Atsuhiro Kawaguchi

Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans

Abstract 1. The absorption, metabolism and excretion of teneligliptin were investigated in healthy male subjects after a single oral dose of 20 mg [14C]teneligliptin. 2. Total plasma radioactivity reached the peak concentration at 1.33 h after administration and thereafter disappeared in a biphasic manner. By 216 h after administration, ≥90% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 45.4% and 46.5%, respectively. 3. The most abundant metabolite in plasma was a thiazolidine-1-oxide derivative (designated as M1), which accounted for 14.7% of the plasma AUC (area under the plasma concentration versus time curve) of the total radioactivity. The major components excreted in urine were teneligliptin and M1, accounting for 14.8% and 17.7% of the dose, respectively, by 120 h, whereas in faeces, teneligliptin was the major component (26.1% of the dose), followed by M1 (4.0%). 4. CYP3A4 and FMO3 are the major enzymes responsible for the metabolism of teneligliptin in humans. 5. This study indicates the involvement of renal excretion and multiple metabolic pathways in the elimination of teneligliptin from the human body. Teneligliptin is unlikely to cause conspicuous drug interactions or changes in its pharmacokinetics patients with renal or hepatic impairment, due to a balance in the elimination pathways.

Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

AIMS Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. METHODS Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Japanese males, 18-55 years). Study 2: Caucasian males (18-55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21-28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests. RESULTS Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated. CONCLUSIONS TA-8995 is a potent CETP inhibitor and warrants further investigation.

Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk.

We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT‐1303), a second‐generation sphingosine 1‐phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators.

A Comparative Pharmacokinetic Study of Recombinant Human Serum Albumin With Plasma-derived Human Serum Albumin in Patients With Liver Cirrhosis

We conducted an open‐label, parallel‐group study of the high purity, mass‐produced recombinant human serum albumin (rHSA), derived from the methylotrophic yeast Pichia pastoris, to compare pharmacokinetics and ensure bioequivalence with plasma‐derived human serum albumin (pHSA) in 22 patients with liver cirrhosis. Both rHSA and pHSA groups enrolled 11 patients each, assigned according to predose serum albumin concentrations using the minimization method. Pharmacokinetic and safety profiles for 3‐day repeated intravenous infusions at a daily dose of 25 g were evaluated for 8 days. Geometric mean AUC0–168hr (g·hr/dL) was 637.12 and 635.93 in the rHSA and pHSA groups, respectively, with a 90% confidence interval (CI) for the difference (92.9%‐108.1%) lying within the bioequivalence range. The other major parameter, geometric mean Cmax (g/dL), was 4.16 and 4.19 in the rHSA and pHSA groups, respectively, with a 90% CI for the difference (92.7%‐106.4%). The pHSA group presented with 3 adverse events: 1 case of insomnia, and 2 laboratory abnormalities with no serious adverse events. Results from this study show similar pharmacokinetic profiles following intravenous administration of 25g/day of rHSA and pHSA for 3 days, indicating bioequivalence.

Effect of ketoconazole on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor teneligliptin: an open-label study in healthy white subjects in Germany.

OBJECTIVE The aim of this study was to examine the effect of ketoconazole, a potent cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, on teneligliptin pharmacokinetics and to evaluate the safety of combined administration of teneligliptin with ketoconazole. METHODS This open-label, fixed-sequence study was conducted in 16 healthy adult volunteers in Germany. On day 1, under fasting conditions, 20 mg of teneligliptin was administered to evaluate the pharmacokinetics of teneligliptin alone. For 3 days (days 8-10), 400 mg of ketoconazole was administered once daily. On day 11, teneligliptin 20 mg and ketoconazole 400 mg were concurrently administered, and for 2 days (days 12 and 13), ketoconazole was administered once daily. The pharmacokinetic parameters (Cmax, Tmax, AUC, terminal t½, apparent total plasma clearance, and Vd during the terminal phase) of teneligliptin on days 1 and 11 were calculated. The safety profile was evaluated based on adverse events and clinical findings. To investigate the role of human P-gp in membrane permeation of teneligliptin, an in vitro study was performed to measure the transcellular transport of teneligliptin across monolayers of human P-gp-expressing cells and control cells. RESULTS For Cmax and AUC, the geometric least squares mean ratios (90% CIs) of teneligliptin with ketoconazole to teneligliptin alone were 1.37 (1.25-1.50) and 1.49 (1.39-1.60), respectively. There was no change in t½ of the terminal elimination phase. In addition, the tolerability of teneligliptin coadministered with ketoconazole was acceptable. The in vitro study revealed corrected efflux ratios for teneligliptin of 6.81 and 5.27 at teneligliptin concentrations of 1 and 10 μM, respectively. CONCLUSIONS Because the exposure to teneligliptin in combined administration with ketoconazole, a potent CYP3A4 and P-gp inhibitor, was less than twice that of administration of teneligliptin alone, it is suggested that combined administration of teneligliptin with drugs and foods that inhibit CYP3A4 should not cause a marked increase in exposure. The results of our in vitro study suggest that teneligliptin is a substrate of P-gp. CLINICAL TRIAL REGISTRATION EudraCT No. 2009-016652-51.

Favorable effect on postgraduate clinical practice of a drug-interaction exercise for undergraduate students

AimUndergraduate students in Jichi Medical School participated in a laboratory exercise investigating the furosemide–probenecid interaction at the end of their clinical pharmacology (CP) course. The aim of this study was to determine whether they learned to recognize drug interactions better than students who did not take such a course.MethodsWe conducted a postal survey of physicians who had graduated from Jichi Medical School or from other medical schools without a CP course including the exercise. Questions were asked concerning: (1) the recognition of furosemide–probenecid and nine other drug interactions, and (2) the need to anticipate drug interactions and their adverse effects before writing prescriptions.ResultsThe degree of the recognition of all drug interactions, and the percentage of physicians who responded that knowledge of drug interactions and adverse effects were essential before writing prescriptions, were significantly greater in physicians who had taken an undergraduate CP course than in those who had not.ConclusionsCP courses with specific laboratory exercises on drug interactions lead future physicians to recognize drug interactions and their adverse effects.

Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations

Abstract Background: Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease. Objective: To compare the pharmacokinetics (PK) of edaravone between Japanese and Caucasian populations. Methods: Data from five PK studies among Japanese and Caucasian healthy volunteers were pooled and evaluated. In population PK (PPK) modelling, compartment models and other models with linear elimination were evaluated for appropriateness. Covariate effects by race, sex, weight, and age were investigated to explain variability in PK parameters. Simulations of the final PPK model were performed using a virtual population based on ALS clinical trials. Results: The analysis included 86 subjects. A three-compartment model with Michaelis-Menten plus linear elimination was selected as the best fit model. Race was statistically detected as a covariate for the second peripheral volume of distribution (V2), indicating a 26% increase for Caucasian subjects compared to Japanese subjects. However, based on simulation of PPK model for a virtual ALS population, the small difference of V2 was associated with a difference of Ctau around 1 ng/mL after infusion, which was minimal compared to Cmax of approximately 1000 ng/ml. Conclusion: The PPK analyses demonstrated no clinically relevant difference in the PK profiles of edaravone by race, sex, weight, or age.

Clearance of imidapril, an Angiotensin-converting enzyme inhibitor, during hemodialysis in hypertensive renal failure patients: comparison with quinapril and enalapril.

The dialyzability of imidaprilat, an active metabolite of the angiotensin‐converting enzyme (ACE) inhibitor imidapril, was determined and compared with those of enalaprilat and quinaprilat in hypertensive patients on chronic hemodialysis. Imidapril (5 mg/d, n = 6), enalapril (2.5 mg/d, n = 6), or quinapril (2.5 mg/d, n = 6) was given for at least 8 weeks prior to the trial. During dialysis, enalaprilat, but not imidaprilat or quinaprilat, concentrations in both sides decreased significantly. Compared to enalaprilat, the dialyzabilities of imidaprilat and quinaprilat were significantly lower (dialyzer clearance [mL/min/m2]: enalaprilat, 41.8 ± 7.4; imidaprilat, 19.0 ± 7.8; quinaprilat, 8.9 ± 1.3). The dialyzabilities of the 3 drugs were negatively correlated with their respective protein‐binding rates. During hemodialysis, blood pressure did not change significantly in any group. These results suggest that imidapril provides good blood pressure control without a large fluctuation of drug concentration in hypertensive patients undergoing chronic hemodialysis.

Absorption, Disposition and Metabolic Pathway of Amiselimod (MT-1303) in Healthy Volunteers in a Mass Balance Study

Abstract The absorption, metabolism and excretion of MT-1303 were investigated in healthy male subjects after a single oral dose of 0.4 mg [14C]-MT-1303 (ClinicalTrials.gov NCT02293967). The MT-1303 concentration in the plasma reached a maximum at 12 h after administration. Thereafter, the concentration declined with a half-life of 451 h. At the final assessment on Day 57, 91.16% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 35.32% and 55.84%, respectively. The most abundant metabolite in plasma was MT-1303-P, which accounted for 42.6% of the area under the plasma concentration–time curve (AUC) of the total radioactivity. The major component excreted in urine was Human Urine (HU)4 (3066434), accounting for 28.1% of radioactivity in the sample (4.05% of the dose), whereas MT-1303 was a major component in the faeces, accounting for 89.8% of radioactivity in the sample (25.49% of the dose) up to 240 h after administration. This study indicates that multiple metabolic pathways are involved in the elimination of MT-1303 from the human body and the excretion of MT-1303 and MT-1303-P via the kidney is low. Therefore, MT-1303 is unlikely to cause conspicuous drug interactions or alter pharmacokinetics in patients with renal impairment. Trial registration: ClinicalTrials.gov identifier: NCT02293967.