Pharmacokinetic study of lascufloxacin in non-elderly healthy men and elderly men.

We conducted this phase I clinical study to examine the pharmacokinetic profiles and safety of lascufloxacin (LSFX), a novel quinolone antibacterial agent, in non-elderly Japanese healthy men and the effects of aging on LSFX pharmacokinetics in elderly Japanese healthy men. 1. After single-dose oral administration of LSFX 100-800 mg (capsules) to six healthy adults in fasting state, the Cmax and AUClast roughly increased in proportion to the doses. 2. After multiple-dose oral administration of LSFX 75 mg (tablets) once daily for 7 days to six healthy adults, plasma LSFX reached the steady state by Day 7. The cumulative factor of LSFX on Day 7 to Day 1 was 1.65 for the Cmax and 1.96 for the AUCtau. 3. Regarding pharmacokinetic parameters of plasma LSFX after single-dose administration of LSFX 75 mg tablets (final product) to 24 healthy adults in fed state, the Cmax was somewhat higher, 1.28 times more than that in fasting state, whereas no changes were found in the AUClast. We therefore proposed that food effects of LSFX on absorption were negligible. 4. No clinically significant safety problems of LSFX were found in a series of studies involving healthy adults conducted this time. 5. After single-dose oral administration of LSFX 200 mg (capsules) to six elderly people in fasting state, its pharmacokinetic parameters were similar to those in non-elderly people, with no significant safety concerns. Therefore, adjustment of dosage and administration was considered to be unnecessary for LSFX administration to elderly individuals.

Safety, Tolerability, Pharmacokinetics, and Food Effects on TAC-302 in Healthy Participants: Randomized, Double-Blind, Placebo-Controlled, Single-Dose and Multiple-Dose Studies.

TAC-302 stimulates neurite outgrowth activity and is expected to restore urinary function in patients with lower urinary tract dysfunction. We conducted 2 phase 1, randomized, placebo-controlled studies to confirm the safety and pharmacokinetics (PK) of TAC-302 in healthy adult Japanese male volunteers. In the first-in-human single-dose study (n = 60), TAC-302 was administered at doses from 100 to 1200 mg after an overnight fast. The effects of a meal on the PK of TAC-302 400 mg were also examined. A multiple-dose study (n = 36) evaluated the effects of meal fat content on the PK of single doses of TAC-302 (100, 200, or 400 mg) and multiple doses of TAC-302 administered for 5 days (100, 200, and 400 mg twice daily). TAC-302 showed linear PK up to doses of 1200 mg in the fasting state, and across the dose range of 100-400 mg in the fed state. No accumulation of TAC-302 was observed. Food, particularly with high fat content, increased TAC-302 plasma concentrations. No differences were observed in the adverse event incidence between the TAC-302 and placebo groups in either study. TAC-302 showed a wide safety margin.

Determination of creatinine-related molecules in saliva by reversed-phase liquid chromatography with tandem mass spectrometry and the evaluation of hemodialysis in chronic kidney disease patients.

The serum concentrations of creatinine (Cre) and urea are used for the determination of the renal function. However, the use of blood is not always suitable due to the invasive, hygienic and infection problems during its sample collection and handling. In contrast, saliva is relatively clean and the samples can be quickly and noninvasively collected and easily stored. Therefore, the simultaneous determination of Arginine (Arg), creatine (Cr) and Cre in the saliva of chronic kidney disease (CKD) patients was performed by UPLC-ESI-MS/MS together with the saliva of healthy volunteers. The evaluation of hemodialysis of CKD patients was also carried out by the determinations before and after the dialysis. An HS-F5 column was used for the simultaneous determination of Arg, Cr and Cre in the saliva. These molecules were rapidly separated within 4 min and sensitively determined by the multiple reaction monitoring (MRM) of the precursor ion [M+H](+) â†’ product ions (m/z 175.1 â†’ 70.1 for Arg; m/z 132.0 â†’ 44.1 for Cr; m/z 114.0 â†’ 44.1 for Cre). The concentration of Cre in the CKD patients was higher than that in the healthy persons. The concentrations of Cre in the saliva of the patients before hemodialysis were moderately correlated with the serum Cre concentrations (R(2) = 0.661). Furthermore, the concentration in the saliva obviously decreased after hemodialysis (before 0.73 mg/dL, after 0.25 mg/dL; p < 0.02). Thus, the proposed detection method using saliva by UPLC-MS/MS is useful for the evaluation of the renal function in CKD patients. The present method offers a new option for monitoring the hemodialysis of CKD patients.

Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: a Phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male Japanese subjects.

BACKGROUND: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese populations, linagliptin showed potential as a once-daily oral antidiabetic drug. OBJECTIVE: This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans. METHODS: This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests. RESULTS: Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean [SD] age, 24.5 [3.6] years; mean weight, 61.2 [6.2] kg; mean height, 171.5 [5.3] cm) and multiple-dose groups (mean age, 25.4 [3.7] years; mean weight, 61.6 [5.2] kg; mean height, 170.9 [4.9] cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and C(max)) increased in a manner that was less than dose proportional. T(max) ranged from 1.50 to 6.00 hours, and elimination t((1/2)) ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent V(d) (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t((1/2)) ranged from approximately 10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (approximately 1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was >or=80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study. CONCLUSIONS: In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted.