A Single-Dose, Open-Label, Randomized, Two-Way Crossover Study in Healthy Japanese Participants to Evaluate the Bioequivalence and the Food Effect on the Pharmacokinetics of Daprodustat.

Daprodustat is a prolyl hydroxylase inhibitor that stimulates erythropoiesis in a manner similar to the natural response to hypoxia, whereby inhibition of hypoxia inducible factor (HIF) prolyl-4-hydroxylases by daprodustat ultimately results in increased levels of HIF-responsive genes. Daprodustat is under development as an emerging new class of agents for the treatment of anemia associated with chronic kidney disease (CKD). This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male participants consisting of 2 parts. The primary objective was to evaluate the bioequivalence (BE) between daprodustat tablet strengths (part 1) and to evaluate the food effect on the pharmacokinetics (PK) of daprodustat (part 2). A total of 64 healthy Japanese male participants were enrolled; 52 participants were included in part 1 and 12 in part 2. BE was demonstrated between the daprodustat 2-mg tablet and the daprodustat 4-mg tablet. A standard CKD meal did not have a large effect on the PK parameters of daprodustat after a single oral dose of daprodustat 4 mg. Administration of single oral doses of daprodustat 4 mg was generally well tolerated in the healthy Japanese participants, and no new safety signals were identified without regard to food.

Levocetirizine Oral Disintegrating Tablet: A Randomized Open-Label Crossover Bioequivalence Study in Healthy Japanese Volunteers.

Levocetirizine is classified as a second-generation antihistamine. Levocetirizine is available for the treatment of allergic disorders such as allergic rhinitis and chronic idiopathic urticaria. This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male subjects consisting of 2 parts. Part 1 compared the bioavailability of levocetirizine oral disintegrating tablet (ODT) and levocetirizine immediate-release tablet (IRT) taken with water in the fasted state in 24 subjects; all subjects completed this part of the trial. In part 2, the bioavailability of levocetirizine ODT without water was compared with that of levocetirizine IRT with water in the fasted state in 48 subjects; 47 subjects completed this part of the trial. Bioequivalence was demonstrated between levocetirizine IRT 5 mg and ODT 5 mg. The safety profiles were generally similar between levocetirizine ODT and levocetirizine IRT, with no serious adverse events, deaths, or adverse events leading to withdrawal reported during the study.

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants.

Danirixin is a selective and reversible CXC chemokine receptor 2 antagonist that may be useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of danirixin after administration of single oral doses of 10, 50, and 100 mg danirixin hydrobromide (HBr) tablets in the fed state (high-fat meal) (part 1) and to evaluate the food effect (low-fat meal) on the pharmacokinetics of danirixin after administration of a single oral dose of 50 mg danirixin HBr tablets (part 2). A total of 34 Japanese healthy elderly male participants were enrolled; 18 participants were included in part 1, and 16 in part 2. The systemic exposure to danirixin (maximum blood concentration [Cmax ] and area under the concentration-time curve [AUC0-t ]) increased in an approximately dose-proportional manner. The exposure to danirixin was lower in the fed state (low-fat meal) than in the fasted state (a 56% and 35% decrease in Cmax and AUC0-t , respectively). This first study of danirixin in Japanese healthy elderly participants showed a favorable safety profile with no drug-related adverse events and no clinically significant concerns in clinical laboratory values, vital signs, ocular examination, or electrocardiograms.

Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Evaluations Following Single Oral Doses of GSK2330672 in Healthy Japanese Volunteers.

GSK2330672 is an inhibitor of the ileal bile acid transporter, designed to have minimal systemic exposure, and is under development as a potential therapeutic for pruritus associated with primary biliary cholangitis and other cholestatic liver diseases. A phase 1, double-blind, placebo-controlled, 4-period crossover study was conducted to evaluate the safety, tolerability, and pharmacokinetic/pharmacodynamic characteristics of GSK2330672 in healthy Japanese participants. Sixteen healthy male participants received single oral doses of GSK2330672 (10-180 mg) or placebo in each period. No serious adverse events and no adverse events leading to study discontinuation or withdrawal were reported. Drug-related adverse events reported included gastrointestinal symptoms (mostly diarrhea) and positive fecal occult blood tests, and were all mild and resolved without any interventions. GSK2330672 was undetectable in the majority of participants' plasma. Pharmacodynamic observations included a tendency for total serum bile acids to reduce and for serum 7α-hydroxy-4-cholesten-3-one, a key intermediate of bile acid synthesis, to increase with increasing doses of GSK2330672. In the context of recently published indications of potential efficacy for cholestatic pruritus in non-Japanese populations, these data support further evaluations of GSK2330672 in Japanese patients.

Proposed selection strategy of surrogate matrix to quantify endogenous substances by Japan Bioanalysis Forum DG2015-15.

It is important to select an appropriate surrogate matrix for preparing calibration standards and quality control samples while quantitatively assaying for endogenous substances, because a blank matrix that does not contain the endogenous substance cannot be derived from the species from which the target study samples are collected. This is because the assay results might be affected, depending on the characteristics of the analyte in the surrogate matrix. Our discussion group that participated in the Japan Bioanalysis Forum discussed the recommended selection strategies, focusing on large and small molecules in ligand binding assays and LC-MS, respectively. We established an efficient selection strategy for a surrogate matrix, with simple compositions as the first candidates stated in this article.

Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.

This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3-1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD.

Systemic exposure to benzoic acid and hippuric acid following topical application of clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel in Japanese patients with acne vulgaris.

Clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel (CLDM/BPO3%) is a topical product for the treatment of acne vulgaris. In this study, plasma and urine concentrations of benzoic acid (BA) and hippuric acid (HA) were analyzed to estimate the pharmacokinetics (PK) of BPO after application of CLDM/BPO3% twice-daily for 7 days in Japanese patients with acne vulgaris. Seven-day repeated application of CLDM/BPO3% appears to be safe in this patient population. Concentrations of plasma and urine BA were below the limit of quantification before and after repeated application in most of the 12 adult male patients. Mean difference in Cmax and AUC0-last for plasma HA indicated increased exposures after repeated application, but with wide 90% confidence intervals. Mean Ae0-12 for urine HA was similar before and after repeated application. Repeated application of CLDM/BPO3% is thus unlikely to result in accumulation of BA and HA. The study suggests negligible systemic exposure to BPO metabolites from CLDM/BPO3% after 7-day repeated application in male patients with acne vulgaris.

The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects.

OBJECTIVE: To evaluate the safety, pharmacokinetics and pharmacodynamics of fluticasone furoate (FF) and vilanterol (VI) administered alone or in combination in three Phase I studies in healthy Japanese male subjects. MATERIALS: FF, VI and FF/VI inhalation powder in a novel dry powder inhaler (nDPI). METHODS: Study A: 48 subjects received the first dose on Day 1, followed by a 4-day washout and once-daily (OD) repeat doses of FF 200, 400 or 800 µg or placebo from Day 5 to Day 11 (7 days). Study B: 32 subjects received repeat doses of VI (12.5, 25 µg) OD for 7 days. Study C: 16 subjects received single doses of FF (800 µg), VI (50 µg), FF/VI (800/50 µg) and placebo. RESULTS: Overall, there were no safety concerns and no major differences were found in treatment-related adverse events when FF and VI were administered alone or in combination. Peak plasma concentration of FF and VI following repeat dosing was up to two times higher compared with the single dose. Individual pharmacokinetic parameters of FF and VI differed when co-administered but the differences from monotherapy were not clinically significant. Repeat dosing of FF affected weighted mean (0 - 24 hours) serum cortisol with FF 200, 400 and 800 µg resulting in respective reductions from placebo of 32%, 38% and 97%, respectively. Mean maximum heart rate (0 - 4 hours) was comparable between placebo, VI 12.5 and 25 µg over 7 days of dosing; for single dosing of FF/VI 800/50 and VI 50 µg, heart rate was comparable (70 and 73 bpm, respectively) and this was higher than FF 800 µg (66 bpm) or placebo (64 bpm), but the difference was not clinically significant. CONCLUSIONS: In healthy Japanese subjects, no safety concerns were found following repeat dosing of FF and VI or single dosing of FF, VI and FF/VI. Systemic exposure to FF and VI increased in a dose-dependent manner. Serum cortisol level was suppressed by 97% after 7 days repeat administration of FF at a dose of 800 µg. Heart rate with a single dose of VI 50 µg was higher than that of placebo, though not to a clinically significant extent.

Safety and pharmacokinetic evaluation of intravenous colistin methanesulfonate sodium in Japanese healthy male subjects.

OBJECTIVES: The study aimed at evaluating the pharmacokinetics of colistin methanesulfonate sodium (CMS-Na) and describing observed safety findings in Japanese healthy male subjects. METHODS: A total of 22 Japanese healthy males were enrolled in this randomized double-blind, placebo controlled study. Dosing regimens of a single dose and twice-daily repeat doses of CMS-Na (2.5 mg/kg as colistin activity, 75,000 IU/kg) were employed. Safety variables included urinary N-acetyl-ß-D-glucosaminidase, protein and ß(2)-microblobulin. Concentrations of CMS and colistin were determined by LC-MS/MS. Pharmacokinetic parameters were obtained by noncompartmental analysis. CLINICAL TRIAL REGISTRATION NUMBER: NCT01449838. RESULT: The urinary N-acetyl-ß-D-glucosaminidase for the detection of early renal damage showed transient increases during the repeat dose period. Otherwise, no clinically significant findings related to study medication were observed. After 2.5-day twice-daily dosing, mean t(1/2) and CL(R) of colistin were 4.98 h and 0.0073 L/h/kg, respectively. Repeat dose C(max) and AUC(0-12) were increased by 72% and 63%, respectively, compared to single dose. The dosing regimen had little effect on renal excretion rate (fe) of both CMS and colistin. The previously reported area under the unbound concentration-time curve to minimum inhibitory concentration (MIC) ratio (fAUC/MIC) target values in mouse lung and thigh infection models compared with the distribution of fAUC/MIC in humans estimated by a Monte Carlo simulation indicated that a bacteriostatic effect was predicted in 84% and 96% of patients, respectively, whereas bactericidal effect was predicted in 65% and 78% of patients, respectively. As this study was conducted with a relatively small number of healthy subjects, safety and PK profiles in critically ill patient population may be different than was observed in this study. CONCLUSION: CMS-Na was safely administered to healthy volunteers but resulted in transient increase of urinary N-acetyl-ß-D-glucosaminidase (NAG) and protein. Based on this study, the highest recommended dose of CMS-Na had sufficient bacteriostatic effect.

A severe peak tailing of phosphate compounds caused by interaction with stainless steel used for liquid chromatography and electrospray mass spectrometry.

A severe peak tailing was observed for adenosine 5'-monophosphate in flow injection analysis with stainless steel tubing and water/methanol mixture (1:1, v/v) as carrier. The cause of the peak tailing was investigated by focusing on the chemical structure of the analytes, the material used for the analytical systems and the composition of the carrier. We clarified that the peak tailing was caused by the interaction between phosphate residues in the analytes and stainless steel. The severe peak tailing did not occur with stainless steel tubing when the phosphate compounds were analyzed with carrier containing phosphoric acid or phosphate buffer. The findings indicate that such ill peak profiles are usually not considerable in conventional HPLC separation because phosphoric acid or phosphate buffer is quite commonly used in eluents. In LC-MS, however, the use of phosphoric acid and phosphate buffer is usually avoided because of their non-volatility; therefore this interaction between stainless steel and phosphate compound becomes predominant and results in severe peak tailings. We also found an effective method for avoiding the interaction. When stainless parts, such as LC tubing and ESI spray capillary, were treated with phosphoric acid prior to analysis, the peak profiles of the phosphate compounds were dramatically improved, even when non-phosphate buffer is used as carrier.