How to Interpret an Investigator's Brochure for Meaningful Risk Assessment: Results of an AGAH Discussion Forum.

PURPOSE: A discussion forum was hosted by the Association for Applied Human Pharmacology (AGAH e.V.) to critically debate how to interpret and optimise the Investigator's Brochure (IB) for meaningful risk assessment of early clinical trials. MATERIALS AND METHODS: Four topics were specifically discussed: deficiencies/uncertainties in IBs, guidance for the investigator, reference safety information, and potential risks for human subjects associated with inadequate non-clinical safety assessment in the IB. In each case, 43 participants took part in a real-time online survey with pre-defined questions to capture the audience's opinion. RESULTS: The 'Summary of Data and Guidance for the Investigator' was considered as the section of the IB with the highest need for improvement with emphasis on readability, comprehensibility, timeliness of data, and appropriateness for risk assessment. It was suggested that the IB should at least be signed by the sponsor's scientist responsible for the content on pharmacology and toxicology. It was agreed that sponsors should consider thoroughly whether changes to an IB constitute a substantial amendment, and that the IB should include a section on the change history. Non-clinical pharmacology studies with negative outcomes should be reported in the IB in order to avoid assessment bias. The reference safety information for expectedness assessment of suspected serious adverse reactions should be provided as a stand-alone section of the IB. CONCLUSION: The overall consensus was that an optimised presentation of data will ensure the best possible understanding of a compound's characteristics and an optimal benefit-risk assessment which will safeguard the participants in clinical trials.

Safety of healthy subjects in first-in-human multiple-dose studies: A pooled analysis.

PURPOSE: Reflecting the extended scope of the valid EMA regulation, this analysis intends to contribute to the knowledge about risk for participants in first-in-human (FiH) multiple-dose studies. MATERIALS AND METHODS: All FiH multiple-dose studies in healthy subjects performed by the Bayer Department of Clinical Pharmacology, Cardiovascular, between 2006 and 2019 were analyzed. Study reports were reviewed for study designs, demographics, treatment-emergent adverse events (TEAEs), and safety laboratory results above the 1.5-fold of the upper limit of normal (aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), amylase, lipase, glutamate dehydrogenase (GLDH), gamma glutamyl transpeptidase (GGT), total bilirubin, and creatinine in serum), and data were analyzed. RESULTS: 12 out of 16 studies were included. Indications for development were cardiovascular (7), pulmonary (3), kidney (1), and hematological (1) diseases. 496 healthy male subjects (mean age 33.8 years, mean BMI of 24.7 kg/m2) received treatment (370 active, 126 placebo). 293 subjects had at least 1 TEAE (59.1%): 231 (62.4%) after active treatment and 126 (49.2%) after placebo. Subjects with a maximum TEAE intensity of moderate did not differ between active and placebo. The only severe TEAE was unrelated to the study, the only serious TEAE on active treatment was not considered drug-related. Subjects had a significantly higher relative risk on active treatment versus placebo to experience an overall TEAE. No relevant differences between active and placebo for the analyzed laboratory increases were seen. CONCLUSION: Subjects were not exposed to an undue risk in the analyzed studies. Adverse events and laboratory value increases occur frequently under placebo treatment. The results can help in the risk stratification for and interpretation of other phase I studies.

How safe are our studies? Analysis of adverse events in Bayer First-in-Human trials from 2006 to 2016
.

PURPOSE: In regard to the current scientific discussion, this analysis aims to broaden the database for a risk evaluation of First-in-Human (FiH) trials with healthy volunteers. MATERIALS AND METHODS: Study documents of each FiH study conducted between 2006 and 2016 for Bayer Clinical Pharmacology Cardiovascular were reviewed for inclusion. Study types, treatments, dose steps, study population, number, incidence, and intensity of treatment-emergent adverse events (AEs) were cumulatively analyzed using descriptive statistics. A comparison to a previous similar analysis (period 2000 - 2005) was made. RESULTS: 22 out of 25 studies were included (20 small molecules, 2 biologics) investigating drugs for cardiovascular (9), hematological (7), pulmonary (3), kidney (2), and metabolic (1) diseases. The mean age of subjects was 34.2 years. 1,250 subjects received treatment (950 active, 300 placebo). 952 AEs occurred (0.76 AEs/treatment, 0.85 AEs/active treatment, 0.49 AEs/placebo treatment). 88.2% (840/952) of AEs were mild, 11.3% (108/952) moderate, and 0.4% (4/952) were severe. 0.4% (5/1250) of subjects had active drug- or procedure-related serious AEs. The most frequent AE was headache (12.9% (123/952)), the mostly affected system organ class was CNS (14.4% of all subjects). The relative risk for an AE was significantly higher under active drug compared to placebo (1.24, 95% LCL >1). The incidence of AEs increased with higher dose steps. A higher incidence of AEs (active and placebo) in recent compared to previous studies was observed. CONCLUSION: The risk of severe harm for healthy participants was low. The risk to experience any AE was higher under active drug compared to placebo. A trend change towards more frequent reporting of AEs in the recent studies was observed.

Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials.

INTRODUCTION/METHODS: A 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. RESULTS: Pivotal 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. CONSEQUENCES: The application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority.

Assessment of the effects of renal impairment and smoking on the pharmacokinetics of a single oral dose of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521).

Renal impairment is a common comborbidity in patients with pulmonary hypertension. The breakdown of riociguat, an oral soluble guanylate cyclase stimulator used to treat pulmonary hypertension, may be affected by smoking because polycyclic aromatic hydrocarbons in tobacco smoke induce expression of one of the metabolizing enzymes, CYP1A1. Two nonrandomized, nonblinded studies were therefore performed to investigate the pharmacokinetics and safety of a single oral dose of riociguat 1.0 mg in individuals with mild, moderate, or severe renal impairment compared with age-, weight-, and sex-matched healthy controls, including either smokers and nonsmokers (study I) or nonsmokers alone (study II). Pharmacokinetic analyses focused on the integrated per-protocol data set of both studies (N = 63). In patients with renal impairment, the renal clearance of riociguat was reduced and its terminal half-life prolonged compared with those in healthy controls. There was a monotonic relationship between creatinine clearance on treatment day and riociguat renal clearance (R (2) = 0.62). However, increased riociguat exposure with decreasing renal function was not strictly proportional. Riociguat exposure appeared to be greater in nonsmokers than in the combined population of smokers and nonsmokers, irrespective of renal function. Adverse events were mild to moderate and in line with the mode of action of riociguat. No serious adverse events occurred. In conclusion, renal impairment was associated with reduced riociguat clearance compared with that in controls; however, riociguat exposure in patients with renal impairment was highly variable, and ranges overlapped with those observed in healthy controls.

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.

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 nonrandomized, 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. Riociguat's 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 (C max) to dose were within bioequivalence criteria. After food, dose-normalized AUC and C max 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 C max increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased C max 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.

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 (C max) of levonorgestrel during combined administration versus levonorgestrel-ethinylestradiol alone. A 20% increase in the C max 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.

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.

Correlation of genotype, phenotype, and mRNA expression of CYP2D6 and CYP2C19 in peripheral blood leukocytes (PBLs).

INTRODUCTION: The genetic polymorphism of drug metabolizing enzymes of the cytochrome P450 (CYP) families, especially CYP2D6 and CYP2C19, is the most important cause of variable responses of many drugs. Enzyme activity ranges from complete deficiency, so called poor metabolizers (PMs), to an ultrafast metabolism. While PMs and extensive metabolizers (EMs) can be well distinguished by genotyping, phenotyping is necessary to subdivide EMs from intermediate metabolizers (IMs). The aim of the study was to evaluate if messenger RNA (mRNA) concentration for CYP-enzymes in peripheral blood leukocytes (PBLs) will be predictive of systemic enzyme activity, allowing an easy and safe determination of metabolic activity. METHODS: The genotype, phenotype, and mRNA-expression in PBLs were evaluated in 124 healthy Caucasian volunteers (males and females, age range 23 - 59 years) on three occasions (every 4 weeks). Genotyping was performed by Taqman allelic discrimination on the most common null alleles for CYP2D6 (*3, *4, *6, *7, and *8) and CYP2C19 (*2 and *3). For phenotyping CYP2D6, dextromethorphan/dextrorphan metabolic ratios were determined in collected urine (8 hours) after administration of 30 mg dextromethorphan. For phenotyping CYP2C19, we used the plasma concentration ratio of omeprazole/hydroxyomeprazole 4 hours after ingestion of 40 mg omeprazole. mRNA-expression in PBLs for CYP2D6 and CYP2C19 was measured by Taqman real-time PCR before medication and 4 hours afterwards. RESULTS: Genotyping for CYP2D6 and CYP2C19 showed a regular distribution of EMs and PMs compared to studies of a comparable population. The median dextromethorphan/dextrorphan metabolic ratio was 0.47 in EMs/IMs and 2.29 in PMs. The median omeprazole/hydroxyomeprazole metabolic ratio was 3.06 in EMs/IMs and 35.29 in PMs. CYP2D6 and CYP2C19 mRNA expression was detected without evidence of correlation to the respective metabolic ratio. CONCLUSION: The results do not support the concept of using mRNA expression profiles for CYP2D6 and CYP2C19 enzymes in PBLs for prediction of systemic enzyme activity.

Selective 5-HT(1A)-R-agonist repinotan prevents remifentanil-induced ventilatory depression and prolongs antinociception.

BACKGROUND: 5-HT(1A)-R-agonist repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 µg/kg). It remained to be clarified (1) whether a moderate dose of repinotan, sufficient to stimulate spontaneous breathing, impairs antinociception if plasma concentration decreases over time, and if (2) moderate doses prevent ventilatory depression if given before the opioid. METHODS: A dose-response curve of the repinotan effects on spontaneous minute ventilation during continuous remifentanil infusion in anesthetized rats was established to identify moderate doses: (1) tail-flick reflex latencies to assess nociception were recorded until 60 min after cessation of a continuous remifentanil infusion with or without a concomitant moderate repinotan dose (10 µg/kg), and (2) remifentanil boluses (2.5 µg/kg) were given after repinotan (10 and 20 µg/kg). RESULTS: (1) Remifentanil-induced antinociception lasted only 5 min after infusion was stopped (tail-flick reflex latencies; median [interquartile range], 97 [54-100]% of maximum possible effect; P = 0.034), but was extended by repinotan (10 µg/kg) to 30 min (tail-flick reflex latencies, 100 [75-100]% of maximum possible effect; P = 0.031). Repinotan (10 µg/kg) alone did not have any significant antinociceptive effect. (2) The ventilatory depression by remifentanil boluses (2.5 µg/kg; minute ventilation, -65 [-81 to -56]%; P = 0.031, n = 5) was blunted by repinotan (20 µg/kg; minute ventilation, -24 [-53 to 13]%; P = 0.313, compared with the pretreatment level). CONCLUSIONS: Repinotan prevented remifentanil-induced ventilatory depression in spontaneously breathing, anesthetized rats. Although repinotan did not depress nociception itself, it prolonged the profound antinociception after discontinuation of remifentanil infusion.

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 of the soluble guanylate cyclase activator cinaciguat in individuals with hepatic impairment.

Cinaciguat is intended for use in patients with acute decompensated heart failure. The drug is eliminated predominantly via the liver and, therefore, the potential impact of hepatic impairment on cinaciguat pharmacokinetics needs to be determined. This nonrandomized, open-label, observational study investigated the pharmacokinetics of cinaciguat in individuals with mild (Child-Pugh A; n = 8) or moderate (Child-Pugh B; n = 8) hepatic impairment and matched healthy volunteers (n = 16). An exploratory analysis of pharmacodynamic parameters was also conducted. Individuals with mild hepatic impairment and their controls received a single (4-hour) intravenous infusion of 100 µg/h cinaciguat, whereas individuals with moderate hepatic impairment and their controls received 50 µg/h. Cinaciguat was well tolerated and had a favorable safety profile. The most frequent treatment-emergent adverse events were headache (4 participants) and spontaneous penile erection (2 participants). In individuals with mild hepatic impairment, only minor increases in plasma cinaciguat concentrations and no significant differences in pharmacodynamic parameters were observed, compared with controls. Individuals with moderate hepatic impairment had a substantially higher cinaciguat exposure than controls. This higher exposure was associated with more pronounced vasodilatation. This study demonstrates that in individuals with mild hepatic impairment, individual dose adaptation may not be required.

Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study.

Riociguat (BAY 63-2521) and warfarin are likely to be used concomitantly to treat pulmonary hypertension. The aim of this double-blind, crossover, clinical pharmacological study in 30 healthy volunteers was to investigate potential pharmacodynamic and pharmacokinetic interactions between the 2 drugs. Healthy volunteers took 2.5 mg of oral riociguat or matching placebo 3 times daily for 10 days. A single oral dose of warfarin sodium (25 mg) was given 21 days before the study and on the seventh day of riociguat/placebo treatment. Twenty-one participants valid for safety analysis reported 89 treatment-emergent adverse events, all of mild or moderate severity. No serious adverse events occurred. The most frequently reported treatment-emergent adverse events considered to be drug-related were dyspepsia, headache, flatulence, nausea, and vomiting. Twenty-two participants were valid for pharmacodynamic/pharmaco-kinetic analysis. Riociguat (2.5 mg 3 times daily) had no pharmacodynamic interaction with warfarin. Steady-state plasma levels of riociguat did not affect prothrombin time, factor VII clotting activity, or the pharmacokinetics of warfarin. The single dose of warfarin led to a slight decrease (16%) in maximum concentration of riociguat in plasma, which is not likely to be clinically relevant. Clinical studies will confirm the finding here that combined use of riociguat with warfarin will not require dose adaptation.

Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure.

BACKGROUND: Cinaciguat (BAY 58-2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure > or =18 mm Hg). METHODS AND RESULTS: After initial dose finding (part A; n=27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; n=33) using a starting dose of 100 microg/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by > or =4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 microg/h (n=2), 200 microg/h (n=12), and 400 microg/h (n=16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (-7.9 mm Hg), mean right atrial pressure (-2.9 mm Hg), mean pulmonary artery pressure (-6.5 mm Hg), pulmonary vascular resistance (-43.4 dynes . s . cm(-5)), and systemic vascular resistance (-597 dynes . s . cm(-5)), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension. CONCLUSIONS: Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted.

Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers.

Preclinical data indicate that the nitric oxide-independent soluble guanylate cyclase activator cinaciguat (BAY 58-2667), which is a new drug in development for patients with heart failure, induces vasodilation preferentially in diseased vessels. This study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat. Seventy-six healthy volunteers were included in this randomized, placebo-controlled study. Cinaciguat (50-250 microg/h) was administered intravenously for up to 4 hours in a maximum of 6 individuals per dose group. No serious adverse events were reported. Four-hour infusions (50-250 microg/h) decreased diastolic blood pressure and increased heart rate (all P values < .05) versus placebo, without significantly reducing systolic blood pressure (P between 0.07 and 0.56). At higher doses (150-250 microg/h), 4-hour infusions decreased mean arterial pressure and increased plasma cyclic guanosine monophosphate levels (all P values < .05). Pharmacokinetics showed dose-proportionality with low interindividual variability. Plasma concentrations declined below 1.0 microg/L within 30 minutes of cessation of infusion. Cinaciguat had potent cardiovascular effects reducing preload and afterload, warranting further investigation in patients with heart failure.

Quantification of vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor in plasma of cancer patients and healthy volunteers - comparison of ELISA and microsphere-based multiplexed immunoassay.

BACKGROUND: Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (basic FGF) are angiogenic growth factors which may be useful as biomarkers in drug development, where they could give early information on the antiangiogenic activity of novel anticancer compounds. METHODS: We compared two commercially available assays, enzyme linked immunosorbent assay (ELISA) and a multiplexed bead-based immunoassay (xMAP), for the quantification of these factors in plasma samples from more than 100 cancer patients and healthy individuals. RESULTS: For VEGF and IL-8, but not for basic FGF, xMAP was more sensitive than the respective ELISA. This was true for healthy subjects as well as for cancer patients. Intraassay precision was comparable between both assay formats. Linear regression analysis of VEGF concentrations demonstrated a good correlation between ELISA and xMAP. Bland-Altman analysis showed a systematic difference between both assays, with ELISA giving higher concentration values. VEGF levels were higher in female volunteers, and both assays were able to detect this difference. CONCLUSIONS: Multiplexed microsphere-based immunoassays have the potential to substitute ELISA for the detection of proangiogenic growth factors in clinical studies. Their shorter assay times and their ability to quantify multiple analytes in a small sample volume are advantageous.

Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers.

The aim of the study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of BAY 63-2521, a new drug in development for pulmonary hypertension. Fifty-eight healthy male volunteers received a single oral dose of BAY 63-2521 (0.25-5 mg) or placebo. No serious adverse events were reported; there were no life-threatening events. Heart rate over 1 minute, an indicator of the effect of a vasodilating agent on the cardiovascular system in healthy subjects, was increased dose dependently versus placebo at BAY 63-2521 doses of 1 to 5 mg (P < .01). Mean arterial and diastolic pressures were decreased versus placebo at doses of 1 mg (P < .05) and 5 mg (P < .01). Systolic pressure was not significantly affected. BAY 63-2521 was readily absorbed and exhibited dose-proportional pharmacokinetics. The pharmacodynamic and pharmacokinetic properties of BAY 63-2521 suggest that it can offer a unique mode of action in the treatment of pulmonary hypertension.

First assessment in humans of the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of the new artemisinin derivative artemisone.

In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t(1/2)) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t(1/2), its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t(1/2) is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.