Effects of food and ethnicity on the pharmacokinetics of venadaparib, a next-generation PARP inhibitor, in healthy Korean, Caucasian, and Chinese male subjects.

AIM: Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects. METHODS: In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing. RESULTS: Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated. CONCLUSION: The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.

Effect of haemodialysis on the pharmacokinetics and pharmacodynamics of evogliptin.

AIM: To investigate the possible effect of haemodialysis (HD) on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. METHODS: A single-dose, open-label, parallel-group study of eight end-stage renal disease (ESRD) patients and eight matched healthy subjects was conducted. ESRD patients received a single oral dose of evogliptin 5 mg after and before HD with a 2-week washout between each dose, and healthy subjects received a single oral dose of evogliptin 5 mg. Serial blood, dialysate, and urine samples were collected to assess the PK and PD profiles of evogliptin. To compare PK parameters before and after HD, geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were calculated. RESULTS: The GMRs for the maximum concentration and area under the concentration-time curve from time 0 to the last measurable timepoint (AUClast ) of evogliptin when administered before HD compared with after HD were 0.7293 (90% CI 0.6171-0.8620) and 0.9480 (90% CI 0.8162-1.1010), respectively. The maximum DPP-4 inhibitory effect, area under the DPP-4 inhibitory effect-time curve, and time duration of more than 80% DPP-4 inhibition were comparable when evogliptin was administered before and after HD. Compared with healthy subjects, the mean AUClast of evogliptin was approximately 1.4-fold greater in ESRD patients, but the difference is unlikely to affect the safety and efficacy of evogliptin. CONCLUSION: The effect of HD on the PK and PD characteristics of evogliptin was not clinically significant; therefore, dose adjustment according to HD status is not necessary.

Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy.

OBJECTIVE: Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity. METHODS: Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected. RESULTS: The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 µg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 µg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 µg/ml). SIGNIFICANCE: Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.

Dose-dependent glucosuria of DWP16001, a novel selective sodium-glucose cotransporter-2 inhibitor, in healthy subjects.

AIMS: DWP16001 is a novel sodium-glucose cotransporter-2 inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics, pharmacodynamics and safety of DWP16001 after single and multiple doses in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, single- and multiple-dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0 or 5.0 mg) or multiple doses (0.1, 0.3, 0.5, 1.0 or 2.0 mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10 mg or placebo at a ratio of 8:2:2. Serial blood and interval urine samples were collected for the pharmacokinetic and pharmacodynamic analyses. The safety and tolerability of DWP16001 were also assessed. RESULTS: A dose-dependent increase in the urinary glucose excretion was observed after a single dose, and the steady state urinary glucose excretion was 50-60 g/d after multiple doses in the dose range of 0.3-2.0 mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0-3.0 hours, and it exhibited a mean elimination half-life of 13-29 hours. The systemic exposure to DWP16001 increased proportionally with multiple dose administrations in the range of 0.1-2.0 mg. DWP16001 was well tolerated in all dose groups. CONCLUSION: DWP16001 induced glucosuria in a dose-dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated in single oral doses of up to 5.0 mg and in multiple oral doses of up to 2.0 mg.

A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators.

Isoniazid is a therapeutic agent for the treatment of latent tuberculosis infection. Genetic variants in the N-acetyltransferase 2 (NAT2) are associated with the safety and pharmacokinetics of isoniazid. The study aimed to evaluate the safety and pharmacokinetics of a NAT2 genotype-guided regimen of isoniazid monotherapy. A randomized, open-label, parallel-group and multiple-dosing study was performed in healthy subjects. The subjects received isoniazid for 29 days. The NAT2 slow acetylators (NAT2*5/*5, -*5/*6, -*5/*7, -*6/*6, -*6/*7, -*7/*7) randomly received standard dose (300 mg, standard-treatment group) or reduced dose (200 mg, PGx-treatment group) of isoniazid. Also, all the NAT2 rapid acetylators (NAT2*4/*4) received isoniazid 300 mg (reference group). The safety and pharmacokinetics were evaluated during the study. The PGx-treatment group showed a more stable serum liver enzyme profile and a lower incidence of adverse drug reactions (ADRs) than the standard-treatment group. The emergence rates of ADRs were 12.5, 60 and 33.3% in the reference, standard-treatment and PGx-treatment groups, respectively. The PGx-treatment group showed higher plasma isoniazid concentrations than the reference group, although the PGx-treatment group received a reduced dose of isoniazid. Our results showed that a NAT2 genotype-guided regimen may reduce ADRs during isoniazid monotherapy without concern over insufficient drug exposure.

Oral absorption of voriconazole is affected by SLCO2B1 c.*396T>C genetic polymorphism in CYP2C19 poor metabolizers.

High pharmacokinetic variability of voriconazole is mainly explained by CYP2C19 phenotype, but there are still unknown factors affecting the variability. In this study, the effect of solute carrier organic anion transporter family member 2B1 (SLCO2B1) genotype on the pharmacokinetics (PKs) of voriconazole was evaluated in 12 healthy CYP2C19 poor metabolizers after a single administration of voriconazole 200 mg intravenously and orally. In addition, the influence of CYP3A4 enzyme activity was also explored. The oral absorption of voriconazole was decreased and delayed in the subjects with the SLCO2B1 c.*396T>C variant compared to the subjects with wild type. However, the CYP3A activity markers measured in this study did not show significant association with metabolism of voriconazole. The results suggest that the SLCO2B1 c.*396T>C may be associated with the decreased function of intestinal OATP2B1, and it could contribute to interindividual PK variability of voriconazole.

Pharmacokinetics of human antithrombin III concentrate in the immediate postoperative period after liver transplantation.

AIMS: Antithrombin III (AT-III) concentrates have been used to prevent critical thrombosis in the immediate post-liver transplantation period without clear evidence regarding the optimal dose or administration scheme. The relationship between the AT-III dosage and the plasma activity levels during the period was evaluated in this study. METHODS: The plasma AT-III activity levels and clinical data obtained from patients who received liver transplantation from January 2017 to September 2018 were retrospectively analysed. A population pharmacokinetic (PK) model was developed using nonlinear mixed-effects method and externally validated thereafter. Several dosing scenarios were simulated to maintain the plasma AT-III activity level within the normal range using the developed PK model to search for an optimal AT-III dosing regimen. RESULTS: The plasma AT-III activity levels were best described by a single compartment model with first order elimination kinetics. The recovery of endogenous AT-III level during the postoperative days was modelled using an Emax model. The typical values (95% confidence interval) of volume of distribution and clearance were 3.86 (3.40-4.32) L, and 0.129 (0.111-0.147) L h-1 , respectively. Serum albumin and body weight had significant effect on clearance and were included in the model. External validation of the proposed model demonstrated adequate prediction performance. Furthermore, simulation of previously suggested or modified dosing scenarios showed successful maintenance of AT-III activity level within the normal range. CONCLUSION: A population PK model of AT-III concentrate was developed using data from liver recipients. Dosing scenarios simulated in our study may help establish a practical guide for AT-III concentrate titration after liver transplantation.

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.

AIMS: We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1ß. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. RESULTS: HL2351 was eliminated more slowly than anakinra (terminal half-life: 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range: 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. CONCLUSION: HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

Population Pharmacokinetic Study of Prophylactic Fluconazole in Preterm Infants for Prevention of Invasive Candidiasis.

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 NCT01683760).

Pharmacokinetic Characteristics and Limited Sampling Strategies for Therapeutic Drug Monitoring of Colistin in Patients With Multidrug-Resistant Gram-Negative Bacterial Infections.

BACKGROUND: Colistin is increasingly used as the last therapeutic option for the treatment of multidrug-resistant, Gram-negative bacterial infections. To ensure safe and efficacious use of colistin, therapeutic drug monitoring (TDM) is needed due to its narrow therapeutic window. This study aimed to evaluate the pharmacokinetic (PK) characteristics of colistin and to guide TDM in colistin-treated patients in Korea. METHODS: In a prospective study, we analyzed PK characteristics in 15 patients who intravenously received colistin methanesulfonate twice per day. Colistin methanesulfonate doses were adjusted based on renal function of the subjects. The appropriate blood sampling points for TDM were evaluated by analyzing the correlations between the PK parameters and the plasma concentrations at each time point. RESULTS: The mean values for the minimum, maximum, and average concentrations (Cmin, Cmax, and Caverage) of colistin at steady state were 2.29, 5.5, and 3.38 mg/L, respectively. The dose-normalized Cmin, Cmax, Caverage, and area under the plasma concentration-time curve from 0 to the last measurable concentration (AUClast) showed negative correlations with the creatinine clearance. The combination of the 0- and 2-hour post-dose plasma concentrations was evaluated as the appropriate sampling point for TDM. Two patients reported nephrotoxic adverse events during colistin administration. CONCLUSIONS: Our study clarifies the PK characteristics of successful colistin treatment using TDM. Further evaluations in a larger patient population are needed to confirm the clinical usefulness of colistin TDM.

Characteristics of sauna deaths in Korea in relation to different blood alcohol concentrations.

Although the benefits of sauna bathing have been demonstrated in epidemiological studies, sauna deaths have been reported. The aim of this study was to determine the demographic and forensic characteristics associated with different blood alcohol concentrations (BACs) in sauna deaths in Korea. In this retrospective analysis, data were collected from a nationwide pool in Korea between January 2008 and December 2015 to determine the role of alcohol intoxication in sauna deaths based on the subjects' BAC and to evaluate the demographic and forensic characteristics associated with different BACs. One hundred and three deaths were classified into 2 groups: the non-intoxication (NI) group (BAC,<0.08%; n = 27) and the intoxication (I) group (BAC,≥0.08%; n = 76). Demographic and forensic characteristics were compared between the groups using a multinomial logistic regression analysis. The proportions of decedents who were male (odds ratio: 17.4, 95.0% confidence interval: 3.8-79.8) and in a prone position at the scene of death (odds ratio: 11.3, 95.0% confidence interval: 2.1-60.1) were significantly higher (P < 0.001 and P < 0.05, retrospectively) in the I group than in the NI group. However, no significant differences were observed with respect to obesity, coronary artery narrowing, and liver pathology. Sauna deaths exhibited different characteristics according to BACs detected at autopsy. The differences in sauna deaths between the I and NI groups may have implications for the targeted prevention of sauna deaths associated with alcohol consumption.

Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel dipeptidyl peptidase-4 inhibitor, evogliptin (DA-1229).

Evogliptin is a novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor. The aim of the present study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin in participants with renal impairment (RI). An open-label, parallel-group clinical study was conducted in participants with mild, moderate and severe RI and in matched participants with normal renal function (NRF). A single oral 5-mg dose of evogliptin was administered and serial blood and urine samples were obtained to assess the PK and PD characteristics of evogliptin. Baseline urine samples were collected to evaluate endogenous CYP3A metabolic markers. The plasma exposure to evogliptin and degree of DPP-4 activity inhibition increased with decreasing renal function. The mean areas under the concentration-time curves from 0 to 120 hours were increased 1.2-, 1.8- and 1.98-fold in the mild, moderate and severe RI groups, respectively, compared with the NRF group. The levels of CYP3A metabolic markers were lower in the RI group than in the NRF group. The increase in the plasma concentration of evogliptin is unlikely to result in changes in its efficacy or safety, considering the results of previous clinical studies.

Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants.

AIMS: The purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants. METHODS: Preterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2 h, 4 h or 6 h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants. RESULTS: A total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P < 0.001). Total, renal and nonrenal clearances of theophylline were 0.50 ± 0.29 ml kg-1  min-1 , 0.16 ± 0.06 ml kg-1  min-1 and 0.34 ± 0.28 ml kg-1  min-1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance. CONCLUSIONS: CYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants.

Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers.

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers.

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.

Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.).

Pharmacogenetic Analysis of an 8-Year Old Girl with Reye Syndrome Associated with Use of Naproxen.

BACKGROUND Reye syndrome is a rare, yet potentially life-threatening disease characterized by acute encephalopathy and hepatic failure. This report presents the case of an 8-year-old girl with Reye syndrome and seizures after the use of naproxen. CASE REPORT An 8-year-old girl experienced a 3-day episode of fever and abdominal pain. After receiving naproxen (375 mg twice daily) starting from day -3, she exhibited hypotension, tonic seizure, and loss of consciousness (day 1). Physical examination and laboratory test results revealed acute kidney injury, metabolic acidosis, and elevated levels of lactate dehydrogenase (LDH), liver enzymes, and ferritin. On day 2, the maximum values of aspartate aminotransferase, alanine aminotransferase, LDH, creatinine, and ferritin were 955 U/L, 132 U/L, 8040 U/L, 2 mg/dL, and >40000 ug/L, respectively. She was given supportive care and recovered after 11 days (day 12), with normalization of kidney function and metabolic abnormalities. To identify possible genetic polymorphisms associated with the patient's symptoms, genotypes were tested using a drug metabolizing enzymes and transporters (DMET) gene chip. Among genes involved in the metabolism of naproxen, UGT1A6 (*1/*2) and UGT2B7 (*1/*2) resulted in possibly decreased function. Other results which may have had clinical significance included homozygote results for NAT2*6/*6 (rs1799930). CONCLUSIONS A rare case of Reye syndrome after administration of naproxen was presented in this case. A DMET gene chip was used to screen for possible genetic polymorphisms associated with Reye syndrome, but the result was inconclusive.

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects.

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used for the treatment of type 2 diabetes mellitus (T2DM). CKD-370 was newly developed as a cocrystal formulation of empagliflozin with co-former L-proline, which has been confirmed to be bioequivalent in South Korea. This study aimed to quantify the differences in the absorption phase and pharmacokinetic (PK) parameters of two empagliflozin formulations in healthy subjects by using population PK analysis. The plasma concentration data of empagliflozin were obtained from two randomized, open-label, crossover, phase 1 clinical studies in healthy Korean subjects after a single-dose administration. A population PK model was constructed by using a nonlinear mixed-effects (NLME) approach (Monolix Suite 2021R1). Interindividual variability (IIV) and interoccasion variability (IOV) were investigated. The final model was evaluated by goodness-of-fit (GOF) diagnostic plots, visual predictive checks (VPCs), prediction errors, and bootstrapping. The PK of empagliflozin was adequately described with a two-compartment combined transit compartment model with first-order absorption and elimination. Log-transformed body weight significantly influenced systemic clearance (CL) and the volume of distribution in the peripheral compartment (V2) of empagliflozin. GOF plots, VPCs, prediction errors, and the bootstrapping of the final model suggested that the proposed model was adequate and robust, with good precision at different dose strengths. The cocrystal form did not affect the absorption phase of the drug, and the PK parameters were not affected by the different treatments.

Establishment of Advanced Regulatory Innovation for Clinical Trials Transformation (ARICTT): a multi-stakeholder public-private partnership-based organization to accelerate the transformation of clinical trials.

Clinical trials have evolved with digital technologies and tend towards patient-centricity. A multi-stakeholder approach is needed to address the emerging complexities in clinical trials. In particular, the introduction of digital technologies and an emphasis on patient-centricity are the major trends in clinical trials. In response, we established a public-private partnership-based organization named Advanced Regulatory Innovation for Clinical Trials Transformation (ARICTT). Eleven organizations in total, from academia, industry, and regulatory agencies, participate in ARICTT. Based on multi-stakeholder collaboration from academia, industry, and government/regulatory bodies, we collected and prioritized current topics in clinical trials based on an internal survey. We established a three-year roadmap with axes that were termed trend, goal, structure, theme, topic, and method. In addition, we planned the development of recommendations based on real-world cases with feasibility studies. We developed appropriate organizational structure to fulfill the roadmap of ARICTT. The selected topics were decentralized clinical trials during the first year, followed by the three topics that were awarded the highest priority according to the internal survey: advances in the informed consent process, supporting sites using digital technology, and an effective recruitment strategy. We developed a case-based recommendation paper presenting an overview of the regulatory landscape and practical considerations with explanatory cases. We also designed and conducted fully decentralized trials to evaluate considerations in real-world settings for the selected topics. Overall engagement and communication were supported by the online platform and annual symposiums. In conclusion, we established a multi-stakeholder, public-private partnership-based organization to accelerate the transformation of clinical trials.

Effects of meal type on the bioavailability of vutiglabridin, a novel anti-obesity agent, in healthy subjects.

Vutiglabridin, which affects the pharmacokinetics (PKs) of food, is currently under clinical development for the treatment of obesity. This study aimed to evaluate the effects of low- and high-fat meals on PKs of vutiglabridin in healthy male subjects. A randomized, open-label, single-dose, three-period, six-sequence crossover study was conducted. The subjects received a single oral dose of vutiglabridin 480 mg in a fasted state, 30 min after the intake of a low-fat meal (total 500-600 kcal, fat content 100-125 kcal) and high-fat meal (total 800-1000 kcal, fat content 500-600 kcal), with a 21-day washout period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve to the last measurable timepoint (AUClast ) were calculated. After intake of low- and high-fat meals, systemic exposure to vutiglabridin was increased, and the time to reach Cmax (Tmax ) was delayed compared to that in the fasted state. The GMRs (90% CIs) of low-fat meal to fasted state for Cmax and AUClast were 2.14 (1.76-2.60) and 2.15 (1.92-2.42), respectively, and those of high-fat meal to fasted state were 3.07 (2.53-3.72) and 3.00 (2.67-3.37), respectively. The median Tmax was delayed by 1.5 h in both fed states compared with that in the fasted state. The study drug was well-tolerated after administration in both the fed and fasted states. Food ingestion substantially increased the extent of oral vutiglabridin absorption in healthy subjects, and this enhancement increased with the fat content of the meal.

Pharmacokinetic Interactions Between the Fixed-Dose Combination of Ezetimibe/Rosuvastatin 10/20 Mg and the Fixed-Dose Combination of Telmisartan/Amlodipine 80/5 Mg in Healthy Subjects.

Background: Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA). Methods: An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study. Results: Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (µg/L) and the area under the plasma concentration-time curve (h·µg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765-1.2017) and 0.9359 (0.7847-1.1163); free ezetimibe, 1.5713 (1.2821-1.9257) and 0.9941 (0.8384-1.1788); rosuvastatin, 2.1673 (1.7807-2.6379) and 1.1714 (0.9992-1.3733); telmisartan, 1.0745 (0.8139-1.4186) and 1.1057 (0.8379-1.4591); and amlodipine, 0.9421 (0.8764-1.0126) and 0.9603 (0.8862-1.0405). Both combination therapy and monotherapy were well tolerated by the subjects. Conclusion: The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.