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Interleukin-7 (IL-7) is an essential cytokine for T-cell homeostatic proliferation and maintenance. Clinical studies have shown the potential benefits of IL-7 therapy in various diseases associated with lymphopenia. However, the kinetics of the T-cell response to a single administration of IL-7 in humans have not been fully elucidated. Here, we investigated the effects of Fc-fused long-acting recombinant human IL-7 (hIL-7-hyFc, efineptakin alfa) on lymphocytes in healthy adults after a single subcutaneous or intramuscular administration. Administration of hIL-7-hyFc increased the CD8+ and CD4+ T-cell numbers up to 2.5-fold, with corresponding upregulation of Ki-67 and Bcl-2 expression, peaking at day 3 or 7. Regulatory T cells (Tregs) did not expand. Among CD8+ and CD4+ T cells, all T-cell subsets (TN, TEM, TCM, TEMRA, and TSCM) increased for 56 days. The T-cell receptor repertoire diversity of naive CD8+ and CD4+ T cells was increased by hIL-7-hyFc, whereas the memory T-cell subsets did not differ between day 56 and day 0. Transcriptomic analysis revealed that hIL-7-hyFc induced robust T-cell expansion without changes in gene expression profiles associated with T-cell functions or genes related to T-cell exhaustion, senescence, and anergy. The effector functions of antigen-specific CD8+ T cells were preserved after hIL-7-hyFc administration. Our results suggest that hIL-7-hyFc administration induced a sustained increase in the numbers of CD8+ and CD4+ T cells, but not Tregs, without qualitative changes. These results support the potential of hIL-7-hyFc as a treatment for patients with compromised T-cell immunity or as a vaccine adjuvant.

Hyun Chul Kim,1,2 Sangmi Lee,1,2 Siyoung Sung,3 Eunjin Kim,3 In-Jin Jang,1 Jae-Yong Chung4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; 3Dong-A ST Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of KoreaCorrespondence: Jae-Yong Chung, Seoul National University College of Medicine and Bundang Hospital, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea, Tel +82-31-787-3955, Fax +82-31-787-4045, Email jychung@snubh.orgBackground: Dapagliflozin formate (DAP-FOR, DA-2811), an ester prodrug of dapagliflozin, was developed to improve the stability and pharmaceutical manufacturing process of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor.Purpose: This study aimed to evaluate the pharmacokinetics (PKs) and safety of dapagliflozin for DAP-FOR compared to those for dapagliflozin propanediol monohydrate (DAP-PDH, Forxiga) in healthy subjects.Methods: This was an open-label, randomized, single-dose, two-period, two-sequence crossover study. The subjects received a single dose of DAP-FOR or DAP-PDH 10 mg in each period, with a 7-day washout. Serial blood samples for PK analysis were collected up to 48 hours after a single administration to determine plasma concentrations of DAP-FOR and dapagliflozin. PK parameters were calculated using a non-compartmental method and compared between the two drugs.Results: In total, 28 subjects completed the study. DAP-FOR plasma concentrations were not detected in all of the blood sampling time points except for one time point in one subject, and the corresponding DAP-FOR plasma concentration in the subject was close to the lower limit of quantification. The mean plasma concentration–time profiles of dapagliflozin were comparable between the two drugs. The geometric mean ratios and its 90% confidence intervals of the maximum plasma concentration and area under the plasma concentration–time curve of dapagliflozin for DAP-FOR to DAP-PDH were within the conventional bioequivalence range of 0.80– 1.25. Both drugs were well-tolerated, with a similar incidence of adverse drug reactions.Conclusion: The rapid conversion of DAP-FOR into dapagliflozin led to the extremely low exposure of DAP-FOR and comparable PK profiles of dapagliflozin between DAP-FOR and DAP-PDH. The safety profiles were also similar between the two drugs. These results suggest that DAP-FOR can be used as an alternative to DAP-PDH.Keywords: prodrugs, dapagliflozin, pharmacokinetics, clinical trial, phase I

CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab (EU-tocilizumab) in healthy Asian adults. This double-blind, multicenter, parallel-group trial randomized healthy adults (1:1) to receive a single (162 mg/0.9 mL) subcutaneous dose of CT-P47 or EU-tocilizumab. The primary endpoint (Part 2) was PK equivalence by area under the concentration – time curve (AUC) from time zero to last quantifiable concentration (AUC0–last), AUC from time zero to infinity (AUC0–inf), and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the 80–125% equivalence margin. Additional PK endpoints, immunogenicity, and safety were evaluated. In Part 2, 289 participants were randomized (146 CT-P47; 143 EU-tocilizumab); 284 received study drug. AUC0–last, AUC0–inf, and Cmax were equivalent between CT-P47 and EU-tocilizumab: 90% CIs for the ratios of gLSMs were within the 80–125% equivalence margin. Secondary PK endpoints, immunogenicity, and safety were comparable between groups. CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults. www.clinicaltrials.gov identifier is NCT05188378. Tocilizumab is a biologic medicine used to treat inflammatory diseases including rheumatoid arthritis. Biosimilars are drugs that are highly similar to an already approved, ‘reference’ biologic medicine. This means that they do not have any differences from the reference product in factors including structure, biologic function, efficacy, and safety, that might affect how well they work in patients. Biosimilars are often available at a lower cost than reference drugs, so their use can provide patients with better access to expensive treatments. There are no approved biosimilars of tocilizumab so far: CT-P47 is currently in development as a potential tocilizumab biosimilar. In the main part of this study, 289 healthy Asian volunteers were randomly allocated to receive a single injection of either CT-P47 or the reference drug, European Union-approved tocilizumab (EU-tocilizumab). The main aim of the study was to find out whether CT-P47 and EU-tocilizumab were equivalent in terms of pharmacokinetics (drug absorption, distribution, metabolism, and excretion by the body). This is part of a standard process required by regulatory authorities to ensure that biosimilars work as well as their reference drugs. Analysis of blood samples taken over 43 days showed that the pharmacokinetic profiles of CT-P47 and EU-tocilizumab were equivalent, after the volunteers received a single dose of either drug. Safety and immunogenicity (immune responses made to the drug) were also comparable between CT-P47 and EU-tocilizumab. While only healthy Asian adults were included, further research comparing CT-P47 with reference tocilizumab will help to ensure that the findings from the study can be applied to broader populations.

Interleukin-7 (IL-7) is an essential cytokine for T-cell homeostatic proliferation and maintenance. Clinical studies have shown the potential benefits of IL-7 therapy in various diseases associated with lymphopenia. However, the kinetics of the T-cell response to a single administration of IL-7 in humans have not been fully elucidated. Here, we investigated the effects of Fc-fused long-acting recombinant human IL-7 (hIL-7-hyFc, efineptakin alfa) on lymphocytes in healthy adults after a single subcutaneous or intramuscular administration. Administration of hIL-7-hyFc increased the CD8+ and CD4+ T-cell numbers up to 2.5-fold, with corresponding upregulation of Ki-67 and Bcl-2 expression, peaking at day 3 or 7. Regulatory T cells did not expand. Among CD8+ and CD4+ T cells, all T-cell subsets (TN, TEM, TCM, TEMRA, and TSCM) increased for 56 days. The TCR repertoire diversity of naïve CD8+ and CD4+ T cells was increased by hIL-7-hyFc, while the memory T-cell subsets did not differ between D56 and D0. Transcriptomic analysis revealed that hIL-7-hyFc induced robust T-cell expansion without changes in gene expression profiles associated with T-cell functions or genes related to T-cell exhaustion, senescence, and anergy. The effector functions of antigen-specific CD8+ T cells were preserved after hIL-7-hyFc administration. Our results suggest that hIL-7-hyFc administration induced a sustained increase in the numbers of CD8+ and CD4+ T cells, but not regulatory T cells, without qualitative changes. These results support the potential of hIL-7-hyFc as a treatment for patients with compromised T-cell immunity or as a vaccine adjuvant.

Purpose Herpes zoster (HZ), or shingles, is a clinical syndrome resulting from the reactivation of latent varicella zoster virus (VZV) within the sensory ganglia. We evaluated the safety and tolerability of ES16001 (ethanol extract of Elaeocarpus sylvestris var. ellipticus), a novel inhibitor of varicella zoster virus reactivation in healthy adults. Method Single-center, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) studies were conducted in 20- to 45-year-old healthy adults without chronic disease. In the SAD study (n = 32), subjects randomly received a single oral dose of 240, 480, 960, or 1440 mg ES16001 or a placebo. In the MAD study (n = 16), subjects randomly received once daily doses of 480 or 960 mg ES16001 or a placebo for 5 days. The safety and tolerability of the drug were evaluated by monitoring participants’ treatment emergent adverse events (TEAEs) and vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory tests. Results In the SAD study, 11 adverse reactions were seen in 5 subjects, and in the MAD study, 8 adverse reactions were seen in 6 subjects. All adverse reactions were mild, and no serious adverse reactions occurred. The most common adverse reaction was an increase in alanine aminotransferase (ALT), but all test values were in the clinically non-significant range, and their clinical significance was judged to be small considering the fact that most of the test values returned to normal immediately after the end of drug administration. Conclusion ES16001 has good safety and tolerability when administered both once and repeatedly to healthy subjects. Further research is needed to identify any possible drug-induced hepatotoxicity, which appears infrequently. Our findings provide a rationale for further clinical investigations of ES16001 for the prevention of HZ. Trial registration: CRIS, KCT0006066. Registered 7 April 2021—Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/19071).

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT‐P17 to United States‐licensed adalimumab (US‐adalimumab) and European Union‐approved adalimumab (EU‐adalimumab). This double‐blind, parallel‐group, phase I trial (clinicaltrials.gov NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT‐P17, US‐adalimumab, or EU‐adalimumab. Primary end points were PK equivalence in terms of: area under the concentration–time curve from time zero to infinity (AUC0–inf); AUC from time zero to the last quantifiable concentration (AUC0–last); and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80–125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT‐P17; 103 US‐adalimumab; 106 EU‐adalimumab), 308 subjects received study drug. AUC0–inf, AUC0–last, and Cmax were equivalent among CT‐P17, US‐adalimumab, and EU‐adalimumab, because 90% CIs for the ratios of GLSMs were within the 80–125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single‐dose administration of CT‐P17, EU‐adalimumab, and US‐adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

Sejung Hwang,1 Dae Young Lee,2 Joo-Youn Cho,1,3 Jae-Yong Chung,4 In-Jin Jang,1 Kyung-Sang Yu,1,3 SeungHwan Lee1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Drug Metabolism and Pharmacokinetics (DMPK), Drug Evaluation, Dong-A ST Research Institute, Gyonggi-do, Republic of Korea; 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of KoreaCorrespondence: SeungHwan LeeDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of KoreaTel +82-2-2072-2343Fax +82-2-2072-0720Email leejh413@snu.ac.krPurpose: DA-8031 is a novel selective serotonin reuptake inhibitor for the treatment of premature ejaculation. This study investigated the pharmacokinetics, safety and tolerability of multiple oral doses of DA-8031. In addition, a genetic analysis was explored to evaluate the effect of genetic polymorphisms on the pharmacokinetics of DA-8031.Subjects and Methods: A dose block-randomized, double-blind, placebo-controlled study was conducted in 3 dose groups with 20, 30 and 40 mg of DA-8031. Healthy male subjects were randomized to DA-8031 or placebo at a 4:1 ratio in each dose group of 10 subjects by oral administration once daily for 7 consecutive days. Serial blood and urine samples were collected for the pharmacokinetic evaluation, and the pharmacokinetic-related genes were analyzed by DMETTM plus. A safety evaluation was conducted including adverse events (AEs) monitoring and 12-lead electrocardiogram (ECG).Results: The plasma DA-8031 concentration reached the maximum concentration (Cmax) in 2.2 to 3.0 h and was eliminated with a mean half-life of 25.5 to 26.7 h at steady state. The accumulation index of DA-8031 ranged 2.3 to 2.8. The systemic exposure of DA-8031 of the CYP2D6 intermediate metabolizer (IM) was significantly higher compared to the CYP2D6 poor metabolizer (PM). There were no clinically significant QTc interval changes, and all the adverse events were mild.Conclusion: After multiple oral doses of DA-8031 20, 30, and 40 mg in this study, the systemic exposure of DA-8031 increased in a more than dose-proportional manner with the increasing doses, and DA-8031 was generally well tolerated. In addition, the genetic polymorphisms of CYP2D6 have an impact on the pharmacokinetics of DA-8031.Keywords: selective serotonin reuptake inhibitors, clinical pharmacology, phase 1 study, pharmacogenomics

Aims Rifampicin is a key drug for the treatment of tuberculosis (TB). Little is known for the relationship between the rifampicin pharmacokinetics and genetic polymorphisms in the Asian population. We aimed to investigate relationship between genetic polymorphism of SLCO1B1 and rifampicin exposure and its impact on clinical outcomes in Korean patients with active pulmonary TB. Methods From February 2016 to December 2019, patients with active pulmonary TB who were taking rifampicin for >1 week were prospectively enrolled. Serial or 1-time blood sampling was conducted to determine rifampicin concentrations. The genotype of 4 single nucleotide polymorphisms of SLCO1B1 was determined. To estimate the drug clearance and exposure, population pharmacokinetics analysis was conducted. Clinical outcomes such as time to acid-fast bacteria culture conversion, chest radiograph score changes from baseline, and all-cause mortality were also evaluated. The exposure among different SLCO1B1 genotype was compared and relationship between drug exposure and clinical outcomes were explored. Results A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age of patients was 55.4 years. The mean drug clearance and exposure were 13.6 L/h and 57.9 mg h/L, respectively. The genetic polymorphisms of SLCO1B1 were not related to rifampicin clearance or exposure. As the rifampicin exposure increased, the chest radiographs improved significantly, but the duration of acid-fast bacteria culture conversion was not related to the drug exposure. Conclusion SLCO1B1 gene polymorphisms did not influence rifampicin concentrations and clinical outcomes in Korean patients with active pulmonary TB.

Acid-reducing agents are commonly used for the prevention of aspirin-induced gastrointestinal complications such as peptic ulcers. As a novel potassium-competitive acid blocker, fexuprazan is expected to prevent aspirin-induced gastrointestinal complications. This randomized, open-label study aimed to evaluate the pharmacodynamic and pharmacokinetic interactions between aspirin and fexuprazan in healthy Koreans. Subjects randomized to the aspirin group received 500 mg aspirin in combination with 80 mg fexuprazan. For the fexuprazan group, fexuprazan 80 mg was administered alone and then in combination with aspirin 500 mg. Platelet aggregation inhibited by aspirin and the pharmacokinetic parameters of aspirin and fexuprazan were compared between monotherapy and combination therapy. A total of 22 subjects completed the study. The platelet aggregation-inhibitory activity and systemic exposure to aspirin were not significantly affected by fexuprazan coadministration. The systemic exposure of fexuprazan was decreased up to 20% by aspirin coadministration, which was not regarded as clinically meaningful considering the previously reported exposure–response relationship. In conclusion, there were no clinically relevant pharmacodynamic or pharmacokinetic interactions between aspirin and fexuprazan. This finding suggests the potential of fexuprazan for the prevention of aspirin-induced gastrointestinal complications, serving as a baseline for optimizing its therapeutic application with aspirin.

Aims: The aim of this study was to evaluate the safety/tolerability, and pharmacokinetics (PKs) of rhEGF eyedrops after administration of a single and multiple doses in healthy subjects. Methods: A phase 1, randomized, double-blind, placebo-controlled, and single ascending dose (SAD) and multiple ascending dose (MAD) study were conducted in 3 dose groups (10, 50, and 100 μg/mL). The subjects randomly received rhEGF eyedrops or their placebo in a 3:1 ratio. Serial blood and tear samples for PK analysis were collected up to 36 h and 180 h post-dose in SAD and MAD study, respectively. In addition, the serum and tear EGF concentrations were measured. Immunogenicity evaluations were conducted using serum anti-EGF antibody level. Results: A total of 50 subjects were enrolled and 48 subjects completed the study. Adverse drug reactions were mild and transient. There were no serious adverse events in this study. The tear EGF concentrations rapidly increased and returned to baseline after 4 hours without serum EGF level change after the administration of rhEGF eyedrops. Conclusion: rhEGF eyedrops were safe and well-tolerated in healthy subjects in a dose range of 10-100 μg/mL, which indicated it was suitable for further studies for corneal injury patients.

Aims Although metformin has been reported to affect the gut microbiome, the mechanism has not been fully determined. We explained the potential underlying mechanisms of metformin through a multiomics approach. Methods An open-label and single-arm clinical trial involving 20 healthy Korean was conducted. Serum glucose and insulin concentrations were measured, and stool samples were collected to analyze the microbiome. Untargeted metabolomic profiling of plasma, urine, and stool samples was performed by GC-TOF-MS. Network analysis was applied to infer the mechanism of the hypoglycemic effect of metformin. Results The relative abundances of Escherichia, Romboutsia, Intestinibacter, and Clostridium were changed by metformin treatment. Additionally, the relative abundances of metabolites, including carbohydrates, amino acids, and fatty acids, were changed. These changes were correlated with energy metabolism, gluconeogenesis, and branched-chain amino acid metabolism, which are major metabolic pathways related to the hypoglycemic effect. Conclusions We observed that specific changes in metabolites may affect hypoglycemic effects through both pathways related to AMPK activation and microbial changes. Energy metabolism was mainly related to hypoglycemic effects. In particular, branched-chain amino acid metabolism and gluconeogenesis were related to microbial metabolites. Our results will help uncover the potential underlying mechanisms of metformin through AMPK and the microbiome.

Several classes of antibiotics have reduced the mortality caused by infectious diseases; however, orally administered antibiotics alter the composition of gut microbiota, leading to dysbiosis-related disease. Therefore, in this study, we used 16S rRNA gene sequencing- and metabolomics-based approaches to investigate the effects of oral vancomycin on gut bacterial microbiota and the metabolome in biospecimens collected from healthy men. Samples collected from 11 healthy men were analyzed using 16S rRNA gene sequencing and metabolomics. 16S rRNA gene sequencing was performed to analyze the gut bacterial microbiota, and GC-TOFMS-based untargeted metabolomics was performed to analyze fecal, urine, and plasma metabolomics. Spearman’s rank correlation was utilized to explore the associations between gut bacterial microbiota and metabolome. Fecal 16S rRNA gene sequencing analysis showed decreased relative abundance of genera belonging to the phyla Bacteroidetes and Firmicutes, and increased relative abundance of genera of the phyla Proteobacteria and Fusobacteria. Fecal metabolomics analysis showed that levels of uracil, L-aspartic acid, lithocholic acid, and deoxycholic acid were significantly higher at baseline, whereas that of dihydrouracil was significantly higher after vancomycin administration. No significant metabolic markers were selected from urine and plasma metabolomics analysis. This study demonstrates that oral vancomycin administration induces alterations in gut bacterial microbiota and metabolome. Correlation analysis between our two datasets shows that alteration of the gut bacterial microbiota, induced by oral vancomycin, potentially affected the systemic activity of dihydropyrimidine dehydrogenase. This correlation should be further examined in future studies to define the effects of gut bacterial microbiota on drug-metabolizing enzymes, thereby contributing to the development of personalized therapy.

Sorafenib, an oral multikinase inhibitor, exhibits a highly variable absorption profile due to enterohepatic reabsorption and poor solubility. SYO-1644 improved the solubility of sorafenib by nanoparticulation technology leading to enhanced bioavailability. To evaluate the pharmacokinetically equivalent dose of SYO-1644 to the reference Nexavar® 200 mg, a randomized, open-label, replicated two-period study was conducted in healthy volunteers. A total of 32 subjects orally received a single dose of the following assigned treatment under a fasted state in the first period and repeated once more in the second period with a two-week washout: SYO-1644 100, 150 and 200 mg and Nexavar® 200 mg. Pharmacokinetic (PK) samples were collected up to 168 h post-dose. The PK profile was evaluated by both non-compartmental analysis and population PK method. With the final model, 2 × 2 crossover trial scenarios with Nexavar® 200 mg and each dose of SYO-1644 ranging from 100 to 150 mg were repeated 500 times by Monte Carlo simulation, and the proportion of bioequivalence achievement was assessed. Transit absorption compartments, followed by a one-compartment model with first-order elimination and enterohepatic reabsorption components were selected as the final model. The simulation results demonstrated that the SYO-1644 dose between 120 and 125 mg could yielded the highest proportion of bioequivalence.

Background A vancomycin loading dose is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, clinicians often do not adhere to these recommendations, mainly due to nephrotoxicity risk, unfamiliarity with the guideline, or complexity of calculating an individual dose. Therefore, we introduced a computerised clinical decision support system (CDSS) for vancomycin loading (hereafter Vancomycin CDSS) to promote the use of vancomycin loading dose. Methods We describe a quasi-experimental study spanning 6 months before and 18 months after the deployment of a Vancomycin CDSS. The Vancomycin CDSS was integrated into the hospital’s electronic medical record system in the form of a vancomycin order set. Our primary endpoint was the incidence of nephrotoxicity; the secondary endpoint was mean initial vancomycin trough levels. We also conducted a survey to evaluate the reasons why clinicians opted not to utilise a vancomycin loading dose. Results After implementation of Vancomycin CDSS, 363 out of 746 patients (49 %) who were first administered vancomycin received a loading dose. We did not find significant differences in nephrotoxicity between the pre- and post-intervention groups, nor between the loading- and non-loading groups. In the pre-intervention group, the mean initial vancomycin trough level was 7.10 mg/L, which was significantly lower than that in the post-intervention group of 11.11 mg/L. In the vancomycin loading group, the mean initial trough level was 11.95 mg/L, compared to 7.55 mg/L in the non-loading group. The main reason stated for not prescribing a vancomycin loading dose was concern about nephrotoxicity. Conclusion Introduction of the Vancomycin CDSS did not increase nephrotoxicity and increased the mean initial dose and trough level of vancomycin.

Purpose To investigate the intraocular distribution and kinetics of antibodies and nanoparticles in the experimental model. Methods Antibodies (whole IgG 149kDa, antigen-binding fragments 48.39 kDa) and four kinds of nondegradable nanoparticles (25, 50, 200, and 250 nm) were intravitreally injected in the right eye of New Zealand white rabbits. The average optical density and concentration were used to measure intraocular distribution and kinetics. Results After intravitreal injection, antibodies were distributed throughout the vitreous humor and eliminated gradually into anterior and posterior routes. Fluorescence intensity decreased 1 day after injection and was not detected 25 days after injection. The nondegradable nanoparticles migrated posteriorly to the retina 7 days after injection onward and anteriorly to the aqueous humor from 1 hour to 1 day after injection. The fluorescence intensity of the nanoparticles was relatively stable in the vitreous humor, compared to antibodies. Nanoparticles accumulated on the internal limiting membrane of the retina with no penetration into deeper retinal tissue, whereas the smaller size 25 nm nanoparticles passed across the ciliary body and moved into choroid, retina, and suprachoroidal space. A gradual decrease of nanoparticles by their sizes in the vitreous after 30 days after injection was described as the percentage ratio: 61.1% (25 nm), 69.1% (50 nm), 78.6% (200nm), and 85.3% (250 nm). Conclusions Our study revealed the in vivo intraocular distribution and kinetics of antibodies and nanoparticles with diverse sizes and the result might help to develop newer intraocular drugs and drug delivery systems to treat retinal diseases. Translational relevance These experimental results can be valuable data for human research.

INTRODUCTION AND OBJECTIVE:To predict the prognosis of localized prostate cancer (PCa) patients and evaluate the actual contribution of tumor volume (TV) to the prognosis of PCa.METHODS:We prospect...

Organic cation transporter 3 (OCT3) is expressed in various organs in humans and plays an important role in the transport of organic cations and drugs including metformin. In this study, we identified genetic variations of the OCT3 promoter and functionally characterized each variant by in vitro assays. Next, the association between the functional haplotype of the OCT3 promoter and pharmacokinetics of metformin was evaluated. In our study population, 7 variations and 2 major haplotypes were identified, of which H2 haplotype yielded a significantly higher luciferase activity than did the wild type. Two variants of H2, c.-1603G > A and c.-1547T > G, yielded significantly lower luciferase activities, whereas the luciferase activity of another variant, c.-29G > A, was significantly higher. Two transcription factors, Sp1 and USF1, were involved in the regulation of OCT3 transcription. Analysis of clinical data revealed that 25 subjects, either homozygous or heterozygous for H2, showed increased AUCinf and Cmax by 17.2% and 15.9%, respectively [P = 0.016 and 0.031, GMR (90% CI) = 1.17 (1.06–1.29) and 1.17 (1.04–1.31), respectively], compared to the 20 subjects in the control group. Our study suggests that an OCT3 promoter haplotype affects the pharmacokinetics of metformin in Koreans as well as the OCT3 transcription rate.

Jung Sunwoo,1 Yu Kyong Kim,1 Yewon Choi,1 Kyung-Sang Yu,1 Heesook Nam,2 Young Lag Cho,2 Seonghae Yoon,3 Jae-Yong Chung3 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2LegoChem Biosciences, Inc., Daejeon, 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea Background: LCB01-0371 is a novel oxazolidinone antibiotic that blocks protein production by binding to bacterial 23S ribosomes. This antibiotic is active against Gram-positive bacteria. This study aimed to evaluate the effect of food on the pharmacokinetics (PKs) of LCB01-0371 and evaluate its safety profile.Subjects and methods: A randomized, open-label, two-way crossover study was performed in 18 healthy Korean male subjects. All subjects received a single oral 800mg dose of LCB01-0371 in each period under fed or fasting condition with a 7-day washout in between. The fed condition was defined as consumption of a meal of 800–1,000kcal containing ~50% of fat content. Serial blood samples were collected over 24h after dosing, and the PK parameters were calculated by noncompartment analysis. All available data of the subjects who received LCB01-0371 at least once were included in the safety data summaries.Results: In the fed condition, both the maximum plasma concentration (Cmax) and the total systemic exposure (area under the plasma concentration–time curve from time zero to the last observed time point [AUClast]) decreased by ~33% and 10%, respectively. The time to reach Cmax was delayed by ~1.25h in the fed condition, whereas the mean elimination half-life remained similar in both conditions. In the fed/fasting condition, the geometric mean ratios and 90% CI of the Cmax and AUClast were 0.666 (0.470–0.945) and 0.897 (0.761–1.057), respectively. There were no drug-related adverse events (AEs) or serious AEs.Conclusion: Although the Tmax after a single oral 800mg dose of LCB01-0371 was slightly delayed under the fed condition compared to the fasting condition, the total systemic exposure was similar under both conditions. Therefore, LCB01-0371 could be administered regardless of food intake. Keywords: antibiotic resistance, gram-positive bacteria, clinical trial

Metformin, an oral hypoglycemic agent belonging to biguanide class, is widely used to treat type 2 diabetes mellitus, and several drug transporters such as organic cation transporters (OCTs), multidrug and toxin extrusion transporter (MATE), and plasma membrane monoamine transporter (PMAT) are thought to affect its disposition. We evaluated the role of PMAT genetic variations on the pharmacokinetic characteristics of metformin in a Korean population. In this retrospective study, 91 healthy subjects from four different metformin pharmacokinetic studies were analyzed; in each study, the subjects were administered two oral doses of metformin at intervals of 12 hours and dose-normalized pharmacokinetic parameters were compared between the subjects' genotypes. Subjects who had more than one allele of c.883-144A>G single nucleotide polymorphism (SNP) in PMAT gene (rs3889348) showed increased renal clearance of metformin compared to wild-type subjects (814.79 ± 391.73 vs. 619.90 ± 195.43 mL/min, p=0.003), whereas no differences in metformin exposure were observed between the PMAT variant subjects and wild-type subjects. Similarly, subjects with variant rs316019 SNP in OCT2 showed decreased renal clearance of metformin compared to wild-type subjects (586.01 ± 160.54 vs. 699.13 ± 291.40 mL/min, p=0.048). Other SNPs in PMAT and MATE1/2-K genes did not significantly affect metformin pharmacokinetics. In conclusion, the genetic variation of c.883-144A>G SNP in PMAT significantly affects the renal clearance of metformin in healthy Korean male subjects.

We developed linearly linked spherical fillers in polymer composites with incorporating Al2O3-Fe3O4 hybrid particles under a magnetic field to form thermal networks for high thermal conductivity. The Al2O3-Fe3O4 hybrid particles were prepared by a simple precipitation method and their magnetic properties were characterized with magnetic hysteresis. The Al2O3-Fe3O4 hybrid particles were well aligned through direction of magnetic field as confirmed by microscopic observation. The polymer composites obtained with Al2O3-Fe3O4 hybrid particles possessed high thermal conductivity in a parallel magnetic alignment direction at low filler loading, which is more than 240% outperformed the composites with randomly dispersed fillers.

Background LCB01-0371 is a new oxazolidinone antibiotic, which targets most Gram-positive organisms. High rates of adverse reactions including myelosuppression have been reported for existing oxazolidinones, limiting their long-term use. Objectives The safety, tolerability and pharmacokinetics (PK) of 21 day multiple oral administrations of LCB01-0371 in healthy male subjects (clinicaltrials.gov: NCT02540460) were investigated. Methods In this randomized, double-blind, placebo-controlled study, subjects received 800 mg of LCB01-0371 once or twice daily or 1200 mg of LCB01-0371 twice-daily for 21 days in a fasting state. Safety and tolerability profiles including laboratory tests were evaluated during the study and on a post-study visit and the results were analysed using repeated-measures analysis of variance (RM-ANOVA). Serial blood samples for PK analysis were collected up to 12 h after dosing on day 21. Results A total of 40 subjects were enrolled and 34 subjects completed the study. Two subjects dropped out according to stopping rules. In the 1200 mg twice-daily dose group, the absolute value of red blood cell count, haematocrit and haemoglobin decreased by 500 × 106/L (6.5%), 4.5% (6.8%) and 1.6 g/dL (6.9%), respectively, after 21 day administrations of LCB01-0371. However, mean relative changes from baseline of all haematology values were not significantly different among doses, including placebo (all, P

Efficient heat transport along through-plane direction is one of the primary requisites for thermal interface materials (TIMs) to relieve heat accumulation at the interface between chip and heat sinks. We report enhanced thermal conduction of Al 2 O 3 -based polymer composites by surface wetting and texturing of thermally conductive hexagonal boron nitride (h-BN) nanoplatelets with large anisotropy (diameter 2 O 3 macrobeads and surface modified h-BN nanoplatelets. Here, the clustering or assembly of h-BN nanoplatelets is analyzed based on depletion interaction of colloidal particles. In addition, further addition of minimal amount of SiO 2 nanoparticles shows a drastic improvement of thermal transport properties, which is attributed to the depletion interaction between nanoplatelets mediated by spherical nanoparticles. Here, the benefits of surface wetting for thermal management composite materials are illustrated.

Deok Yong Yoon,1 Sang-In Park,2 Jin-A Jung,3 Yong-Il Kim,3 In-Jin Jang,1 Jae-Yong Chung4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of KoreaCorrespondence: Jae-Yong ChungDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of KoreaTel +82-31-787-3955Fax +82-31-787-4045Email jychung@snubh.orgBackground: A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet.Subjects and Methods: A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUClast) and the maximum plasma concentration (Cmax) were calculated. Safety was monitored throughout the study.Results: The GMR (90% CI) values of AUClast and Cmax were 0.9946 (0.9663– 1.0238) and 0.9690 (0.9379– 1.0011) for amlodipine, 0.9855 (0.9422– 1.0308) and 0.9178 (0.8349– 1.0089) for losartan, 0.9814 (0.9501– 1.0136) and 0.9756 (0.9313– 1.0219) for EXP3174, and 0.9448 (0.8995– 0.9923) and 0.9609 (0.8799– 1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment.Conclusion: We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.Keywords: fixed-dose combination, loose combination, bioequivalence, pharmacokinetics, hypertension, dyslipidemia

Because bioequivalence studies are performed using a crossover design, information on the intra-subject coefficient of variation (intra-CV) for pharmacokinetic measures is needed when determining the sample size. However, calculated intra-CVs based on bioequivalence results of identical generic drugs produce different estimates. In this study, we collected bioequivalence results using public resources from the Ministry of Food and Drug Safety (MFDS) and calculated the intra-CVs of various generics. For the generics with multiple bioequivalence results, pooled intra-CVs were calculated. The estimated intra-CVs of 142 bioequivalence studies were 14.7±8.2% for AUC and 21.7±8.8% for Cmax. Intra-CVs of Cmax were larger than those of area under the concentration-time curve (AUC) in 129 studies (90.8%). For the 26 generics with multiple bioequivalence results, the coefficients of variation of intra-CVs between identical generics (mean±sd (min ~ max)) were 38.0±24.4% (1.9 ~ 105.3%) for AUC and 27.9±18.2 % (4.0 ~ 70.1%) for Cmax. These results suggest that substantial variation exists among the bioequivalence results of identical generics. In this study, we presented the intra-CVs of various generics with their pooled intra-CVs. The estimated intra-CVs calculated in this study will provide useful information for planning future bioequivalence studies.

A lack of information regarding whether genetic polymorphisms of SLCO1B1 and ABCG2 affect the pharmacokinetics (PKs)/pharmacodynamics (PDs) of rosuvastatin in elderly subjects prevents optimal individualized pharmacotherapy of rosuvastatin in clinical settings. This study aimed to investigate the effect of age and genetic polymorphisms and possible differences in genetic effects on the PKs/PDs of rosuvastatin between elderly and young subjects. Two separate clinical studies designed as open-label, one-sequence studies with multiple-dose administration for elderly (n = 20) and young (n = 32) subjects were conducted. All subjects received 20 mg of rosuvastatin once daily for 21 days. The exposure to rosuvastatin, characterized by the area under the time curve (AUC), increased by 23% in the elderly subjects compared with that of young subjects, which was not significant. When compared to the subjects with breast cancer resistance protein (BCRP) normal function, the exposure to rosuvastatin increased by 44% in young subjects (p = 0.0021) with BCRP intermediate function (IF) and by 35% and 59% (p > 0.05 for both) in elderly subjects with BCRP IF and low function, respectively. SLCO1B1 521T > C was also partially associated with a higher AUC of rosuvastatin in young subjects and a less pronounced increasing trend in elderly subjects (p > 0.05 for both). The lipid-lowering effect of rosuvastatin was less pronounced in the elderly subjects than in the young subjects, and genetic polymorphisms of neither SLCO1B1 nor ABCG2 significantly affected the PDs of rosuvastatin. The ABCG2 421C > A polymorphism was associated with the PKs of rosuvastatin and was identified as a more important determinant than the SLCO1B1 521T > C polymorphism in both elderly and young subjects.

To explore potential biomarkers for amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial in 32 healthy subjects based on multi-omics approaches. Every subject was administered amoxicillin/clavulanate for 14 days. The liver-specific microRNA-122 (miR-122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase. This result indicates its potential as a sensitive early marker for AC-DILI. We also identified urinary metabolites, such as azelaic acid and 7-methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC-DILI, including metabolic changes, increased miR-122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration. In conclusion, this study provides potential biomarkers for AC-DILI based on currently known mechanisms using comprehensive multi-omics approaches.

Purpose To investigate intraocular pharmacokinetics of 10-fold dose of intravitreally injected ranibizumab compared with the conventional dose in an experimental model. Methods Ranibizumab 30 µL at 10 mg/mL (conventional) and 100 mg/mL (10-fold) doses was injected separately into each eye of 28 rabbits. Ranibizumab concentrations in the aqueous humor, vitreous, and retina were estimated at each time period after injection, using enzyme-linked immunosorbent assay. The pharmacokinetic properties of ranibizumab were determined using a one-compartment model in all three ocular tissues. The time-concentration profile and predictive trends were plotted to determine drug efficacy in the retina. Results Maximum concentrations after conventional and 10-fold dosing were observed in the retina at 1 and 4 days after injection, respectively. The half-life of ranibizumab after conventional and 10-fold dosing did not differ in the anterior chamber and vitreous, whereas the half-life was prolonged approximately twice with the 10-fold dose in the retina (36.74 h vs. 76.85 h) and serum (91.93 h vs. 179.01 h). Similarly, the estimated time for ranibizumab concentration in the retina over 27 ng/mL (minimum effective concentration of ranibizumab) was prolonged approximately twice with the 10-fold dose (1315 h [55 days] vs. 2393 h [100 days]). No adverse effects were observed in either group. Conclusions The retinal half-life and concentration of ranibizumab in rabbit eyes were increased approximately twice after a 10-fold dose compared with the conventional dose. This finding indicates a possibility to lengthen the injection interval to improve the efficacy of ranibizumab in human eyes. Translational relevance Our results highlight the potential for clinical application of a high-dose (10-fold) of anti-VEGF agents to prolong the intravitreal injection intervals, simultaneously improving the drug efficacy.

Ursodeoxycholic acid (UDCA) is a metabolic by-product of intestinal bacteria, showing hepatoprotective effects. However, its underlying molecular mechanisms remain unclear. The purpose of this study was to elucidate the action mechanisms underlying the protective effects of UDCA and vitamin E against liver dysfunction using metabolomics and metagenomic analysis. In this study, we analysed blood and urine samples from patients with obesity and liver dysfunction. Nine patients were randomly assigned to receive UDCA (300 mg twice daily), and 10 subjects received vitamin E (400 IU twice daily) for 8 weeks. UDCA significantly improved the liver function scores after 4 weeks of treatment and effectively reduced hepatic deoxycholic acid and serum microRNA-122 levels. To better understand its protective mechanism, a global metabolomics study was conducted, and we found that UDCA regulated uremic toxins (hippuric acid, p-cresol sulphate, and indole-derived metabolites), antioxidants (ascorbate sulphate and N-acetyl-L-cysteine), and the phenylalanine/tyrosine pathway. Furthermore, microbiome involvement, particularly of Lactobacillus and Bifidobacterium, was demonstrated through metagenomic analysis of bacteria-derived extracellular vesicles. Meanwhile, vitamin E treatment did not result in such alterations, except that it reduced uremic toxins and liver dysfunction. Our findings suggested that both treatments were effective in improving liver function, albeit via different mechanisms.

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 ( C max ) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUC τ ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean C max and AUC τ , 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.)

Taegon Hong,1,2 Seunghoon Han,1,2 Jongtae Lee,1,2 Sangil Jeon,1,2 Gab-Jin Park,1,2 Wan-Su Park,1,2 Kyoung Soo Lim,3 Jae-Yong Chung,4 Kyung-Sang Yu,3 Dong-Seok Yim1,2 1Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 2PIPET (Pharmacometrics Institute for Practical Education and Training), the Catholic University of Korea, Seoul, Republic of Korea; 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea Abstract: A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Peripheral blood samples were also obtained for PK analysis. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. 7.2). A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions. The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects. Keywords: thorough QT study, PK-PD model, NONMEM, Emax model

To determine intraocular pharmacokinetic properties of intravitreally injected vascular endothelial growth factor (VEGF)-Trap in a rabbit model. VEGF-Trap was intravitreally injected in 18 rabbit eyes. Eyes were enucleated 1 h and 1, 2, 5, 14, and 30 days after injections and immediately frozen at −80 °C. Concentration of VEGF-Trap in vitreous, aqueous humor, and retina/choroid was determined using an indirect enzyme-linked immunosorbent assay and analyzed to obtain pharmacokinetic properties. Maximum concentration of VEGF-Trap was achieved at 1 h in all three tissues. A one-compartment model of distribution was selected as the final model for all tissues studied. Estimated half-life of VEGF-Trap in vitreous, aqueous humor, and retinal/choroid was 87.1, 36.8, and 35.0 h, respectively, and estimated mean residence time was 125.7, 53.1, and 50.5 h, respectively. Area under the curve from time 0 to the end point was 10009.8, 3945.1, and 1189.3, respectively. Total exposure of the aqueous humor and retina/choroid to VEGF-Trap was 39.4% and 11.9% of vitreous exposure, respectively. The vitreous half-life of VEGF-Trap is 3.63 days. This is shorter than that of bevacizumab (6.99 days) and longer than that of ranibizumab (2.51 days), as shown in studies using the same experimental settings. The concentration of VEGF-Trap peaked at 1 h after injections in all eye tissues studied.