The safety, tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: Overview of three Phase I randomised trials in healthy volunteers.

Safety, tolerability and pharmacokinetics of BI 409306, a potent and selective phosphodiesterase 9A inhibitor, were assessed in healthy subjects in three Phase I, within-dose group, double-blind trials. Trial 1 randomised young and elderly subjects to receive BI 409306 25, 50, 100 mg, placebo once daily (OD) or BI 409306 50 mg twice daily (young) for 14 days. Trial 2 randomised young poor metabolisers (PM) of cytochrome P450 isoform 2C19 (CYP2C19) and elderly subjects to receive BI 409306 25, 50 mg or placebo OD for 14 days. Trial 3 randomised Chinese and Japanese extensive metabolisers of CYP2C19 to receive single doses (SD) of BI 409306 25, 50, 100 mg or placebo and Chinese (PM) to SD of BI 409306 100 mg or placebo (Part 1). Japanese PM received SD of BI 409306 100 mg or placebo (Day 1) followed by BI 409306 100 mg or placebo OD for 7 days after a 48-hour washout period (Part 2). Reported adverse events (AE) were mild-to-moderate intensity and increased with BI 409306 dose. Eye disorders were most commonly reported (Trial 1: 40.0-41.7%, Trial 2: 29.2-37.5%, Trial 3: 18.2-66.7%) and increased with dose and systemic exposure. PM reported more AEs than other treatment groups, corresponding to higher systemic exposure to BI 409306. Systemic exposure to BI 409306 produced dose-dependent increases and was slightly greater in elderly versus young subgroups (Trial 1). Steady state was achieved by Day 2-3. Overall, BI 409306 demonstrated good safety, tolerability and minor accumulation after multiple dosing.

First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males.

AIMS: The aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)-2C19. METHODS: The present randomized, double-blind, placebo-controlled, single-centre study evaluated single rising doses of BI 409306 (0.5-500 mg) administered as a tablet or oral solution to EMs or PMs. RESULTS: Of 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20-30 min) after administration and mostly resolved within 1-2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (Cmax ) was reached <1 h after drug administration, and the half-life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, Cmax was 2.2-2.3-fold higher, and the area under the plasma concentration-time curve over the time interval 0 extrapolated to infinity was 4.1-5.0-fold higher compared with EMs. CONCLUSIONS: In healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level.

Clinical assessment of potential drug interactions of faldaprevir, a hepatitis C virus protease inhibitor, with darunavir/ritonavir, efavirenz, and tenofovir.

BACKGROUND: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients. METHODS: In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated. RESULTS: Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined. CONCLUSIONS: No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).

Pharmacokinetics and tolerability (Study 1) with particular reference to ocular safety (Study 2) of tiotropium Respimat soft mist inhaler: findings from two dose-ranging studies in healthy men.

Data are presented from two randomized, double-blind, placebo-controlled studies in which the tolerability of tiotropium Respimat Soft MistTM Inhaler (SMI), a new-generation, propellant-free device for use in COPD, and the ocular safety oftiotropium were examined. In Study 1, 36 healthy males received tiotropium 8, 16, or 32 microg (n = 9/dose) or placebo (n = 3/dose level), administered once daily via Respimat SMI for 14 days. Safety and pharmacokinetics were evaluated. In Study 2, 48 healthy males received tiotropium 0.02, 0.04, 0.08, 0.16, 0.28, or 0.40 microg (n = 6/dose) or placebo (n = 2/dose level), applied as two drops to one eye (the highest dose was a significant multiple of a percentage of the proposed Respimat SMI clinical dose that could be inadvertently deposited in the eye). Ocular parameters were measured over 24 hours. Tiotropium Respimat SMI at doses up to 32 microg was well tolerated in Study 1; typical dose-dependent anticholinergic adverse events of mild-to-moderate intensity were observed. In Study 2, ocular tiotropium administration did not affect pupil diameter, pupillary reflex, intraocular pressure, or accommodation. Tiotropium Respimat SMI was well tolerated. Inadvertent ocular exposure to tiotropium up to 0.40 g is unlikely to result in ocular adverse effects.

Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and female volunteers.

This study determined if meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane (Tx) B(2) endpoints in healthy volunteers. Eight male and 8 female volunteers participated in this open-label, randomized, two-treatment, two-way crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7 days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment 2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same time points. Each subject received both treatments with a 2-week washout between the treatment periods. Treatments were safe and well tolerated. The initial 4-day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB(2) by 64% +/- 19%. Addition of aspirin (100 mg qd) for 7 days resulted in complete inhibition of aggregation and TxB(2) for 24 hours. Two-day treatment with only 100 mg aspirin also resulted in complete inhibition of platelet aggregation and TxB(2). These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX-1 in platelets, thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB(2) levels, and that meloxicam is selective for COX-2.

Pharmacokinetics of intravenous, single-dose tiotropium in subjects with different degrees of renal impairment.

Tiotropium, a new potent anticholinergic bronchodilator, is excreted mainly by the kidney. To investigate the pharmacokinetics of tiotropium in renal impairment, the authors evaluated the pharmacokinetics and safety after administration of a single dose of intravenous tiotropium 4.8 microg, given as an infusion over 15 minutes in subjects with normal renal function and a wide range of renal impairment based on measured creatinine clearance (normal: > 80 mL/min, n = 6; mild impairment: > 50-80 mL/min, n = 5; moderate impairment: 30-50 mL/min, n = 7; severe impairment: < 30 mL/min, n =6). As expected for a drug excreted predominantly in unchanged form by the kidneys, tiotropium plasma concentrations increased as renal impairment worsened, with mean values of 55.5 (16.2 percent geometric coefficient of variation [%gCV]), 77.1 (20.1 %gCV), 101 (29.8 %gCV), and 108 (27.3 %gCV) pgh/mL for AUC(0-4h) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. The percentage of tiotropium dose excreted unchanged in the urine decreased from 60.1% of dose (17.7 %gCV) to 59.3% (14.4 %gCV), 39.9% (34.5 %gCV), and 37.4% (10.2 %gCV) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. Plasma protein binding of tiotropium did not significantly change in the renal-impaired subjects. Two subjects with normal renal function experienced headache 10 hours after the infusion, which was mild and transient. No adverse events occurred in subjects with renal impairment. There were no clinically relevant changes in blood pressure, pulse rate, 12-lead ECG, physical examination, hematology, or clinical chemistry, compared with baseline values, in any subject after intravenous administration of tiotropium. Tiotropium should only be used in patients with moderate to severe renal insufficiency if the potential benefit outweighs the potential risks.