Background Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue-type plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low molecular weight compound that inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases. Objectives This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of DS-1040 in healthy subjects. Subjects/Methods Young (18-45 years) or elderly (65-75 years) subjects (N = 103) were randomized to receive single ascending doses of DS-1040 ranging from 0.1 mg to 40 mg, or placebo, administered either as a 0.5-h intravenous infusion or as a 24-h continuous infusion. Results All doses of DS-1040 were tolerated, and no serious adverse events (AEs) or discontinuations resulting from AEs occurred during the study. Bleeding time remained within the normal range for all doses tested in all subjects. Plasma exposure of DS-1040 increased proportionally with increase in dose. Elderly subjects had higher exposures to DS-1040 and prolonged elimination times, probably because of decreased renal clearance. DS-1040 caused a substantial dose-dependent and time-dependent decrease in TAFIa activity and in 50% clot lysis time. The levels of D-dimer, indicative of endogenous fibrinolysis, increased in some individuals following DS-1040 treatment. No effects of DS-1040 on coagulation parameters or platelet aggregation were observed. Conclusions The novel fibrinolysis-enhancing agent DS-1040 has favorable pharmacokinetic/pharmacodynamic properties and a favorable safety profile, warranting further clinical development.

Aliskiren is the first in a new class of orally active, direct renin inhibitors for the treatment of hypertension. This open-label, nonrandomized, single-center, parallel-group study compared the pharmacokinetics and safety of a single 300-mg oral dose of aliskiren in patients with mild, moderate, or severe hepatic impairment to that in healthy subjects. When pooled across subgroups, there were no significant differences between patients with hepatic impairment and healthy subjects in aliskiren AUC(0-infinity) (ratio of geometric means, 1.12; 90% confidence interval, 0.85, 1.48) or Cmax (mean ratio, 1.19; 90% confidence interval, 0.84, 1.68), and there was no correlation between severity of hepatic impairment and either AUC(0-infinity) or Cmax. Aliskiren was well tolerated by healthy subjects and patients with hepatic impairment. In conclusion, hepatic impairment has no significant effect on the pharmacokinetics of aliskiren following single-dose administration, and dosage adjustment is unlikely to be needed in patients with liver disease.

Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double‐blind, placebo‐controlled, single‐ and multiple‐ascending‐dose studies, and 1 open‐label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high‐fat meal) conditions. Forty‐eight and 47 healthy volunteers completed the single‐ and multiple‐dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment‐emergent adverse events (TEAEs)—dizziness and somnolence—were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3‐30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%‐72% urinary excretion). Exposure increased in a dose‐proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.

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Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.

Mirogabalin is a selective calcium channel α 2 δ subunit ligand being developed to treat neuropathic pain. In accordance with US Food and Drug Administration (FDA) guidance, the human abuse potential of mirogabalin (15–105 mg) was examined, relative to placebo, diazepam (15 or 30 mg), and pregabalin (200 or 450 mg), in two single-dose, randomized, double-blind, placebo- and active-controlled crossover studies in recreational polydrug users who could discern between positive comparator and placebo. The primary endpoint was maximum observed effect ( E max ) for Drug Liking Visual Analog Scale. At therapeutic doses, mirogabalin Drug Liking E max did not differ significantly from placebo and was significantly lower than diazepam and pregabalin. This indicates therapeutic doses mirogabalin may have less abuse potential versus diazepam or pregabalin. At supratherapeutic doses (⩾4× therapeutic dose), mirogabalin had significantly higher Drug Liking E max than placebo, but lower E max than pregabalin. In both studies, therapeutic doses of mirogabalin demonstrated limited evidence of abuse potential.

AimsThe primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure.MethodsThis phase 1, open‐label, crossover study randomized healthy adults to receive three treatment regimens, each separated by ≥5‐day washout: a single oral dose of mirogabalin 15 mg on day 2, mirogabalin 15 mg on day 2 plus probenecid 500 mg every 6 h from days 1 to 4, and mirogabalin 15 mg on day 2 plus cimetidine 400 mg every 6 h from days 1 to 4.ResultsCoadministration of mirogabalin with probenecid or cimetidine increased the maximum and total mirogabalin exposure. The geometric mean ratios of Cmax and AUC(0‐t) (90% CI) with and without coadministration of probenecid were 128.7% (121.9–135.7%) and 176.1% (171.9–180.3%), respectively. The geometric mean ratios of Cmax and AUC(0‐t) (90% CI) with and without coadministration of cimetidine were 117.1% (111.0–123.6%) and 143.7% (140.3–147.2%), respectively. Mean (standard deviation) renal clearance of mirogabalin (l h–1) was substantially slower after probenecid [6.67 (1.53)] or cimetidine [7.17 (1.68)] coadministration, compared with mirogabalin alone [11.3 (2.39)]. Coadministration of probenecid or cimetidine decreased mirogabalin mean (standard deviation) apparent total body clearance [10.5 (2.33) and 12.8 (2.67) l h–1, respectively, vs. 18.4 (3.93) for mirogabalin alone].ConclusionsA greater magnitude of change in mirogabalin exposure was observed when coadministered with a drug that inhibits both renal and metabolic clearance (probenecid) vs. a drug that only affects renal clearance (cimetidine). However, as the increase in exposure is not clinically significant (>2‐fold), no a priori dose adjustment is recommended.

DS‐1040, a low‐molecular‐weight imidazole derivative, inhibits the enzymatic activity of thrombin‐activatable fibrinolysis inhibitor (TAFIa), enhancing endogenous tissue plasminogen activator–triggered fibrinolysis. This first‐in‐human, randomized, placebo‐controlled, phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of an oral formulation of DS‐1040. Healthy adults (aged 20‐45 years; N = 56) were randomized 3:1 to receive DS‐1040 orally administered as single ascending doses (50, 100, 200, or 400 mg) or placebo, or DS‐1040 multiple ascending doses (100 mg once daily, 200 mg once daily, or 150 mg twice daily) or placebo for 14 days. Safety, PK, and PD parameters were assessed. All doses of DS‐1040 were well tolerated; no serious/severe adverse events (AEs) or discontinuations due to AEs occurred. DS‐1040 had no effect on coagulation parameters, and no treatment‐related trends in the bleeding time were observed. DS‐1040 exposure (peak concentration and area under the concentration‐time curve) increased in a dose‐proportional manner across the single‐dose range. With multiple doses, steady state was achieved by day 7 with minimal accumulation (mean accumulation ratio 1.15‐1.25), and the PK was time‐independent. After 72 hours, approximately 10% of the DS‐1040 400‐mg single dose was recovered in urine as intact parent drug. The mean terminal half‐life ranged from 17.2 to 24.9 hours, which was similar to previous intravenous administration data. Dose‐dependent inhibition of total TAFIa activity was observed following single and multiple doses of oral DS‐1040. The safety and PK/PD profiles of oral DS‐1040 in healthy subjects support further clinical development.