WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Prior to the commencement of this study, it was already known that rivaroxaban is partially cleared via the kidneys and an influence of renal insufficiency on rivaroxaban pharmacokinetics and exposure was anticipated. WHAT THIS STUDY ADDS• As many patients in the target indications of rivaroxaban will be elderly, a precise quantitative knowledge of the influence of renal function on rivaroxaban pharmacokinetics and exposure is mandatory for adequate labelling recommendations (in the context of benefit/risk provided by phase III studies) to guide therapy. This study provided detailed insight on both rivaroxaban pharmacokinetics and pharmacodynamic behaviour in renal impairment including severely renally impaired subjects. AIMThis study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor. METHODSSubjects (n = 32) were stratified based on measured creatinine clearance: healthy controls (Ն80 ml min -1 ), mild (50-79 ml min -1 ), moderate (30-49 ml min -1 ) and severe impairment (<30 ml min -1 ). RESULTSRenal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONSRivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

AIMSThis study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P1) receptor modulator in development for the treatment of auto-immune diseases. METHODSThis was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1-75 mg or placebo control. RESULTSPonesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half-life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of Ն8 mg reduced total lymphocyte count in a dose-dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts. CONCLUSIONSSingle doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Fingolimod, a nonselective sphingosine-1-phosphate (S1P) immunomodulator, reduces circulating lymphocytes via the S1P1 receptor and decreases heart rate, which may be associated with its effects on the S1P3 receptor.• Ponesimod is selective for S1P1 receptors. It has the potential to reduce lymphocytes without cardiac effects. WHAT THIS STUDY ADDS• This study provides information on the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 modulator, a potential new treatment for auto-immune diseases.• Ponesimod induces a clear dose-dependent effect on circulating lymphocytes in accordance with animal data.• Ponesimod has a shorter half-life than other S1P modulators, allowing a faster reversibility of its effects.• Although preclinical data indicated no cardiac effects with ponesimod, human data showed a clear effect on heart rate. This suggests that cardiac effects of S1P modulators in humans are not only mediated by the S1P3 receptor, but also by the S1P1 receptor.

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Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.

This multiple-ascending-dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator and a potential new treatment for autoimmune diseases. In part A, 10 healthy male and female subjects received once daily oral doses of ponesimod (5, 10, or 20 mg) or placebo for 7 days. Sinus bradycardia and, in some subjects, atrioventricular (AV) block occurred primarily on the first day of dosing, as desensitization developed to ponesimod-induced heart rate (HR) reduction and PR-prolongation. This elicited the design of an up-titration schedule in 17 subjects to a dose of 40 mg in part B. The up-titration regimen reduced HR and PQ/PR effects. Reported adverse events were mainly related to the cardiac and respiratory systems. Respiratory effects increased with higher doses. Ponesimod multiple-dose pharmacokinetics were slightly more than dose-proportional and characterized by a time to maximum concentration and an elimination half-life varying from 2.5 to 4.0 hours and 30.9 to 33.5 hours, respectively, and an accumulation of about 2.3-fold. Ponesimod caused a dose-dependent sustained decrease in total lymphocyte count, reversible within 7 days of discontinuation. A pharmacokinetic-pharmacodynamic model enabled comparing day 1 and steady-state conditions. These results warrant further investigation of ponesimod in patients.

PurposeTo study the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan, an endothelin receptor antagonist, in healthy male subjects.MethodsThis double-blind, placebo-controlled study was performed in seven groups of eight healthy male subjects. Doses of 0.2, 1, 5, 25, 100, 300 and 600 mg or placebo (two subjects per group) were administered. Plasma macitentan and endothelin-1 and serum total bile salt concentrations were measured and analysed non-compartmentally. Plasma and urine were analysed qualitatively for the presence of metabolites and one of these, ACT-132577, was also measured quantitatively in plasma. Standard tolerability measurements were performed throughout the study.ResultsMacitentan was slowly absorbed and, at a dose of 300 mg, the t1/2 (95% confidence interval, CI) was 17.5 h (14.1, 21.8). The dose-proportionality coefficient β for Cmax (95% CI) was 0.83 (0.79, 0.87) indicating less than dose-proportional pharmacokinetics of macitentan. In plasma, a pharmacologically active oxidative depropyl metabolite, ACT-132577, was found whereas in urine two minor metabolites were detected. The t1/2 of ACT-132577 (95% CI) was 65.6 h (53.1, 80.9). Macitentan dose-dependently increased endothelin-1 concentrations up to 2.2-fold (95% CI 1.4, 2.4) at a dose of 600 mg, but had no consistent effect on total bile salts. Macitentan was well tolerated up to and including a dose of 300 mg, the maximum tolerated dose. Headache, nausea and vomiting were dose-limiting adverse events.ConclusionThe pharmacokinetic and tolerability profile of macitentan is consistent with a once-a-day dosing regimen and warrants further investigation in clinical studies.

AIMThis study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor. METHODThis single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child-Pugh classification, and gender-matched healthy subjects (n = 16). RESULTSRivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration-time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect-time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment. CONCLUSIONModerate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Before this study was started, it was already known that approximately two-thirds of the administered rivaroxaban dose is metabolized by the liver to inactive metabolites.• It was anticipated that hepatic impairment would influence the pharmacokinetics and pharmacodynamics of rivaroxaban. WHAT THIS STUDY ADDS• The results of this study provide detailed information on the influence of mild and moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of rivaroxaban.• The data showed that moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects.

Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE. A single 50 mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment.