure would be increased by ~24.5%, while no changes were expected for the exposures of amlodipine and hydrochlorothiazide. The developed PBPK model adequately predicted the pharmacokinetics of fimasartan, amlodipine, and hydrochlorothiazide, suggesting that the model can be used to further investigate the DDI potential of each drug.

Purpose Pregabalin and thioctic acid are likely to be used concomitantly for the treatment of painful diabetic neuropathy. In this study, the pharmacokinetic interaction between pregabalin and thioctic acid was investigated at steady state. Methods A randomized, open-label, 6-sequence, 3-period, 3-treatment crossover study was conducted in 42 healthy male volunteers. The volunteers randomly received pregabalin 300 mg BID for 6 times, thioctic acid 600 mg once daily for 3 times, or the combination of pregabalin and thioctic acid. Serial blood samples were collected up to 24 hours after the last dosing in each period. Pharmacokinetic parameters were calculated by using noncompartmental analysis methods. Findings The mean concentration–time curves were similar between each drug alone and in combination with the other drug. The 90% CIs of the geometric mean ratios with and without the co-administered drug for Cmax at steady state and AUC during the dosing interval were well within the conventional bioequivalence range of 0.8 to 1.25, except for Cmax at steady state for thioctic acid, which barely exceeded only the lower bound (0.78–1.15). Co-administered pregabalin and thioctic acid was well tolerated. Implications Repeatedly administered pregabalin and thioctic acid do not interact pharmacokinetically. This study suggests that the combination of pregabalin and thioctic acid can safely be administered concomitantly without dose adjustment. ClinicalTrials.gov identifier: NCT01808300.

Physiologically based pharmacokinetic (PBPK) modelling and simulation enable researchers to overcome practical limitations for clinical trials on special populations. This study was conducted to investigate how the PBPK model describes the pharmacokinetics of metformin in young adult and elderly populations and to predict the pharmacokinetics of metformin in patients with renal or hepatic impairment in both populations. A first-order absorption/PBPK model for metformin was built in the Simcyp simulator version 14 release 1. A full PBPK model was constructed for metformin based on physicochemical properties and clinical observations. The model was refined and validated using clinical plasma concentration data obtained in healthy young adults and elderly after the oral administration of metformin. Metformin pharmacokinetics in patients with renal or hepatic impairment were then investigated and compared by simulation. The PBPK model reasonably predicted the pharmacokinetic profiles of metformin for both young adults and the elderly. The predicted pharmacokinetic parameters, including maximum concentration, area under the time–concentration curve, and apparent oral clearance values, were within 1.5-fold of the observed data of metformin. In the simulation results, the systemic exposure of metformin was expected to be markedly increased not only with a decrease in renal function but also with severe hepatic impairments. The PBPK model adequately characterised the pharmacokinetics of metformin in both young adult and elderly populations. PBPK modelling and simulation can be used as a useful tool to investigate and compare the pharmacokinetics in geriatric populations incorporating various disease conditions.

Objectives The aim of this study was to compare the pharmacokinetic (PK) characteristics of evogliptin and metformin following the administration of 2 evogliptin/metformin extended-release (XR) 2.5/500 mg FDC tablets with the coadministration of separate evogliptin 5-mg and metformin XR 1,000-mg tablets (separate formulations). Methods A randomized, two-period, two-sequence crossover study was conducted. Subjects were randomly assigned to receive 2 FDC tablets or the individual tablets, followed by a 14-day washout period and the administration of the alternate treatment. Blood samples were collected predose and up to 72 hours postdose for each period. PK parameters including Cmax and AUClast were calculated. The geometric mean ratios (GMRs) and the 90% confidence intervals (CIs) between FDC and the separate formulations were calculated for the Cmax and AUClast of evogliptin and metformin. Results 33 subjects completed the study. The GMR (90% CI) values of Cmax and AUClast for evogliptin were 1.011 (0.959 - 1.066) and 1.010 (0.977 - 1.043), respectively. The GMR (90% CI) values of Cmax and AUClast for metformin were 0.892 (0.827 - 0.963) and 0.893 (0.841 - 0.947), respectively. There was no significant difference between the FDC and separate formulations regarding the occurrence of adverse events. All drug-related adverse events were considered to be mild and resolved without any treatment. Conclusions Two FDC tablets of evogliptin/metformin XR 2.5/500 mg showed a similar PK profile to the separate formulations of evogliptin 5 mg and metformin XR 1,000 mg. All of the 90% CIs of GMR satisfied the regulatory bioequivalence criteria of 0.800 - 1.250. .

Purpose Few studies have been investigated the in vivo efficacy of generic vancomycin products available outside of the United States. In this study, we aimed to compare the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of five generic vancomycin products available in Korea with those of the innovator. Materials and Methods The in vitro vancomycin purity of each product was examined using high-pressure liquid chromatography. Single-dose PK analyses were performed using neutropenic mice. The in vivo efficacy of vancomycin products was compared with that of the innovator in dose-effect experiments (25 to 400 mg/kg per day) using a thigh-infection model with neutropenic mice. Results Generic products had a lower proportion of vancomycin B (range: 90.3–93.8%) and a higher proportion of impurities (range: 6.2–9.7%) than the innovator (94.5% and 5.5%, respectively). In an in vivo single-dose PK study, the maximum concentration (Cmax) values of each generic were lower than that of the innovator, and the geographic mean area under the curve ratios of four generics were significantly lower than that of the innovator (all p

A simple, fast and reliable high-performance liquid chromatography-triple quadrupole mass spectrometry method (HPLC-MS/MS method) was developed, validated and used for the simultaneous quantification of irinotecan and 7-ethyl-10-hydroxycamptothecin (SN38) in heparinized mouse plasma. Camptothecin was used as the internal standard. A single-step protein precipitation without evaporation and reconstitution steps was adopted as sample processing method. Our bioanalytical method was validated in compliance with the guidelines from the European Medicines Agency. The lower limit of quantification for both irinotecan and SN38 was 5 ng/mL. The calibration curves for both analytes fitted to a 1/x(2) weighted linear regression model and ranged from 5 to 1000 ng/mL. The intra-run and inter-run precisions were within 8.6%, and the intra-run and inter-run accuracies were within 96.4-103.9%. Our validated bioanalytical method was successfully applied to the pharmacokinetic study in mice, in which 4 mg/kg irinotecan was intraperitoneally injected.

Su-jin Rhee,1,* SeungHwan Lee,1,2,* Seo Hyun Yoon,1 Joo-Youn Cho,1 In-Jin Jang,1 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Clinical Trials Center, Seoul National University Hospital, Seoul, Republic of Korea *These authors contributed equally tothis work Abstract: A new fixed-dose combination formulation of evogliptin 5 mg and metformin extended-release (XR) 1,000 mg (FDC_EVO5/MET1000) was developed to improve medication adherence for type 2 diabetes mellitus. The pharmacokinetics of FDC_EVO5/MET1000 was compared to the corresponding loose combination in a randomized, open-label, crossover study in 36 healthy male subjects (Part 1), and the food effect on FDC_EVO5/MET1000 was assessed (under fasted or fed conditions) in a randomized, open-label, crossover study in 28 healthy male subjects (Part 2). Serial blood samples for pharmacokinetic analysis were collected up to 72 hours,and pharmacokinetic parameters of evogliptin and metformin were calculated using non-compartmental methods. The geometric mean ratios (fixed-dose combination to loose combination) and 90% confidence intervals of pharmacokinetic parameters for evogliptin and metformin were all within 0.800–1.250, suggesting bioequivalent pharmacokinetic. After a single oral dose of FDC_EVO5/MET1000, food did not significantly affect evogliptin pharmacokinetic while systemic exposure of metformin was increased about 47.5% under the fed condition, which is consistent with the already established food effect on metformin XR. FDC_EVO5/MET1000 was generally well tolerated without any drug-related serious adverse events. In conclusion, FDC_EVO5/MET1000 can be substituted for the loose combination of FDC_EVO5/MET1000, providing better compliance with convenient administration. Keywords: pharmacokinetics, bioequivalence, food effect, fixed-dose combination, evogliptin, metformin XR

Chronic obstructive pulmonary disease (COPD) is a type of progressive, obstructive lung disease characterized by long-term poor airflow. The symptoms of COPD may be relieved and its progression delayed by fluticasone (FTS), salmeterol (SM), and tiotropium (TTP). The aim of this study is to investigate pharmacokinetic (PK) characteristics of inhaled FTS, SM, and TTP after co-administration. An open-label, single-arm, three-period, simple ascending dose study was conducted in 10 healthy male subjects. A single dose of FTS/SM (250/50 µg) and TTP (18 µg) were concomitantly inhaled in period 1, and the dose of each drug was escalated to two- and three-fold in periods 2 and 3, respectively, with a 2-week washout between periods. Activated charcoal was co-administered before and after inhalation to block gastrointestinal absorption. Blood samples for PK analysis were collected up to 24 hours. PK parameters were obtained by non-compartmental analysis. FTS, SM, and TTP rapidly reached maximum plasma concentration after inhalation (0.08–3.00 h, 0.03–0.10 h and 0.03–0.10 h, respectively) and were eliminated with mean half-lives of 9.29–10.44 h, 6.09–12.39 h and 0.25–47.42 h, respectively. PK assessment of the lowest dose of TTP was limited due to relatively low systemic exposure compared to the lower limit of quantification. In conclusion, PK characteristics of FTS, SM, and TTP by pulmonary absorption were evaluated after concurrent inhalation. FTS and SM showed dose-proportional PK profiles between 250–750 µg and 50–150 µg, respectively, while TTP presented dose-proportionality in the early phase exposure between 18-54 µg.