AJM300, a novel oral antagonist of α4-integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects.

AIMS: AJM300 is an oral antagonist of α4-integrin that reduces inflammation by blocking leucocyte trafficking. This study aimed to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of AJM300 in healthy male subjects. METHODS: A total of 23 subjects were randomised to receive 240 mg (n = 6), 480 mg (n = 5), 960 mg (n = 6) of AJM300 or the corresponding placebo (n = 2 per group). The study drugs were taken orally 3 times daily after each meal on the first day followed by a 4-day washout period. Thereafter, multiple-dose administration was conducted for 6 consecutive days. The pharmacokinetic parameters of AJM300 and its active metabolite (HCA2969) were assessed, and total white blood cells and the differential cell count were used to determine the pharmacodynamic effects. Adverse events (AEs) were also monitored. RESULTS: The plasma AJM300 and HCA2969 concentration-time curves displayed a triphasic pattern on Day 1 (single-day administration) and Day 10 (last day of multiple dosing), whereas the concentration of HCA2969 was much higher than that of AJM300. A significant but transient increase in lymphocyte count was observed after AJM300 dosing at all dosages tested compared with the placebo. The increase was sustained over a 24-h period only at the 960-mg dosage. In particular, a significant increase in the lymphocyte count compared to placebo (mean, 50.58%; 95% confidence intervals, 20.40-80.76) was observed at the first 960-mg dose on Day 10. Six (26.1%) subjects reported ≥1 AEs, all of which were mild and resolved spontaneously. CONCLUSION: The maximal and 24-h sustained pharmacodynamic effects were demonstrated at the 960-mg dosage after oral administration of AJM300 3 times daily for 6 days, which was also found to be safe and well tolerated.

Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects.

BACKGROUND: Cefiderocol, a novel siderophore cephalosporin, has shown potent activity against Gram-negative bacteria, including MDR pathogens. Cefiderocol is under clinical investigation for the treatment of serious Gram-negative infections including nosocomial pneumonia. OBJECTIVES: This study assessed intrapulmonary penetration after a single intravenous dose of cefiderocol (2000 mg infused over 60 min) in healthy adult males. MATERIALS AND METHODS: Each subject underwent one bronchoscopy with bronchoalveolar lavage (BAL) to collect BAL fluid (BALF). Fifteen subjects were assigned to one of three collection timepoints (1, 2 or 4 h from start of infusion). Five additional subjects were assigned to a collection timepoint at 6 h, which was added based on concentration data between 1 and 4 h predicting measurable BALF cefiderocol concentrations at 6 h. RESULTS: Cefiderocol concentrations in plasma, epithelial lining fluid (ELF) and alveolar macrophages (AMs) were calculated for each subject. The ELF concentration of cefiderocol was 13.8, 6.69, 2.78 and 1.38 mg/L at 1, 2, 4 and 6 h after single intravenous dosing, respectively. Over 6 h, geometric mean concentration ratios ranged from 0.0927 to 0.116 for ELF to total plasma and from 0.00496 to 0.104 for AMs to total plasma. AUC ratios of ELF and AMs to plasma were 0.101 and 0.0177 based on total drug in plasma, respectively, and 0.239 and 0.0419 based on free drug in plasma, respectively. There were no major drug-related adverse events. CONCLUSIONS: Results of this study indicate that cefiderocol penetrates into ELF, and ELF and plasma concentrations appear to be parallel.

Intrapulmonary Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Nebulized Administration of Laninamivir Octanoate in Healthy Japanese Subjects.

A single dose of laninamivir octanoate (LO) inhaled using a dry powder inhaler (DPI) is effective for the treatment and prophylaxis of influenza. Nebulizers are an option for pediatric and elderly patients who may have difficulty in using a DPI. A single-center, open-label study was conducted to evaluate the plasma and intrapulmonary pharmacokinetics (PK) of laninamivir after a single nebulized administration of LO in healthy male Japanese subjects for identifying a safe and effective dosage regimen for a nebulizer. A single dose of LO (40 to 320 mg) was administered using a nebulizer, and plasma concentrations of LO and laninamivir were analyzed up to 168 h after inhalation by validated liquid chromatography-tandem mass spectrometry methods. Subgroups of 6 subjects each underwent bronchoalveolar lavage at specified time intervals over 4 to 168 h following a single nebulized administration of LO (160 mg), and the concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. PK parameters were determined by noncompartment analysis. Inhaled nebulized LO was found to be safe and well tolerated up to the highest dose evaluated (320 mg). Plasma laninamivir concentrations increased almost dose proportionally. Laninamivir concentrations in ELF exceeded the 50% inhibitory concentrations for viral neuraminidase up to 168 h after the nebulized inhalation of 160 mg LO. Thus, similarly to the DPI, ELF concentration profiles of laninamivir after a single nebulized administration support its long-lasting effect against influenza virus infection. This study has been registered at JAPIC Clinical Trials Information (http://www.clinicaltrials.jp/) under registration no. JAPIC CTI-152996.

Intrapulmonary Pharmacokinetics of Lascufloxacin in Healthy Adult Volunteers.

This study was performed to investigate the intrapulmonary penetration of lascufloxacin in humans. Thirty healthy adult male Japanese subjects, allocated into five groups, received lascufloxacin in a single oral dose of 75 mg. Bronchoalveolar lavage and blood sampling were performed simultaneously in each subject at 1, 2, 4, 6, or 24 h after administration, and lascufloxacin concentrations in plasma, epithelial lining fluid, and alveolar macrophages were determined. Lascufloxacin was rapidly distributed to the epithelial lining fluid with a time to maximum drug concentration (Tmax) of 1 h, which was identical to that in plasma. The maximum concentration of drug (Cmax) values in plasma, epithelial lining fluid, and alveolar macrophages were 0.576, 12.3, and 21.8 µg/ml, respectively. The corresponding area under the concentration-time curve from 0 to 24 h (AUC0-24) values were 7.67, 123, and 325 µg · h/ml. The mean drug concentrations in the epithelial lining fluid and alveolar macrophages were much higher than those in plasma at all time points examined, and the average site-to-free plasma concentration ratios fell within the ranges of 57.5 to 86.4 and 71.0 to 217, respectively. Drug levels in epithelial lining fluid and alveolar macrophages exceeded the MIC90 values for common respiratory pathogens. (This study was registered at JAPIC under registration number JapicCTI-142547.).

Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects.

AIMS: To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men. METHODS: Double-blind, placebo-controlled, sequential, dose-escalation studies were conducted in subjects randomized to receive oral once-daily esaxerenone (ranges: 5-200 mg [single-dose]; 10-100 mg over 10 days [multiple-dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated. RESULTS: In total, 48/48 and 39/40 subjects completed the single- and multiple-dose studies, respectively. Exposures were generally dose-proportional. The tmax , t1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5-4.0 h, 22.3-25.1 h, and 4.0-5.2 l h-1 (multiple-dose study). Vz /F ranged from 136.5 to 283.7 l in the multiple-dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36-1.98. The urinary Na+ /K+ ratio increased after single-dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose-dependently. Although blood potassium levels increased dose-dependently in the multiple-dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l-1 in the 100-mg group), no safety/tolerability-related problems were detected in either study. CONCLUSIONS: Exposure levels in healthy adults receiving esaxerenone were generally dose-proportional. Dose-dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple-dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial.

AIMS: Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation. METHODS: This study consisted of single-dose and multiple-dose tests with a dose-escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single-dose test. Patients received test tablets once daily for 14 days in multiple-dose test. We assessed pharmacokinetic-dose proportionality, levels of serum high- and low-density lipoprotein cholesterol and plasma 7α-hydroxy-4-cholesten-3-one (C4), food effect and sex-specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated. RESULTS: Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371-0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple-dose test, elobixibat reduced low-density lipoprotein cholesterol and increased C4 whilst unaltering high-density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2  = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild. CONCLUSIONS: Elobixibat should be taken before breakfast. Once-daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.

Long Term Follow-Up Study of a Randomized, Open-Label, Uncontrolled, Phase I/II Study to Assess the Safety and Immunogenicity of Intramuscular and Intradermal Doses of COVID-19 DNA Vaccine (AG0302-COVID19).

Pharmacological studies have demonstrated antibody production and infection prevention with an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19). This clinical trial aimed to investigate the safety and immunogenicity of high doses of AG0302-COVID19 when injected intramuscularly and intradermally. Healthy adults were randomly divided into three intramuscular vaccination groups (2 mg, three times at 2-week intervals; 4 mg, twice at 4-week intervals; and 8 mg, twice at 4-week intervals) and two intradermal groups (1 mg, three times at 2-week intervals or twice at 4-week intervals). After a one-year follow-up, no serious adverse events were related to AG0302-COVID-19. At Week 52, the changes in the geometric mean titer (GMT) ratios of the anti-S antibodies were 2.5, 2.4, and 3.2 in the 2, 4, and 8 mg intramuscular groups, respectively, and 3.2 and 5.1 in the three times and twice injected intradermal groups, respectively. The number of INF-γ-producing cells responsive to S protein increased after the first dose and was sustained for several months. AG0302-COVID-19 showed an acceptable safety profile, but the induction of a humoral immune response was insufficient to justify progressing to a Phase 3 program.

Intrapulmonary distribution and pharmacokinetics of laninamivir, a neuraminidase inhibitor, after a single inhaled administration of its prodrug, laninamivir octanoate, in healthy volunteers.

A single inhaled dose of laninamivir octanoate (LO), a long-acting neuraminidase inhibitor, exhibits efficacy in treating both adult and pediatric patients with influenza virus infection. The intrapulmonary pharmacokinetics (PK) of LO and laninamivir, a pharmacologically active metabolite, were investigated by a single-center, open-label study of healthy adult volunteers. Subgroups of five subjects each underwent bronchoalveolar lavage (BAL) 4, 8, 24, 48, 72, 168, and 240 h following a single inhaled administration of LO (40 mg). Plasma, BAL fluid, and alveolar macrophages (AM) were analyzed to determine LO and laninamivir concentrations, using validated liquid chromatography-tandem mass spectrometry methods. The concentrations in epithelial lining fluid (ELF) and AM from the first and subsequent BAL fluid samples were determined separately to explore the drug distribution in airways. Mean laninamivir concentrations in ELF, calculated using the first BAL fluids and BAL fluids collected 4 h after inhaled administration, were 8.57 and 2.40 µg/ml, respectively. The laninamivir concentration in ELF decreased with a longer half-life than that in plasma, and it exceeded the 50% inhibitory concentrations for viral neuraminidases at all time points examined for 240 h after the inhalation. Laninamivir exposure in ELF from the first BAL samples was 3.2 times higher than that in ELF from the subsequent BAL fluid samples. ELF concentration profiles of laninamivir support its long-lasting effect for treatment of patients with influenza virus infection by a single inhaled administration.

Effects of Repeated Oral Administration of Esaxerenone on the Pharmacokinetics of Midazolam in Healthy Japanese Males.

BACKGROUND AND OBJECTIVE: Esaxerenone showed the potential to inhibit and induce activity against cytochrome P450 (CYP) 3A in in vitro studies. We investigated whether repeated administration of 5 mg/day esaxerenone for 14 days influences the pharmacokinetics of midazolam, a sensitive CYP3A substrate, in healthy Japanese males. METHODS: This single-centre, open-label, single-sequence study had two administration periods: period 1: single oral dose of 2 mg midazolam (day 0); period 2: repeated oral doses of 5 mg/day esaxerenone for 14 days, with a single oral dose of 2 mg midazolam on day 14. Full pharmacokinetic profiles of midazolam and 1-hydroxymidazolam on days 0 and 14 and safety data were obtained. Primary pharmacokinetic endpoints for midazolam were area under the plasma concentration-time curve (AUC) from zero to time of the last measurable concentration (AUClast), AUC from zero to infinity (AUCinf), and peak plasma concentration (Cmax). RESULTS: The study included 28 male subjects. One subject was withdrawn because of a mild adverse event (increased hepatic enzyme levels) that resolved without intervention. Repeated administration of esaxerenone increased midazolam AUClast, AUCinf, and Cmax by about 1.2-fold (1.201, 1.201, and 1.224, respectively) compared with administration of midazolam alone. However, repeated administration of esaxerenone did not affect the elimination half-life of midazolam (2.86 versus 2.63 h with and without esaxerenone). There were no safety concerns associated with concomitant administration of esaxerenone and midazolam. CONCLUSIONS: Esaxerenone 5 mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments. CLINICAL TRIAL REGISTRATION: JapiCTI-152832.

Intrapulmonary pharmacokinetics of S-013420, a novel bicyclolide antibacterial, in healthy Japanese subjects.

S-013420 (EDP-420) is a novel bicyclolide (bridged bicyclic macrolide) antibacterial currently under development for the treatment of respiratory tract infections. The objective of the present study was to determine the plasma and intrapulmonary pharmacokinetic parameters of orally administered S-013420 in healthy volunteers. Twenty-eight healthy Japanese male subjects who never smoked were randomly allocated to seven groups of four subjects each who underwent bronchoalveolar lavage (BAL) at different times after dosing (2, 4, 6, 8, 10, 12, or 24 h). Blood samples were also taken at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h after dosing. The S-013420 concentrations in plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs) were measured by using a combined high-performance liquid chromatography-mass spectrometric technique. A pharmacokinetic analysis of the plasma, ELF, and AM S-013420 concentration profiles was performed. S-013420 was rapidly absorbed in plasma, and the mean time to the maximum concentration in plasma was 2.27 h. S-013420 was rapidly distributed to the ELF and was slowly distributed to AMs. The areas under the concentration-time curves from time zero to 24 h (AUC0-24) for S-013420 were 20.3 times higher in ELF than in plasma and 244.6 times higher in AMs than in plasma. The mean maximum concentration in plasma was higher in ELF than in plasma and was much higher in AM than in plasma. Furthermore, pharmacodynamic calculations were done by using the AUC0-24/MIC90 ratio for common pneumonia pathogens (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis). The AUC0-24 for plasma/MIC90s for these four organisms were 41.8, 83.6, 1.3, and 20.9, respectively. The AUC0-24 for ELF/MIC90s were 849.6, 1,699.2, 26.6, and 424.8, respectively. Considering the good efficacy shown in a subsequent phase 2 study (S. Kohno, K. Yamaguchi, Y. Tanigawara, A. Watanabe, A. Aoki, Y. Niki, and J. Fujita, Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L-485), the good distribution of S-013420 in AMs and ELF observed in the present study is predictive of the good efficacy of S-013420 against respiratory pathogens.

Food Effect on a Single High Dose of Carotegrast Methyl, an Oral Antagonist of α4-Integrin, in Healthy Male Subjects: A Randomised, Placebo-Controlled, Double-Blind Study.

BACKGROUND AND OBJECTIVES: Carotegrast methyl, a novel prodrug, oral antagonist of α4-integrin, is in development for the treatment of active ulcerative colitis. This randomised, placebo-controlled, double-blind, crossover study evaluated the effect of food on the pharmacokinetics and pharmacodynamics as well as the safety profile after a single dose of carotegrast methyl in healthy male subjects. METHODS: Subjects were randomised to receive a single dose of carotegrast methyl (240, 480 or 960 mg) or placebo in a 6:2 ratio and received the study drug under both fed and fasted conditions separated by an 8-day washout. The pharmacokinetic profiles of carotegrast methyl and its active metabolite, carotegrast, were assessed. The pharmacodynamic profile was evaluated according to a change in the peripheral lymphocyte count. Safety was monitored throughout. RESULTS: Based on the area under the time curve from zero to the time of the last quantifiable concentration (AUClast), food reduced systemic exposure to both carotegrast methyl and carotegrast by 21-57% and 5-29%, respectively. The fed-to-fasted ratio of least square means for the increase in the lymphocyte count was almost at unity in each dose, indicating no food effect on pharmacodynamics. The time ≥ 90% of maximum effect was prolonged dose dependently, suggesting that a 960 mg-dose can provide a long-lasting effect. Reported adverse events were all mild. CONCLUSIONS: Despite the reduced systemic exposure to both carotegrast methyl and carotegrast, food had no effect on the increase in lymphocyte count. A single administration of carotegrast methyl up to 960 mg was found to be safe.

Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: This paper describes two studies, which aimed to compare the safety and plasma antithrombin activity of recombinant human antithrombin gamma (rhAT-gamma) with plasma-derived antithrombin (pAT) 60 IU/kg, and to establish bioequivalence by adjusting the rhAT-gamma dose to that at which plasma antithrombin activity equaled that for pAT 60 IU/kg, based on results of the first study. METHODS: Healthy adult men aged 20-45 years received once-daily doses of rhAT-gamma or pAT intravenously for 3 days (first study: 60 IU/kg of each; second study: 72 IU/kg of rhAT-gamma and 60 IU/kg of pAT). Maximum plasma antithrombin activity after three doses (Cmax,day3) and area under the plasma antithrombin activity-time curve after the third dose (AUC48-t) were analyzed. Safety was also assessed. RESULTS: In the first study, we compared AUCs to 121 h (when the lower limit of quantification was first observed). Mean Cmax,day3 was 1.67 IU/mL in the rhAT-gamma group and 1.77 IU/mL in the pAT group; mean AUC48-121 was 58.44 and 71.94 IU·h/mL, respectively. Thus, we set the dose of rhAT-gamma in the second study to 72 IU/kg. As a result, ratios of Cmax,day3 and AUC48-t in the rhAT-gamma vs. the pAT group were 105.7% (90% confidence interval 100.3, 111.3) and 100.5% (90% confidence interval 91.5, 110.4), respectively. Adverse events were more frequent in the rhAT-gamma group. CONCLUSIONS: As 90% confidence intervals for Cmax,day3 and AUC48-t ratios for rhAT-gamma:pAT were within the acceptability range for bioequivalence, rhAT-gamma (72 IU/kg) and pAT (60 IU/kg) are considered bioequivalent.

Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study.

INTRODUCTION: To investigate the absolute bioavailability of esaxerenone and the effects of food on its pharmacokinetics (PK) after a single oral dose in healthy Japanese subjects. METHODS: Twenty-four Japanese males aged 20-45 years were randomised to six groups (each n = 4) in this single-centre, open-label, three-way, three-period crossover study. Esaxerenone (5 mg) was administered in the fasting state as a single oral dose, single intravenous infusion over 1 h, or in the postprandial state as a single oral dose. Plasma samples were taken before and during the 96 h after drug administration. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry. PK parameters were calculated using noncompartmental analysis, and safety was assessed. RESULTS: After fasting intravenous administration, total body clearance was 3.69 L h-1 and volume of distribution was 92.7 L. The plasma concentration-time profile of esaxerenone was similar after fasting and postprandial administration. Absolute bioavailability of a single oral 5-mg dose of esaxerenone was 89.0% in the fasting state and 90.8% postprandially. Point estimates (1.010 and 1.019, respectively) and 90% confidence intervals for geometric least squares mean peak plasma concentrations and area under the plasma concentration-time curve ratios after postprandial versus fasting oral esaxerenone were within the prespecified range (0.80, 1.25). No severe adverse events occurred throughout the study. CONCLUSIONS: Esaxerenone has a high absolute bioavailability of approximately 90% and food has no effect on esaxerenone PK after a single oral dose of 5 mg in healthy Japanese subjects. Additionally, no safety concerns were identified. CLINICAL TRIAL REGISTRATION: JapicCTI No. 163452. FUNDING: Daiichi Sankyo Co., Ltd.

Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects.

BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878.

Safety and Pharmacokinetics of DS-8500a, a Novel GPR119 Agonist, After Multiple Oral Doses in Healthy Japanese Males.

BACKGROUND AND OBJECTIVES: G protein-coupled receptor 119 (GPR119) agonists reduce plasma glucose by promoting insulin secretion in a glucose-dependent manner. We evaluated the safety and pharmacokinetics of multiple oral doses of DS-8500a, a GPR119 agonist, under fed conditions in healthy adult Japanese male subjects. METHODS: In this Phase 1, randomized, placebo-controlled, double-blind, multiple oral dose study, participants were aged ≥ 20 and ≤ 45 years with a body mass index ≥ 18.5 and < 25.0 kg/m2. DS-8500a 50 and 100 mg or placebo were administered orally, once daily, 30 min after breakfast for 7 days. The primary endpoints were pharmacokinetics and safety. RESULTS: Twenty-four subjects were included (6, 9, and 9 in the placebo, 50-, and 100-mg groups, respectively). On Day 7, the mean maximum plasma concentration (Cmax) was 812 ng/mL in the 50-mg group and 1310 ng/mL in the 100-mg group. The mean area under the plasma concentration-time curve during dosing interval (AUCtau) was 7910 and 13,200 ng·h/mL in the two treatment groups, respectively. The observed accumulation ratio was 1.25 in the 50-mg group and 1.32 in the 100-mg group. All adverse events were mild and judged unrelated to the study drug. CONCLUSIONS: DS-8500a plasma concentrations reached steady state from Day 3, and Cmax and AUCtau increased in a less than dose-proportional manner. After repeated doses of DS-8500a at 100 mg, the DS-8500a trough concentration was expected to reach a pharmacologically active dose. DS-8500a was well tolerated up to 100 mg after a 7-day administration. STUDY REGISTRY IDENTIFICATION: JAPIC ID: JapicCTI-173550 (registered retrospectively on 30 March 2017).

Pharmacokinetic Bioequivalence Studies of an Extended-Release Oxycodone Hydrochloride Tablet in Healthy Japanese Subjects Under Fasting and Fed Conditions Without an Opioid Antagonist.

Oxycodone is a semisynthetic opioid used for the treatment of moderate to severe pain. Two separate studies were conducted to assess the pharmacokinetic bioequivalence of a newly formulated oxycodone hydrochloride extended-release tablet to a marketed oxycodone product in Japan under fasting and fed conditions. Each study was a randomized, open-label, single-dose, single-center, two-period, two-way crossover study. Healthy male Japanese subjects received the oxycodone 10-mg products under fasting and fed conditions. Blood samples were collected at specified time intervals, and plasma concentrations of oxycodone were analyzed using a validated liquid chromatography tandem mass spectrometry assay method. The pharmacokinetic parameters were determined via non-compartmental analysis. Pharmacokinetic metrics used for bioequivalence assessment were the maximum observed plasma concentration (C max) and the area under the concentration-time curve up to the last sampling time (AUC t ). A total of 24 healthy subjects were enrolled in each study. One subject withdrew after completion of the first sequence under fed conditions. The ratios of geometric least square means for C max and AUC t under fasting conditions were 1.1110 (90% confidence interval [CI] 1.0562-1.1687) and 0.9946 (90% CI 0.9670-1.0231), respectively. The ratios of geometric least square means for C max and AUCt under fed conditions were 1.1417 (90% CI 1.0959-1.1895) and 1.0135 (90% CI 0.9810-1.0470), respectively. The 90% CIs were within the predefined range (0.80-1.25). Both treatments were well tolerated when taken without an opioid antagonist in healthy Japanese subjects. Pharmacokinetic bioequivalence between test and reference formulations under fasting and fed conditions was concluded in terms of both rate and extent of absorption.

Pharmacokinetics and pharmacodynamics of landiolol hydrochloride, an ultra short-acting beta1-selective blocker, in a dose escalation regimen in healthy male volunteers.

OBJECTIVES: We conducted a randomized, double-blind, placebo-controlled study to evaluate the pharmacokinetics and pharmacodynamics of landiolol hydrochloride in a dose escalation regimen in healthy male volunteers. METHODS: We set two-dose escalation regimen (LM and MH groups) using three different doses [L (low): 0.03 mg/kg/min (1 min) loading-->0.01 mg/kg/min (10 min) continuous, M (medium): 0.06 mg/kg/min (1 min) loading-->0.02 mg/kg/min (10 min) continuous, H (high): 0.125 mg/kg/min (1 min) loading-->0.04 mg/kg/min (10 min) continuous]. Sixteen subjects were allocated randomly to the LM, MH, and placebo groups (n=6, 6, and 4, respectively). RESULTS: In both the LM and MH groups, the blood concentration of landiolol hydrochloride changed within a constant range from 2 minutes after initiation of administration to just before the higher dose escalation. By 2 minutes following the higher dose escalation, the concentration of landiolol hydrochloride reached C(max), and reached almost steady state levels until 6 minutes following administration of the higher dose. The t(1/2) of landiolol hydrochloride was 3.5 minutes. The heart rates and blood pressures of subjects administered landiolol hydrochloride decreased, but there were no adverse events in any subject. CONCLUSIONS: The concentration of landiolol hydrochloride rapidly reached steady state levels, and rapidly dissipated after completion of administration.

Assessment of the immunogenicity and safety of varying doses of an MF59®-adjuvanted cell culture-derived A/H1N1 pandemic influenza vaccine in Japanese paediatric, adult and elderly subjects.

INTRODUCTION: Effective vaccination strategies are required to combat future influenza pandemics. Here we report the results of three independent clinical trials performed in Japan to assess the immunogenicity, tolerability and safety of varying doses of a cell culture-derived MF59(®)-adjuvanted A/H1N1 pandemic vaccine in healthy Japanese paediatric, adult and elderly subjects. METHODS: One hundred and twenty-three children (6 months-18 years), and 200 adults (19-60 years) were randomly assigned in a 1:1 ratio to receive two doses of vaccine containing either 7.5 µg antigen with a full (9.75 mg) adjuvant dose, or 3.75 µg antigen with a half (4.875 mg) adjuvant dose. One hundred elderly (≥ 61 years) subjects received only the low antigen/adjuvant vaccine formulation. Immunogenicity was assessed by haemagglutination inhibition assay at baseline and three weeks after the first and second vaccine doses on Days 22 and 43, respectively. Solicited and unsolicited adverse reactions were recorded for seven and 21 days post-immunization, respectively. RESULTS: In adult and elderly subjects, a single low antigen/adjuvant dose vaccination was sufficient to meet all of the three European licensure criteria established for influenza vaccines. One high, or two low antigen/adjuvant dose vaccinations were required to meet the licensure criteria in paediatric subjects. Both vaccine formulations were well tolerated, with the majority of adverse reactions mild to moderate in severity. None of the five serious adverse events reported throughout the three trials were considered to be vaccine-related by the investigators. CONCLUSION: The use of MF59 adjuvant allows for much reduced vaccine antigen content, and a single dose administration schedule in adults and the elderly. The production of pandemic vaccine using modern cell culture techniques is highly advantageous in terms of the quantity, quality, and rapidity of antigen production; these benefits, in combination with the use of MF59, maximize manufacturing capacity and global vaccine supply. These data support the suitability of the investigational vaccine for use in the Japanese paediatric, adult, and elderly populations.

Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP.

BACKGROUND AND PURPOSE An ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACH Effects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(-/-) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 µg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTS Curcumin was a potent hBCRP inhibitor in vitro (K(i) 0.70 ± 0.41 µM). Curcumin increased the area under the curve (AUC)(0-8) of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg(-1), but not in Bcrp(-/-) mice. Curcumin increased AUC(0-24) of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose-exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (K(m) 1.7 ± 0.3 µM). Its linear index (dose/K(m)) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONS Curcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose-exposure relationship of sulphasalazine.