The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium-glucose cotransporter-2 inhibitor, in type 2 diabetes.

AIMS: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.

Pharmacokinetic and pharmacodynamic interaction of DWP16001, a sodium-glucose cotransporter 2 inhibitor, with gemigliptin and metformin in healthy adults.

AIMS: DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, is under clinical development for the treatment of type 2 diabetes mellitus. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics interaction of DWP16001 with gemigliptin and metformin. METHODS: A randomized, open-label, 2-sequence, 2-period crossover study was conducted in 34 healthy male subjects. All subjects received a single oral dose of DWP16001 2 mg with and without gemigliptin and metformin (8 days of 50 mg once-daily dose and 1000 mg twice daily dose for gemigliptin and metformin, respectively). Serial blood samples were collected for PK and serum glucose analysis, and timed urine samples were collected to analyse urine glucose excretion (UGE). The PK and pharmacodynamic parameters were analysed by the noncompartmental method. RESULTS: The PK interactions of DWP16001, gemigliptin and metformin were not clinically significant. The geometric mean ratios (with 90% confidence intervals) of coadministration to separate administration for area under the time-concentration curves were 1.04 (1.02-1.06), 1.03 (0.98-1.09) and 1.17 (1.12-1.22), for gemigliptin, metformin and DWP16001 respectively. The UGE induced by DWP16001 was not affected by the coadministration of gemigliptin and metformin. CONCLUSION: The results suggest that the DWP16001 could be added to metformin and gemigliptin combination therapy without dose adjustment.

Pharmacokinetic and pharmacodynamic interaction between DWP16001, an sodium-glucose cotransporter 2 inhibitor and metformin in healthy subjects.

AIMS: DWP16001 is a novel sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes with selective and sustained sodium-glucose cotransporter 2 inhibition. We aimed to evaluate whether the coadministration of DWP16001 and metformin causes any changes in pharmacokinetics (PK) or pharmacodynamics (PD). METHODS: A randomized, open-label, single- and multiple-dose, 2-sequence, crossover study was conducted in healthy male subjects. Subjects received the following treatments: a single oral dose of DWP16001 (DWP) 2 mg, metformin immediate release 1000 mg (MET) twice daily for 7 days and a single oral dose of DWP and MET at steady-state for metformin (DWP+MET). Serial blood and interval urine were collected for PK and PD analyses. Safety and tolerability profiles were assessed throughout the study. RESULTS: DWP+MET displayed increased peak concentration and area under the concentration-time curve from time 0 to time of the last quantifiable concentration compared with DWP (per standard bioequivalence boundaries, 0.8-1.25); the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were 1.22 (1.13-1.31) and 1.09 (1.05-1.14), respectively. DWP+MET and MET showed similar peak concentration and area under the concentration-time curve within a dosing interval at steady state for metformin; the GMRs and 90% CIs were 0.98 (0.90-1.06) and 1.05 (0.98-1.13), respectively. The amount of urinary glucose excretion from time 0 to 144 h was also comparable between DWP+MET and DWP (GMR and 90% CI; 0.99, 0.94-1.05). CONCLUSION: The results suggest that DWP16001 and metformin could be coadministered without clinically relevant PK and PD interactions.

Comparison of the acid suppression effects between low-dose esomeprazole and famotidine in healthy subjects.

OBJECTIVE: Famotidine, an H2 receptor antagonist (H2RA), is mainly prescribed to alleviate the early symptoms of gastritis. Our aim was to explore the possibilities of low-dose esomeprazole as a treatment of gastritis as well as the pharmacodynamic (PD) properties of esomeprazole and famotidine. MATERIALS AND METHODS: A randomized, multiple-dose, 6-sequence, 3-period crossover study was conducted with a 7-day washout between periods. For each period, the subjects were administered one dose of esomeprazole 10 mg or famotidine 20 mg or esomeprazole 20 mg each day. To evaluate the PDs, the 24-hour gastric pH was recorded after single and multiple doses. The mean percentage of time during which the gastric pH was above 4 was evaluated for PD assessment. To confirm the pharmacokinetic (PK) characteristics of esomeprazole, blood was collected for up to 24 hours after multiple doses. RESULTS: 26 subjects completed the study. Following the multiple doses of esomeprazole 10 mg, esomeprazole 20 mg, and famotidine 20 mg, the mean percentages of time during which the gastric pH was above 4 over the course of 24 hour were 35.77 ± 19.56%, 53.75 ± 20.55%, and 24.48 ± 17.36%, respectively. After multiple doses, the time of peak plasma concentration at steady state (tmax,ss) was 1.00 and 1.25 hours for 10 and 20 mg of esomeprazole, respectively. The geometric mean ratio and its 90% confidence interval of area under the plasma drug concentration-time curve in steady state (AUCT,ss) and maximum concentration of drug in plasma in steady state (Cmax,ss) for esomeprazole 10 mg compared to 20 mg were 0.3654 (0.3381 - 0.3948) and 0.5066 (0.4601 - 0.5579), respectively. CONCLUSION: The PD parameters of esomeprazole 10 mg were comparable to those of famotidine after multiple doses. These findings provide support for further evaluating the use of 10 mg of esomeprazole as a treatment option for gastritis.

A Phase 1 Study To Evaluate Safety and Pharmacokinetics following Administration of Single and Multiple Doses of the Antistaphylococcal Lysin LSVT-1701 in Healthy Adult Subjects.

Thirty-two healthy male subjects (8 per cohort) were randomized 6:2 to active:placebo. LSVT-1701, an antistaphylococcal lysin, was administered intravenously as a 6-mg/kg single dose and as 1.5, 3, and 4.5 mg/kg twice daily for 4 days. LSVT-1701 exposure increased in a greater than dose proportional manner and did not accumulate. Treatment-emergent adverse events (TEAEs) were predominantly of mild intensity. The most common TEAEs were chills, pyrexia, headache, infusion site events, cough, rhinorrhea, and increases in C-reactive protein. (This study has been registered at ClinicalTrials.gov under identifier NCT03446053.).

A double-blind, placebo-controlled, single-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue, in healthy subjects.

AIM: To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue under development, in healthy males and females presenting with no childbearing potential. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, single-ascending dose study was conducted in 56 subjects who randomly received a single subcutaneous dose of HM15136 or its matching placebo at a ratio of 6:2 at 10, 20, 30, 50, 80, 100, and 120 µg/kg. RESULTS: All adverse events were mild and transient. Neither serious adverse events nor discontinuation as a result of adverse events occurred. The most frequent adverse drug reaction was nausea (5.3%, only in the 100- and 120-µg/kg groups). HM15136, particularly at doses of 50 µg/kg or higher, increased fasting blood glucose, with a maximum increase and area under the curve of 1.5 mmol/L at day 10 (P = .006) and 166.3 day·mmol/L (P = .022) at the dose of 80 µg/kg, while suppressing the secretion of endogenous glucagon, which continued until day 17. HM15136 also significantly reduced gluconeogenic and ketogenic amino acids. Compensatory changes in endogenous insulin and incretin hormones by HM15136 were not apparent. HM15136 was slowly but steadily absorbed and reached a peak concentration at 46-68 hours after a single subcutaneous injection. HM15136 was eliminated with a terminal phase half-life of 77.1-101.1 hours. CONCLUSIONS: A single subcutaneous dose of HM15136 at 10-120 µg/kg was safe and well tolerated. The long half-life of HM15136, coupled with an increase in blood glucose for ~2 weeks, may warrant a weekly dosing regimen.

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

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

Pharmacokinetic comparison between tablet of varenicline tartrate and orally disintegrating film of varenicline salicylate in healthy subjects.

OBJECTIVE: Varenicline is an efficacious aid for smoking cessation. In this study, the pharmacokinetics and safety were compared between film-coated tablets of varenicline tartrate (reference drug) and the newly developed orally disintegrating films of varenicline salicylate (test drug), both of them contained 1 mg of varenicline. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period crossover study was conducted in healthy male subjects. Serial blood samples were obtained for up to 72 hours in each period, with a washout period of 7 days or more. The pharmacokinetic parameters were calculated using the noncompartmental method. Safety profiles were assessed throughout the study. RESULTS: A total of 28 subjects completed the study. The plasma varenicline concentration-time profiles were similar for the two study drugs. The maximum plasma varenicline concentration (Cmax) was 5,768.95 ng/L (mean) and 5,780.55 ng/L for the test drug and reference drug, respectively. The areas under the concentration-time curve from time 0 to the last measurable time point (AUC0-t) were 94,086.30 h×ng/L and 89,958.55 h×ng/L for the test drug and reference drug, respectively. The geometric mean ratios (90% confidence intervals) of the test drug to the reference drug for Cmax and AUC0-t were 0.9955 (0.9488 - 1.0444) and 1.0449 (0.9848 - 1.1088), respectively, which fell within the bioequivalence range of 0.8 - 1.25. There was no difference in safety between the study drugs. CONCLUSION: The pharmacokinetics and safety profiles were similar between the two study drugs. The orally disintegrating film of varenicline salicylate can be an alternative to varenicline tartrate tablets.

Comparison of the pharmacokinetic characteristics and bioequivalence between two nanosuspension formulations of megestrol acetate in healthy Korean male subjects.

Megestrol is commonly used to address appetite loss, cachexia, and significant weight loss in cancer or acquired immune deficiency syndrome patients. This study aimed to assess the pharmacokinetics and determine the bioequivalence of two orally administered megestrol acetate suspensions (625 mg/5 mL) in healthy Korean male subjects. A randomized, open-label, single-dose crossover study was conducted involving fifty-four healthy male subjects who were randomized into two sequence groups. Each subject received either a test or reference drug formulation of 625 mg/5 mL megestrol acetate with a two-week washout period between treatments. Plasma samples were collected before and up to 120 hours after administration, and their plasma drug concentrations were analyzed using validated liquid chromatography-mass spectrometry/mass spectrometry. The pharmacokinetic parameters were calculated, and bioequivalence was confirmed if the 90% confidence intervals of the geometric mean ratios were within the specified bounds of 80.00% to 125.00%. In total, fifty-two subjects completed the study, contributing to the pharmacokinetic analysis. The 90% confidence intervals for the geometric mean ratios of the test formulation compared to the reference formulation were 93.85% to 108.90% for maximum plasma concentration and 91.60% to 101.78% for area under the concentration-time curve from the point of administration to last time point of blood sampling. Throughout the study, no serious or unexpected adverse events were observed. The pharmacokinetic profiles of both formulations of megestrol acetate (625 mg) were comparable and well tolerated in healthy Korean male adult subjects. The test formulation met regulatory criteria for bioequivalence. Trial Registration: ClinicalTrials.gov Identifier: NCT06147908.

Effects of food and race on the pharmacokinetics of lazertinib in healthy subjects and patients with EGFR mutation-positive advanced non-small cell lung cancer.

OBJECTIVES: Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild type-sparing third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for advanced non-small cell lung cancer (NSCLC). The study aimed to evaluate the effects of food and race on the pharmacokinetics (PK) of lazertinib from a healthy volunteer trial and PK data from NSCLC patients with EGFR mutation. MATERIALS AND METHODS: An open-label, single-dose, two-period, single-sequence crossover study was conducted in healthy subjects with two race groups (non-Asian and Asian). Subjects orally received a single dose of lazertinib 240 mg in fasted and fed state (high-fat meal) in each period separated by a 21-day washout. An open-label, multicenter, phase 1/2 study was conducted in Asian and non-Asian patients with NSCLC. Patients were given oral lazertinib 20-320 mg once daily in fasted state continuously in 21-day cycles. PK parameters were evaluated using non-compartmental analysis. RESULTS: A total of 24 healthy subjects (12 non-Asians and 12 Asians) and 52 NSCLC patients (22 non-Asians and 30 Asians) were evaluated. The change in the overall systemic exposure of lazertinib at fed state was less than 15%. Non-Asians showed 58-76% of the systemic exposure than Asians in healthy subjects. In contrast, there were no significant differences in systemic exposure by race both after single and multiple doses among NSCLC patients. CONCLUSION: Lazertinib can be taken with or without food considering the comparable systemic exposures related to food. Although effect of race was not consistent across studies, there was no evidence for dose adjustment based on race.

Pharmacokinetic and Pharmacodynamic Characteristics of Pelubiprofen Tromethamine vs. Pelubiprofen in Healthy Subjects.

Compared to pelubiprofen, a cyclooxygenase-2-selective inhibitor, pelubiprofen tromethamine has been reported to exhibit improved solubility and absorption. Pelubiprofen tromethamine combines the anti-inflammatory effect of pelubiprofen with the gastric protective function of tromethamine salt, making it a relatively safe class of non-steroidal anti-inflammatory drugs with low levels of gastrointestinal side effects in addition to its original analgesic, anti-inflammatory, and antipyretic effects. This study assessed the pharmacokinetic and pharmacodynamic characteristics of pelubiprofen and pelubiprofen tromethamine in healthy subjects. Two independent clinical trials were performed in healthy subjects using a randomized, open-label, oral, single-dose, two-sequence, four-period, crossover design. In Study I and Study II, subjects received 25 mg of pelubiprofen tromethamine and 30 mg of pelubiprofen tromethamine, respectively, with 30 mg of pelubiprofen being the reference. Study I fell within the bioequivalence study criteria. A trend of increased absorption and exposure for 30 mg of pelubiprofen tromethamine vs. the reference in Study II was observed. The maximum cyclooxygenase-2 inhibitory effect of 25 mg of pelubiprofen tromethamine was approximately 98% compared to the reference, showing no significant pharmacodynamic variation. It is thus predicted that 25 mg of pelubiprofen tromethamine would show no clinically significant discrepancies in clinical analgesic and antipyretic effects from 30 mg of pelubiprofen.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 versus reference tocilizumab: a randomized, double-blind, single-dose phase I study.

BACKGROUND: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults. CLINICAL TRIAL REGISTRATION: 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.

Influence of Renal Function on the Single-Dose Pharmacokinetics of Besifovir, a Novel Antiviral Agent for theTreatment of Hepatitis B Virus Infection.

Per the well-known resistance of hepatitis B virus to nucleoside/nucleotide analogs, alternative treatment options with higher resistance barriers have been approved for use in both treatment-naïve and lamivudine-resistant hepatitis B virus infections. This phase I study was conducted in adults with normal and impaired renal function to evaluate the effect of renal impairment on the pharmacokinetics of besifovir, a prodrug of an acyclic nucleotide phosphonate, that is mainly cleared via renal excretion. An open-label, single-dose parallel-group clinical study was conducted in subjects with normal renal function and mild, moderate, and severe renal impairment. Subjects received a single oral dose of besifovir dipivoxil 150 mg, and serial blood and urine samples were collected for up to 72 hours after dosing to assess the pharmacokinetic characteristics of besifovir. The extent of plasma exposure of besifovir, detected as its major and active metabolites, LB80331 and LB80317, respectively, increased with worsening renal function. Compared to the subjects with normal renal function, the mean areas under the concentration-time curves of LB80331 increased by 1.5-, 2.5-, and 4.5-fold in subjects with mild, moderate, and severe impairment, respectively. LB80317 showed a 1.8-, 3.2-, and 6.2-fold increase in subjects with mild, moderate, and severe renal impairment compared to those with normal function. The ratios of LB80331 renal clearance and the average estimated glomerular filtration rate of each renal impairment group with respect to the normal group were similar. The increase in plasma exposure and decrease in renal clearance suggest the need to adjust dosage regimens in patients with moderate to severe renal impairment.

Common ABCB1 SNP, C3435T could affect systemic exposure of dapagliflozin in healthy subject.

P-glycoprotein (P-gp) is a transporter that plays an excretory role in epithelial cells. It is encoded by ABCB1, and single nucleotide polymorphisms (SNPs) in this gene can affect systemic drug exposure. Dapagliflozin and sitagliptin, used in type 2 diabetes treatment, are P-gp substrates. Here, we aimed to investigate whether ABCB1 polymorphisms affect dapagliflozin and sitagliptin pharmacokinetics (PK) in healthy Korean subjects. The study population consisted of 100 healthy Korean subjects (94 men and 6 women) who participated in four different clinical trials and received dapagliflozin and sitagliptin doses of 10 and 100 mg, respectively. We determined ABCB1 genotypes for the C3435T, C1236T, and G2677T/A SNPs. The relationship between the genotypes and dapagliflozin PKs was examined. Dapagliflozin and sitagliptin PK parameters were not statistically significantly affected by ABCB1 SNP genotypes. However, homozygous 3435TT subjects showed higher dapagliflozin PK parameters than CT and CC subjects. In subjects with the 3435TT and those with 3435CC and 3435CT genotypes, mean Cmax, AUCinf, and AUC0-1 values of dapagliflozin were 223.06 ng/mL and 194.81 ng /mL (p = 0.2767), 673.58 ng*h/mL and 573.96 ng*h/mL (p = 0.0492), and 128.53 ng*h/mL and 104.61 ng*h/mL (p = 0.2678), respectively. In summary, dapagliflozin and sitagliptin PK parameters were not significantly different between individuals with C1236T and C2677T/A ABCB1 genetic polymorphisms. Dapagliflozin exhibited higher systemic exposure in 3435TT subjects than in CC/CT subjects.

No Relevant Pharmacokinetic Drug-Drug Interaction Between the Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin and Lobeglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in Healthy Subjects.

PURPOSE: Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects. SUBJECTS AND METHODS: A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25. RESULTS: The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well. CONCLUSION: The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment. TRIAL REGISTRATION NUMBER: NCT02854748, Registered on August 7, 2016.

An Investigation of the Metabolism and Excretion of KD101 and Its Interindividual Differences: A Microtracing Mass Balance Study in Humans.

The absorption, metabolism, and excretion (AME) profiles of KD101, currently under clinical development to treat obesity, were assessed in humans using accelerator mass spectrometry (AMS) after a single oral administration of KD101 at 400 mg and a microdose of 14 C-KD101 at ~ 35.2 µg with a total radioactivity of 6.81 kBq. The mean total recovery of administered radioactivity was 85.2% with predominant excretion in the urine (78.0%). The radio-chromatographic metabolite profiling showed that most of the total radioactivity in the plasma and the urine was ascribable to metabolites. The UDP-glucuronosyltransferase (UGT), including UGT1A1, UGT1A3, and UGT2B7, might have contributed to the interindividual variability in the metabolism and excretion of KD101. The microtracing approach using AMS is a useful tool to evaluate the AME of a drug under development without risk for high radiation exposure to humans.

Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets.

PURPOSE: A fixed-dose combination (FDC) of fimasartan and atorvastatin is used to treat hypertension and dyslipidemia. The peak plasma concentration (Cmax) of fimasartan and atorvastatin has a large intra-subject variability with a maximum coefficient of variation of 65% and 48%, respectively. Therefore, both drugs are classified as highly variable drugs. The purpose of this study was to compare the pharmacokinetics (PK) between a FDC of fimasartan 120 mg and atorvastatin 40 mg versus separate tablets in healthy male Korean subjects. SUBJECTS AND METHODS: A randomized, single-dose, two-treatment, three-sequence, three-period, partial replicated crossover study was conducted with a 7-day washout interval between periods. Blood samples for fimasartan and atorvastatin were collected until 48 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios (GMRs) for PK parameters of FDC to loose combination and their 90% confidence intervals (90% CIs) were estimated. RESULTS: A total of 56 subjects completed the study. GMRs (90% CIs) of the Cmax for fimasartan and atorvastatin were 1.08 (0.93-1.24) and 1.02 (0.92-1.13), respectively. The expanded 90% CIs of both drugs using the intra-subject variability was calculated range of 0.70-1.43 and 0.73-1.38, respectively. The corresponding values of area under the concentration-time curve from zero to the last measurable time point were 1.02 (0.97-1.08) and 1.02 (0.98-1.07), respectively. CONCLUSION: FDC of fimasartan 120 mg and atorvastatin 40 mg between their loose combination showed similar PK characteristics.

Pharmacodynamics and pharmacokinetics of DWP14012 (fexuprazan) in healthy subjects with different ethnicities.

BACKGROUND: DWP14012 (fexuprazan), a novel potassium-competitive acid blocker, is under development for the treatment of acid-related disorders. AIMS: To compare the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of DWP14012 among healthy subjects of Korean, Caucasian and Japanese descent. METHODS: A randomised, double-blind, placebo-controlled, single- and multiple-dose study was conducted. Ten subjects in each dose group (40, 60 or 80 mg for Koreans; 40 or 80 mg for Caucasians; 20, 40 or 80 mg for Japanese) were randomly assigned to DWP14012 or a placebo. Twenty-four-hour intragastric pH measurements and serial blood samples were collected for PK/PD evaluation. The PK/PD parameters were compared between each ethnicity. RESULTS: The extent of gastric acid suppression was similar among the ethnicities; the mean percentages of time that the intragastric pH was above 4 after multiple doses of 40 mg in the Korean, Caucasian and Japanese subjects were 64.3%, 62.8% and 70.3%, respectively, and the corresponding values for the 80 mg dose were 94.8%, 90.6% and 90.6% respectively. The changes in serum gastrin were not clinically significant between all three ethnicities. The systemic exposure of DWP14012 was similar between the three ethnicities after the 40 mg doses but slightly lower in Caucasian and Japanese subjects after the 80 mg doses. Gastric acid suppression by DWP14012 showed a clear exposure-response relationship in the three ethnicities. CONCLUSIONS: Gastric acid suppression by DWP14012 was similar among the Korean, Caucasian and Japanese subjects in this study, and the PK, PK-PD relationships and safety were also similar among the three ethnicities. DWP14012 could be used without consideration of ethnicity.

Comparison of pharmacokinetic characteristics of two Tegoprazan (CJ-12420) formulations in healthy male subjects.

Proton-pump inhibitors (PPIs) are effectively used to treat acid-related diseases, including gastroesophageal reflux disease (GERD); however, many unmet medical needs still exist. As a new treatment option, potassium-competitive acid blockers (P-CABs), such as tegoprazan, have been developed. This study was performed to compare the pharmacokinetics (PKs) between two formulations (test and reference drugs) of tegoprazan 100 mg tablets. A randomized, single oral dose, two-treatment, two-period, two-sequence study was conducted with 12 healthy subjects. Each subject received the test drug or reference drug in the first period and the alternative treatment in the second period. For PK evaluation, blood samples were collected up to 48 hours post-dose in each period. The plasma concentrations of tegoprazan and its active metabolite (M1) were measured by liquid chromatography-tandem mass spectrometry. PK parameters, including maximum plasma concentration (Cmax) and area under the concentration-time curve from zero to the last measurable time (AUClast), were estimated using a non-compartmental method. The plasma concentration-time profiles of the two formulations were comparable. The geometric mean ratios [90% confidence intervals (CIs)] of the test drug to the reference drug for Cmax and AUClast were 0.98 (0.85-1.12) and 1.03 (0.93-1.13), respectively. The corresponding values of M1 were 0.99 (0.89-1.11) and 1.01 (0.93-1.09), respectively. The two formulations of tegoprazan exhibited comparable PK profiles, fulfilling the regulatory criteria for bioequivalence.

Trends of clinical trials from 2014 to 2016 in South Korea.

Mandatory registration of clinical trials in public registry can ensure the transparency of clinical trials. Public clinical trial registry of can provide current chronological and geographical distribution of clinical trial throughout the country. We used public clinical trial registry provided by Ministry of Food and Drug Safety to analyze current status of clinical trial from 2014 to 2016 in South Korea. The number of clinical trials in antineoplastic and immunomodulating agents area was the greatest, followed by cardiovascular system and antiinfectives for systemic use as a whole. From 2014 to 2016, overall number of clinical trials decreased while the number of phase I clinical trials increased. Seoul accounted for more than half number of clinical trials in Korea. Supports for clinical trials in non-metropolitan area needs to be considered.