Georg Wensing

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

AIMS To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODS The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). RESULTS In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. CONCLUSIONS BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.

Pharmacokinetics, safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone – results from first-in-man and relative bioavailability studies

The safety, tolerability and pharmacokinetics of the selective nonsteroidal mineralocorticoid receptor antagonist finerenone were evaluated in healthy male volunteers in two randomized, single‐centre studies. Study 1 was a first‐in‐man, single‐blinded, placebo‐controlled, parallel‐group, dose‐escalation study. Fasted participants (n = 45) received single oral doses of finerenone 1–40 mg polyethylene glycol (PEG) solution or placebo. Study 2 was a relative bioavailability study comparing a finerenone 10 mg immediate‐release (IR) tablet with finerenone 10 mg PEG solution in the fasted state, investigating the effect of a high‐fat/high‐calorie meal on the pharmacokinetics of the IR tablet and assessing a further dose escalation to finerenone 80 mg (eight × finerenone 10 mg IR tablets), in an open‐label, fourfold crossover design (n = 15). Finerenone was rapidly absorbed from PEG solution (median time to maximum plasma concentration [tmax]: 0.500–1.00 h), exhibited dose‐linear pharmacokinetics and was rapidly eliminated from plasma (geometric mean terminal half‐life [t½]: 1.70–2.83 h). Finerenone IR tablets demonstrated similar pharmacokinetics (median tmax: 0.750–2.50 h; geometric mean t½: 1.89–4.29 h) with, however, enhanced bioavailability versus PEG solution (least‐squares mean tablet/solution ratio of 187% for area under the plasma–concentration curve [AUC] and maximum plasma concentration [Cmax]). High‐fat/high‐calorie food affected the rate but not the extent of finerenone absorption. Finerenone was well tolerated and did not influence clinical laboratory parameters, blood pressure, heart rate, urinary electrolytes or neurohormones, including serum aldosterone and angiotensin II. In conclusion, finerenone has favourable pharmacokinetics and tolerability in healthy men, and is suitable for dosing independent of food intake.

Pharmacokinetics of the soluble guanylate cyclase stimulator riociguat in individuals with renal impairment

Riociguat is the first oral soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. This pooled analysis of two non-randomized, non-blinded, observational studies evaluated the pharmacokinetics of riociguat and its metabolite M1 (BAY 60-4552) in individuals with and without renal impairment. Participants were assigned to 1 of 4 groups according to their creatinine clearance (CLCR): group 1, CLCR > 80 mL/min; group 2, CLCR 50–80 mL/min; group 3, CLCR 30–49 mL/min; group 4, CLCR < 30 mL/min. In the first study, group 4 received 0.5 mg riociguat; all other participants in both studies received 1 mg (single tablet doses). Pharmacokinetics were assessed using dense sampling. 63 participants (40 m, 23 f; age 36–78 years) completed the study. Riociguat was rapidly absorbed; median time to reach maximum concentration in plasma was 1 h in all 4 groups. Mean half-life of total riociguat was longer in groups 2–4 (9.5–11.4 h) than in group 1 (6.2 h), and renal clearance decreased with decreasing renal function. Exposure to total riociguat (mean area under the concentration–time curve/dose per kg body weight), was up to ∼100% higher in groups 2–4 than in group 1. However, exposure was highly variable in groups 2–4. Results for unbound riociguat and unbound M1 were similar to those for total riociguat and total M1. No serious or severe adverse events occurred. No change in safety or tolerability was observed with decreasing CLCR. Thus, the safety profile of riociguat in individuals with renal impairment was similar to that in healthy controls. Riociguat exposure was greater in individuals with renal impairment than in healthy controls, and was highly variable.

Assessment of the Effects of Hepatic Impairment and Smoking on the Pharmacokinetics of a Single Oral Dose of the Soluble Guanylate Cyclase Stimulator Riociguat (BAY 63-2521):

Riociguat, a soluble guanylate cyclase stimulator developed for the treatment of pulmonary hypertension, is metabolized in part by the liver. Expression of one of the metabolizing enzymes, CYP1A1, is induced by aromatic hydrocarbons in tobacco smoke. Two non-∗∗∗randomized, nonblinded studies were conducted to investigate the pharmacokinetics of riociguat in individuals with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment associated with liver cirrhosis compared with that in age-, weight-, and sex-matched healthy controls: study 1 included smokers and nonsmokers, and study 2 included nonsmokers only. Data from these studies were integrated for analysis. All participants (N = 64) received a single oral dose of riociguat 1.0 mg. Riociguat exposure was significantly higher in individuals with Child-Pugh B hepatic impairment than in healthy controls (ratio: 153% [90% confidence interval: 103%-228%]) but was similar in those with Child-Pugh A hepatic impairment and controls. The half-life of the riociguat metabolite M1 was prolonged in patients with Child-Pugh B or A hepatic impairment compared with that in controls by approximately 43% and 24%, respectively. Impaired hepatic function was associated with higher riociguat exposure in nonsmokers compared with the population of smokers and nonsmokers combined. Riociguats safety profile was similar in individuals with impaired or normal liver function. In conclusion, moderate hepatic impairment was associated with increased riociguat exposure compared with that in controls, probably as a result of reduced clearance of the metabolite M1. This suggests that dose titration of riociguat should be administered with particular care in patients with moderate hepatic impairment.

Bioavailability, pharmacokinetics, and safety of riociguat given as an oral suspension or crushed tablet with and without food

Riociguat is approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Some patients have difficulty swallowing tablets; therefore, 2 randomized, nonblinded, crossover studies compared the relative bioavailability of riociguat oral suspensions and immediate-release (IR) tablet and of crushed-tablet preparations versus whole IR tablet. In study 1, 30 healthy subjects received 5 single riociguat doses: 0.3 and 2.4 mg (0.15 mg/mL suspensions), 0.15 mg (0.03 mg/mL), and 1.0 mg (whole IR tablet) under fasted conditions and 2.4 mg (0.15 mg/mL) after a high-fat, high-calorie American-style breakfast. In study 2, 25 healthy men received 4 single 2.5-mg doses: whole IR tablet and crushed IR tablet suspended in applesauce and water, respectively, under fasted conditions, and whole IR tablet after a continental breakfast. In study 1, dose-normalized pharmacokinetics of riociguat oral suspensions and 1.0-mg whole IR tablet were similar in fasted conditions; 90% confidence intervals for riociguat area under the curve (AUC) to dose and mean maximum concentration (Cmax) to dose were within bioequivalence criteria. After food, dose-normalized AUC and Cmax decreased by 15% and 38%, respectively. In study 2, riociguat exposure was similar for all preparations; AUC ratios for crushed-IR-tablet preparations to whole IR tablet were within bioequivalence criteria. The Cmax increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased Cmax of the whole tablet by 16%, with unaltered AUC versus fasted conditions. Riociguat bioavailability was similar between the oral suspensions and the whole IR tablet; exposure was similar between whole IR tablet and crushed-IR-tablet preparations. Minor food effects were observed. Results suggest that riociguat formulations are interchangeable.

Riociguat (BAY 63-2521) and aspirin: a randomized, pharmacodynamic, and pharmacokinetic interaction study

In preclinical studies, drugs that increase cyclic guanosine monophosphate levels have been shown to influence platelet function/aggregation; however, the effect of riociguat on human platelets is unclear. Aspirin, a platelet inhibitor, is likely to be given concomitantly in patients receiving riociguat. It is therefore important to establish clinically whether (1) riociguat affects platelet function and (2) aspirin and riociguat interact. This randomized, open-label, crossover study investigated potential pharmacodynamic and pharmacokinetic interactions between these drugs in healthy male volunteers (N = 18). There were 3 treatment regimens: a single morning dose of riociguat 2.5 mg, aspirin 500 mg on 2 consecutive mornings, and both treatments together, with riociguat given on the second morning. Fifteen participants were available for pharmacodynamic/pharmacokinetic analysis. There was no effect of riociguat alone on bleeding time, platelet aggregation, and serum thromboxane B2 levels. The effects of aspirin on these parameters were not influenced by concomitant administration of riociguat. The pharmacokinetic profile of riociguat showed interindividual variability, which was independent of aspirin coadministration. Six of 17 participants available for safety evaluation reported at least 1 treatment-emergent adverse event. All adverse events were of mild severity, apart from 1 report of moderate headache. No serious adverse events occurred. In conclusion, riociguat demonstrated no clinically relevant pharmacodynamic or pharmacokinetic interactions with aspirin at the doses used in this study in healthy men; coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug.

Pharmacokinetic interaction study between riociguat and the combined oral contraceptives levonorgestrel and ethinylestradiol in healthy postmenopausal women.

Female patients requiring treatment for pulmonary arterial hypertension (PAH) are advised to avoid pregnancy because of the high associated mortality rate. Oral contraception is one of the main methods of preventing pregnancy in this context, mandating pharmacokinetic and safety studies for new agents in this setting. Riociguat is a soluble guanylate cyclase stimulator approved for treatment of PAH and inoperable and persistent or recurrent chronic thromboembolic pulmonary hypertension. This single-center, randomized, nonblinded study involving healthy postmenopausal women investigated the effect of riociguat on plasma concentrations of levonorgestrel (0.15 mg) and ethinylestradiol (0.03 mg) in a combined oral contraceptive. Treatment A was a single oral tablet of levonorgestrel-ethinylestradiol. In treatment B, subjects received 2.5 mg riociguat 3 times daily for 12 days. On the eighth day, they also received a single oral tablet of levonorgestrel-ethinylestradiol. Subjects received both regimens in a crossover design. There was no change in area under the plasma concentration—time curves of levonorgestrel or ethinylestradiol or maximum concentration in plasma (Cmax) of levonorgestrel during combined administration versus levonorgestrel-ethinylestradiol alone. A 20% increase in the Cmax of ethinylestradiol was noted during coadministration; this is not anticipated to adversely impact the contraceptive efficacy or to require any dose adjustment for ethinylestradiol. Plasma concentrations and exposures of riociguat were within the expected range and were not influenced by coadministration with levonorgestrel-ethinylestradiol. Combined treatment was safe and well tolerated. In conclusion, riociguat did not change the exposure to levonorgestrel or ethinylestradiol relative to oral contraceptive administered alone.

Who is a ‘healthy subject’?—consensus results on pivotal eligibility criteria for clinical trials

Introduction/MethodsA discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority.ResultsPivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs. In general, a pulse rate ranging between 50 and 90 beats/min is recommended for first-in-human (FIH) trials, while wider ranges seem acceptable for trials with clinically established IMPs, provided there are no indications of thyroid dysfunction. Hepatic laboratory parameters not to exceed the upper limit of normal (ULN) comprise ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in FIH trials, whereas slight elevations (10% above ULN) seem acceptable in trials with clinically established IMPs without known hepatotoxicity. A normal renal function is required for any clinical trial in healthy subjects. A risk-adapted approach for stopping rules was adopted. Stopping rules for an individual subject are one adverse event of severe intensity or one serious adverse event. In case of a severe adverse event, some stakeholders demand a causal relationship with the IMP (i.e. an adverse reaction). Stopping rules for a cohort are one serious adverse reaction or ≥50% of subjects experiencing any adverse reaction of moderate or severe intensity.ConsequencesThe application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority.

Bioavailability, pharmacokinetics and safety of riociguat given as an oral suspension or crushed tablet with and without food

Background Riociguat is the first oral, soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension [1-3]. For some patients with PAH, e.g. children and the elderly, swallowing tablets may be inappropriate or difficult; therefore, oral suspension and crushed tablet formulations of riociguat were developed. Here we present data from two single-centre, randomised, non-blinded, crossover studies evaluating the relative bioavailability of riociguat as oral liquid and standard “immediate release” (IR) oral tablet under fed and fasted conditions, and as a crushed-tablet preparation versus oral tablet under fasted conditions.