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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.

Objectives The aim of this phase 1/2 study was to evaluate the safety, tolerability, pharmacokinetics and antitumor activity of olmutinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who had failed ≥ 1 previous line of EGFR-tyrosine kinase inhibitor (TKI) therapy. Materials and methods Phase 1 consisted of dose-escalation and four dose-expansion parts (1: olmutinib 300 mg once daily; 2A: 800 mg once daily [EGFR T790 M mutation-positive patients]; 2B: 500 mg twice daily [EGFR T790 M mutation-positive]; 3: 800 mg once daily [EGFR T790 M mutation-negative]). In phase 2, EGFR T790 M mutation-positive patients received olmutinib 800 mg once daily. Data from expansion part 2A and phase 2 were integrated (`pooled phase 2′). Each olmutinib cycle was 21 days. Outcomes included: tumor response, treatment-emergent adverse events (TEAEs), pharmacokinetic parameters. Results Overall, 272 patients received at least one olmutinib dose: dose-escalation (n = 66), expansion parts (n = 165), phase 2 (n = 41). In pooled phase 2, the overall objective response rate, confirmed by independent review, was 55.1% (38/69 evaluable patients; 95% CI, 42.6–67.1). All responses were partial responses; 23 patients had stable disease. Estimated median progression-free survival was 6.9 (95% CI, 5.6–9.7) months; estimated median overall survival was not reached. The most frequent treatment-related AEs were diarrhea (59.2% of patients), pruritus (42.1%), rash (40.8%), and nausea (39.5%). Conclusion Olmutinib showed effective clinical activity with a manageable safety profile, indicating therapeutic potential for T790M-positive NSCLC patients who have failed ≥ 1 previous line of EGFR-TKI therapy.

The main objective of this phase I trial was to investigate pharmacokinetics (PKs) of olmutinib in three racial subjects. We also evaluate safety/tolerability and a population PK and pharmacogenomic analysis were performed for explorative purposes. A dose escalation study was conducted in 56 Korean, Japanese and Caucasian subjects. The food effect was assessed in the 300 mg Korean group. Individual PK parameters were calculated by non-compartmental methods and presented by dose and race. Genotype analysis was performed using DMET® plus to identify genotypes which affect PK characteristics. A population PK model was developed to explore inter-individual variability and to evaluate the influence of possible covariates using NONMEM® . Tmax was 2-3 hour, regardless of race. The mean terminal half-life ranged from 4.8 to 7.4 hour, with no significant differences between dose or racial groups. Dose-normalized Cmax and AUClast were not significantly different between race groups. PK parameters were similar between the fasting and fed conditions. A single-nucleotide polymorphism in the GSTM3 gene (rs4783) and a copy number variation in the GSTM1 gene were significantly related to AUC. A one-compartment model with first-order absorption adequately described the observed olmutinib data. Thirty adverse events were observed in 15 subjects, of which 26 events, all mild, were possibly related to olmutinib. A single oral dose of olmutinib 100-300 mg was safe and well tolerated. PK parameters were dose-proportional and did not differ by race. Food intake did not affect olmutinib absorption. Pharmacogenomic analysis indicated that glutathione S-transferase might be involved in olmutinib metabolism.

Ursodeoxycholic acid (UDCA) is a secondary bile acid component used for treating primary biliary cirrhosis. This study evaluated and compared the pharmacokinetic (PK) profiles of UDCA and its conjugates glyco-UDCA (G-UDCA) and tauro-UDCA (T-UDCA) in healthy elderly subjects and younger adults. In this randomized, open-label, 2-treatment, 1-sequence, and parallel study, subjects received 400 or 800 mg UDCA on day 1, followed by 200 mg UDCA twice daily for 2 weeks. Blood samples were obtained up to 24 hours after the first UDCA dose. Changes in miRNA-122, γ-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase levels from baseline were assessed to determine the safety and pharmacological effects of UDCA. This study examined the outcomes of 16 elderly subjects and 16 younger adults. Dose-normalized peak concentration of and systemic exposure to UDCA were 2 to 4 times higher, and the corresponding values of G-UDCA and T-UDCA were 1.7 times higher in the elderly subjects than in the younger adults. The subjects in both groups showed multiple peak profiles of UDCA and its conjugates. The miRNA-122 levels and hepatic enzyme test results were within the normal range in the elderly subjects after multiple administration of UDCA. This study is the first to confirm that the PK measurements of UDCA were higher in elderly subjects than in younger adults, which may improve the clinical outcomes of elderly subjects.

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.

Objectives To investigate whether discontinuation of prophylactic dexamethasone by gradual dose de-escalation is practicable in older patients with cancer undergoing moderately emetogenic chemotherapy. Materials and Methods This single-arm, feasibility study prospectively enrolled 40 patients (≥70 years old) with colorectal cancer, who were scheduled to undergo adjuvant FOLFOX chemotherapy, and ten patients ≤60 years old to serve as a control group for pharmacokinetic study. All patients received an antiemetic regimen consisting of intravenous dexamethasone 8 mg and palonosetron at day 1 of the first cycle and underwent phone interviews using symptom questionnaires at day 7 of each cycle. Dexamethasone was tapered off through gradual de-escalation by 2 mg per cycle, when complete response (CR; no emesis and no rescue therapy) was achieved. Primary endpoint was the proportion of patients who discontinued dexamethasone completely. Results The median age of the patient was 74 years, and 50% were male. Of the 40 patients, 36 completed twelve cycles of chemotherapy, and 73% (N = 29) were able to discontinue dexamethasone completely. The mean (±SD) dose of dexamethasone per cycle was 3.0 mg (±2.4 mg), which was reduced to 37.5% of the initial dose level. The severity of patient-reported nausea did not significantly change over chemotherapy cycle. Geriatric assessment revealed no decline in any domain and fasting blood glucose and hemoglobin A1c levels were not elevated after twelve cycles of chemotherapy, compared to the baseline. Conclusion Gradual dose de-escalation and discontinuation of prophylactic dexamethasone is feasible without compromising its antiemetic effect in older patients undergoing chemotherapy.

We report a phase I pharmacological study of an oral formulation of CKD‐516, a vascular‐disrupting agent, in patients with refractory solid tumors. Twenty‐seven patients (16 in the dose‐escalation cohort and 11 in the expansion cohort) received a single daily dose (5‐25 mg) of CKD‐516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment‐related adverse events. The recommended phase II dose of oral CKD‐516 was 20 mg/d (15 mg/d with a body surface area (BSA)

Combination therapy of pregabalin and tramadol is used to treat chronic neuropathic pain; however, the pharmacokinetic (PK) interactions of these drugs has not been studied. This study aimed to evaluate PK interactions between pregabalin and tramadol and the safety of combination therapy. A randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence cross-over study was conducted in healthy subjects. All subjects received the following three treatments for 4 days in each period: pregabalin 150 mg twice daily; tramadol extended-release (ER) 200 mg in the morning, and 100 mg in the evening; and co-administration of pregabalin 150 mg and tramadol ER 200 mg in the morning, and pregabalin 150 mg and tramadol ER 100 mg in the evening. A total of 21 subjects completed the study with no clinically significant safety issues. For pregabalin, the geometric mean ratio (GMR) (90% CI; confidence interval) of combination therapy to monotherapy for maximum concentration at steady state (Cmax,ss) and area under the concentration curve from 0 to dosing interval time at steady state (AUCτ,ss) were 0.8801 (0.8043–0.9632) and 1.0830 (1.0569–1.1098), respectively. The corresponding values for tramadol were 1.0177 (0.9839–1.0526) and 1.0152 (0.9896–1.0414), respectively. The GMR (90% CI) of combination therapy to monotherapy of O-desmethyl-tramadol for Cmax,ss and AUCτ,ss was 1.0465 (1.0095–1.0848) and 1.0361 (1.0001–1.0734), respectively. There were no significant drug interactions between pregabalin and tramadol, considering that all of the 90% CI of PK measures were within the conventional bioequivalence range. Both drugs were well tolerated when administered concomitantly.

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

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR 4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR 4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR 4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR 4, and MR 4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

Vancomycin is a glycopeptide antibiotic used to treat Gram-positive infections including methicillin-resistant Staphylococcus aureus (MRSA). The objectives of this study were to evaluate the appropriateness of the initial dosing regimen of vancomycin, identify factors to be considered in regimen selection and develop a new dosing nomogram. Therapeutic drug monitoring (TDM) data of vancomycin obtained from Seoul National University Hospital from 2011 to 2013 were included in this analysis. The vancomycin trough concentrations at steady-state were estimated using Abbott's PKS software program and then categorized into three levels: subtherapeutic, therapeutic and toxic. The newly developed nomograms were evaluated by analysing the percentage of patients with target vancomycin trough concentration using the data of 2,570 patients of the first TDM cases. Therapeutic level was achieved only in approximately one-fifth of the cases, while 56.0% and 23.8% of the TDMs were considered subtherapeutic and toxic, respectively. As body-weight and creatinine clearance (CrCL) increased, the proportion of patients with a subtherapeutic level increased. Using the newly developed nomogram increased the proportion of patients who achieved therapeutic levels from 23.1% to 45.0% or 13.8% to 36.2% (target, 10-15 and 15-20 mg/L, respectively). These results suggest that the vancomycin concentrations fail to reach the therapeutic level or exceed the safe upper margin of the therapeutic level depending on age, body-weight and CrCL. Considering these factors, the new nomograms provide a strategy to achieve target concentrations of vancomycin more rapidly than existing regimens.

Ursodeoxycholic acid (UDCA) is a secondary bile acid that is used to treat primary biliary cholangitis. Although UDCA has a hepatoprotective effect in some diseases, its benefit in nonalcoholic fatty liver disease (NAFLD) remains controversial. We aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of UDCA in overweight subjects with elevated liver enzymes after multiple administrations of UDCA and compare these changes with vitamin E treatment. Overweight subjects (body mass index, 25-30 kg/m2 ) with elevated alanine aminotransferase (ALT) level (40-200 IU/L) were enrolled. Subjects received one of the following three 8-week treatments: UDCA 300 mg twice daily UDCA 300 mg twice daily for 4 weeks followed by UDCA 300 mg twice daily and metformin 500 mg twice daily for 4 weeks, and vitamin E 400 IU twice daily. PK and PD (liver function, lipid profiles, insulin sensitivity, and miR-122) analyses were performed. Thirty subjects were enrolled; 1 subject withdrew his consent during the study. The PK characteristics were similar to those of healthy volunteers. The ALT and miR-122 levels decreased in the UDCA groups, whereas the ALT and aspartate aminotransferase levels decreased in the vitamin E group. The lipid profiles and insulin sensitivity did not show significant changes among the groups. There was no serious adverse event, and the safety profiles were similar among the treatment groups. The liver enzyme and miR-122 levels were decreased by UDCA. Considering UDCA and vitamin E have a hepatoprotective effect and different mechanisms of action, combination therapy could be an option for NAFLD.

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.

Objective This study had a single-dose, randomized, open-label, 2-period, and 2-sequence crossover design to evaluate pharmacokinetic (PK) bioequivalence between the test and reference formulations. Methods and materials Of the 34 healthy male volunteers enrolled, 4 were excluded owing to consent withdrawal before drug administration and the remaining 30 subjects were administered 20 mg each of the test and reference formulations of omeprazole. The blood samples for PK analysis were collected at the scheduled time-points, prior to dosing to 10 hours after dosing. Plasma concentrations of omeprazole were quantified by a liquid chromatography-tandem mass spectrometry method. Bioequivalence was assessed according to current guidelines issued by regulatory authorities. Results The plasma concentration-time profiles of omeprazole were similar between the reference and test drugs. The geometric mean ratios (90% confidence interval: CI) of test to reference were 0.9104 (0.8538 - 0.9708) for peak plasma concentration (Cmax) and 0.9304 (0.8836 - 0.9796) for area under the plasma concentration-time curve from time zero to time of last measureable concentration (AUC0-t). Conclusion The results from the PK analysis suggested that the reference and test formulations of 20 mg omeprazole capsules were bioequivalent in healthy male subjects.

URC102, a novel and potent inhibitor of human uric acid transporter 1 (hURAT1), is currently under clinical development to treat patients with gout. We performed a randomized, double-blind, placebo-controlled, phase I study to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of URC102 after single and multiple oral administration in healthy male subjects.Thirty-one Koreans and 23 Caucasians received a single dose of URC102 at 1-30 mg and 1-10 mg, respectively, while 44 Koreans received URC102 once-daily for 7 days at 1-20 mg. We evaluated safety and tolerability throughout the study, and serially determined serum uric acid, the fractional excretion of uric acid and URC102 concentrations.URC102 was well tolerated over the dose range of 1-10 mg after single and multiple administration. URC102 rapidly reduced serum uric acid, which was maintained over the entire treatment period. Furthermore, URC102 increased the area-under-the-effect curve over 168 h for fractional excretion of uric acid in a dose-dependent manner. The maximum plasma concentration and the area under the plasma concentration-time curve of URC102 increased dose-proportionally. The pharmacokinetic and pharmacodynamics characteristics of URC102 were similar in Koreans and Caucasians.URC102 was safe and effectively lowered serum uric acid, which should be tested and confirmed in patients with hyperuricaemia and/or gout through further studies.ClinicalTrials.gov, www.clinicaltrials.gov, NCT01953497 and NCT02524678.

Objective URC102, a novel and potent inhibitor of human uric acid transporter 1 (hURAT1), is currently under clinical development to treat patients with gout. We performed a randomized, double-blind, placebo-controlled, phase I study to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of URC102 after single and multiple oral administration in healthy male subjects. Methods Thirty-one Koreans and 23 Caucasians received a single dose of URC102 at 1-30 mg and 1-10 mg, respectively, while 44 Koreans received URC102 once-daily for 7 days at 1-20 mg. We evaluated safety and tolerability throughout the study, and serially determined serum uric acid, the fractional excretion of uric acid and URC102 concentrations. Results URC102 was well tolerated over the dose range of 1-10 mg after single and multiple administration. URC102 rapidly reduced serum uric acid, which was maintained over the entire treatment period. Furthermore, URC102 increased the area-under-the-effect curve over 168 h for fractional excretion of uric acid in a dose-dependent manner. The maximum plasma concentration and the area under the plasma concentration-time curve of URC102 increased dose-proportionally. The pharmacokinetic and pharmacodynamics characteristics of URC102 were similar in Koreans and Caucasians. Conclusion URC102 was safe and effectively lowered serum uric acid, which should be tested and confirmed in patients with hyperuricaemia and/or gout through further studies. Trial registration ClinicalTrials.gov, www.clinicaltrials.gov, NCT01953497 and NCT02524678.

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.

Yewon Choi,1 Seonghae Yoon,1 Kyoko Matsumoto,2 Yoshiyasu Ohta,3 SeungHwan Lee,1 Kyung-Sang Yu,1 In-Jin Jang1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Ikuyaku Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan; 3Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan Introduction: Telaprevir, a reversible selective inhibitor of viral protease and a potential blocker of viral replication, is indicated for the treatment of hepatitis C virus genotype 1 infection. In this study, the pharmacokinetic profile, safety, and tolerability of telaprevir and the effect of food on telaprevir exposure were evaluated in healthy Korean subjects, and compared with data from a previous study in Japanese male subjects. Methods: The single ascending dose study was conducted in 3 dose-based groups (500, 750, and 1,250 mg, six subjects each) in a fasted state. In the multiple dose study, eight subjects in the fed state received 750 mg of telaprevir once on Day 1 and every 8 hours from Day 2 until the morning of Day 6. Serial blood samples for pharmacokinetic analysis were collected for up to 24 hours in the single ascending dose study and for 6 days in the multiple dose study. Individual pharmacokinetic parameters were calculated using a non-compartmental analysis method. Safety and tolerability profiles were evaluated throughout the study. Results: Following multiple administrations of telaprevir, maximum plasma concentrations (Cmax), area under the concentration–time curve (AUC0–8), and Ctrough (concentration at 8 h after drug administration) increased by ~2.41-fold. Compared to fasted state values, mean Cmax and AUC0–24 increased by 4.92- and 4.81-fold, respectively, after food intake. The Cmax and AUCinf of Korean subjects were 26%–34% higher than those of Japanese subjects; however, these differences were not clinically significant. All observed adverse events were mild and there was no discontinuation due to AEs. Conclusion: In conclusion, the telaprevir’s pharmacokinetic characteristics were similar in Korean and Japanese subjects. Telaprevir was well tolerated in a single dose of up to 1,250 mg and in multiple doses of 750 mg. Keywords: antiviral agents, hepatitis C virus, NS3/4A protease, ethnicity, pharmacokinetic profile

Cytochrome P450 (CYP) 3A enzymes, the most important phase 1 drug-metabolizing enzymes, are responsible for 50% of the metabolism of clinically used drugs. CYP3A activity varies widely among individuals, which can affect the probability of adverse drug reactions and drug-drug interactions mediated by the induction or inhibition of the enzyme. Hence, it is important to be able to predict CYP3A activity in individuals to reduce the incidence of unexpected drug responses. To specifically and quickly measure CYP3A activity, we developed method based on gas chromatography interfaced with triple-quadrupole mass spectrometry for the quantification of cortisol, cortisone, 6β-hydroxycortisol, and 6β-hydroxycortisone simultaneously in urine and 4β-hydroxycholesterol in plasma. The results were calculated based on charcoal-stripped steroid-free urine and plasma control samples. The accuracy and precision were 93.18% to 110.0% and 1.96% to 5.34%, respectively. This method was then applied to measure endogenous steroids from urine and plasma samples of healthy Korean males and females. The calibration curves of all analytes showed good linearity with a correlation coefficient (r2) that ranged from 0.9953 to 0.9999. Therefore, this validated method can be used to measure endogenous biomarkers to predict CYP3A activity and might be applicable in the prediction of CYP3A-mediated drug interactions of new drug candidates.

Jieon Lee,1 Seonghae Yoon,1 Donghoon Shin,1 HyeKyung Han,1 Hyungmi An,1,2 Jongtae Lee,1 Kyoung Soo Lim,3 Kyung-Sang Yu,1 Howard Lee11Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea; 2Department of Statistics, College of Natural Sciences, Seoul National University, Seoul, Korea; 3Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, KoreaBackground: Several nomograms have been proposed to facilitate the determination of initial gentamicin dosing regimens in clinical settings. This study aimed to assess the predictive performance of these nomograms in Korean patients.Methods: Gentamicin concentrations were determined in 84 patients with infective endocarditis (IE) and in 95 patients with other infections. All patients underwent therapeutic drug monitoring in Seoul National University Hospital from 2006 to 2012. Individual pharmacokinetic parameters were estimated using a Bayesian method, which predicted steady state peak and trough serum concentrations. Six nomograms were evaluated in patients with "other" infections: the Thomson guidelines, Hull-Sarubbi table, and Rule of Eights, for multiple daily dosing; and the Hartford nomogram, Barnes-Jewish Hospital nomogram, and Sanford Guide, for extended-interval dosing. In IE patients, synergistic combination dosing nomograms, based on the American Heart Association dosing interval guidelines, were evaluated.Results: Gentamicin dosing nomograms performed poorly in attaining the target peak serum concentrations. Multiple-daily dosing nomograms predicted peak serum gentamicin concentrations better than did the extended-interval dosing nomograms (31.9%–72.3% vs 4.3%–45.7%, respectively). Similarly, in patients with IE, the once-daily dosing nomogram resulted in a significantly lower percentage of patients achieving target peak gentamicin concentrations than that associated with the thrice-daily dosing nomogram (P=0.0015). All of the multiple-daily dosing, extended-interval dosing, and synergistic combination dosing nomograms predicted the nontoxic target trough concentrations in >80% of patients.Conclusion: Gentamicin dosing nomograms performed poorly in achieving the target peak serum concentrations. New gentamicin nomograms may be required in patients with IE, particularly for once-daily dosing. Therapeutic drug monitoring is highly recommended for gentamicin to ensure that the target concentrations are achieved.Keywords: antibiotics, infectious endocarditis, therapeutic drug monitoring, Bayesian method

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This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [ https://cris.nih.go.kr/cris/ ] under identifier KCT0000968.).

Few data are available on whether adjusting the dose of posaconazole syrup is effective in patients receiving anti-cancer chemotherapy. The aim of this prospective study was to analyse the impact of increasing the frequency of posaconazole administration on optimal plasma concentrations in adult patients with haematological malignancy. A total of 133 adult patients receiving chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome who received posaconazole syrup 200 mg three times daily for fungal prophylaxis were enrolled in this study. Drug trough levels were measured by liquid chromatography-tandem mass spectrometry. In 20.2% of patients (23/114) the steady-state concentration of posaconazole was suboptimal (500 ng/mL) on Day 8. In these patients, the frequency of posaconazole administration was increased to 200 mg four times daily. On Day 15, the median posaconazole concentration was significantly increased from 368 ng/mL [interquartile range (IQR), 247-403 ng/mL] to 548 ng/mL (IQR, 424-887 ng/mL) (P = 0.0003). The median increase in posaconazole concentration was 251 ng/mL (IQR, 93-517 ng/mL). Among the patients with initially suboptimal levels, 79% achieved the optimal level unless the steady-state level was200 ng/mL. This study shows that increasing the administration frequency of posaconazole syrup is effective for achieving optimal levels in patients with haematological malignancy undergoing chemotherapy.

Seonghae Yoon,1 Donghoon Shin,1 Howard Lee,1,2 In-Jin Jang,1 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul National University Hospital, 2Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea Introduction: LC350189 is a novel selective xanthine oxidase inhibitor under clinical development for the management of hyperuricemia in gout patients. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of the drug in healthy subjects. Methods: A dose-block randomized, double-blind, active and placebo-controlled, single- and multiple-dosing study was conducted. A single ascending dose (SAD) study (10–600mg) and a multiple ascending dose (MAD) study with once-daily doses (100–800mg) for 7days were conducted. Serial samples of blood and urine for pharmacokinetics/pharmacodynamics analysis were collected, and tolerability and adverse events were assessed throughout the study. Results: Sixty-seven and 58 subjects were enrolled in the SAD and MAD studies, respectively. The mean Cmax and AUClast values increased with increasing doses, and exposure to LC350189 was dose proportional. The 24-hour mean serum uric acid (Cmean,24) decreased by 8.7%–31.7% (day 1) and 53.5%–91.2% (day 7) from baseline in the SAD and MAD studies, respectively, and the percentage decrease in Cmean,24 increased with higher doses. Conclusion: LC350189 was well tolerated in the dose range of 10–800mg. It lowered the serum and urine uric acid levels substantially in this dose range; the extent of the decrease in the serum uric acid level in the 200mg dose group was similar or higher compared to that of febuxostat 80mg group in the MAD study. It is expected that LC350189 could be safely administered once daily to patients with hyperuricemia or gout, leading to a sufficient decrease in uric acid levels. Keywords: gout, xanthine oxidase inhibitor, pharmacokinetics, pharmacodynamics, LC350189&nbsp

Kyungho Jang, Seonghae Yoon, Sung-Eun Kim, Joo-Youn Cho, Seo Hyun Yoon, Kyoung Soo Lim, Kyung-Sang Yu, In-Jin Jang, Howard LeeDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of KoreaBackground: Megestrol acetate is an effective treatment for improving appetite and increasing body weight in patients with cancer-associated anorexia. However, Megace® oral suspension (OS), a micronized formulation of megestrol acetate, has low bioavailability in the fasting state. To overcome this limitation, a nanocrystal formulation has been developed. This study was performed to evaluate the pharmacokinetics and tolerability of the nanocrystal formulation and to compare them with those of Megace® OS in the fed and fasting states.Methods: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in three parts in 93 healthy subjects. A single 625 mg/5 mL oral dose of a nanocrystal formulation was administered in the fasting and fed states (part I). In parts II and III, a single 625 mg/5 mL oral dose of the nanocrystal formulation or Megace® OS 800 mg/20 mL was given in the fed and fasting states, respectively. Blood samples were collected for up to 120 hours post dose for pharmacokinetic analysis. Tolerability was evaluated throughout the entire study period.Results: The nanocrystal formulation of megestrol acetate was rapidly absorbed in both the fed and fasting states. In the fed state, systemic exposure was comparable between the nanocrystal formulation of megestrol acetate and Megace® OS. In the fasting state, however, the peak plasma concentration and area under the plasma concentration-time curve to the last measurable concentration of megestrol acetate was 6.7-fold and 1.9-fold higher, respectively, for the nanocrystal formulation than for Megace® OS. No serious adverse events were reported.Conclusion: Systemic exposure to megestrol acetate is less affected by lack of concomitant food intake when it is administered using the nanocrystal formulation. The nanocrystal formulation of megestrol acetate could be more effective in treating patients with cachexia or anorexia.Keywords: megestrol acetate, nanocrystal formulation, food, anorexia

Bone marrow stromal cells show distinct gene expression patterns depending on symptomatically involved organs in multiple myeloma

Vancomycin is a widely used glycopeptide antibiotic that requires therapeutic drug monitoring (TDM) owing to its narrow therapeutic window. It is primarily eliminated by renal excretion; thus, estimating the renal function of a patient is vital in the TDM of vancomycin. In patients with Duchenne muscular dystrophy (DMD), it is difficult to estimate the glomerular filtration rate using the serum creatinine level owing to the pathophysiological nature of the disease. Here, we report a case of a patient in whom TDM of vancomycin was performed, and explore the appropriate methods for evaluating renal function in patients with DMD based on serum levels of creatinine and cystatin C.

We have experienced a number of cases of AML1/ETO+ acute myelogenous leukemia that showed remission based on bone marrow (BM) morphological criteria, but that revealed clonal abnormalities in most cells by fluorescence in situ hybridization (FISH). Interestingly, most of these cases had AML with AML1/ETO rearrangement. The malignant cells were differentiated and considered mature cells after granulocyte-colony stimulating factor (G-CSF) treatment. To clarify the possible mechanisms underlying this phenomenon, we investigated the expression levels of G-CSFR in AML cells with AML1/ETO rearrangement by flow cytometry and real-time polymerase chain reaction (PCR). The number of AML1/ETO+ cells expressing G-CSFR at baseline was significantly higher than that of AML1/ETO- AML cells (2673 vs 522). In addition, the G-CSFR gene was more highly expressed in AML1/ETO+ cells than in AML1/ETO- cells by real-time PCR. This study reveals that cases showing remission after treatment with G-CSF mostly had leukemia with AML1/ETO rearrangement. This finding might be explained by the higher expression of G-CSF receptor in AML1/ETO+ cells than in AML1/ETO- cells. We recommend that remission should be confirmed by FISH, because malignant clones can be differentiated and masked in morphological examination or chromosome test, especially for AML with AML1/ETO rearrangement.