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.

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.

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 2004) - 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 y ears. 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.

AimsInsufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia‐inducible factor prolyl hydroxylase (HIF‐PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers.MethodsThis was a single‐centre, randomized, single‐blind, placebo‐controlled, group‐comparison, dose‐escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol‐based solution.ResultsIn total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration–time curve increased dose dependently. The mean terminal half‐life was 4.64–10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l–1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l–1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24–48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters.ConclusionsOral administration of molidustat to healthy volunteers elicited a dose‐dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.

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.

Event Abstract Back to Event Variability in clinical chemistry parameters in healthy male volunteers prior to drug administration, an overview of Bayer in-house phase I trials from 2000 - 2013 INSERT TABLE AST and γGT values are less affected. Conclusion: A 24h predose lab sample may Georg Wensing1 1 Bayer AG, Department of Clinical Pharmacology CV/HEM, Germany Introduction: Recently consensus results on pivotal eligibility criteria for healthy volunteers (HVs) for clinical trials were published. Baseline evaluations immediately prior to dosing were not recommended to confirm inclusion/exclusion criteria. Method: We reviewed all BAYER Phase I trials performed at the Institute of Clinical Pharmacology (Wuppertal) and ClinPharm Cologne between 2000 and 2013. Key parameters were: AST, ALT, GLDH, γGT, total bilirubin, CK, Amylase, lipase, creatinine. All parameters were compared at screening, at 24 hours and 0 hours before dosing. Results: In total, more than 35712 blood samples from 4300 healthy male subjects (aged 18-70 years) were investigated. A wide variability of laboratory parameters exceeding the upper limit of normal (ULN) at all time points was observed. Generally, the incidence of values above ULN is reduced from screening, to 24 and 0 hours before administration. However, despite of a reduced number of HVs from screening to 24 and 0 hours due to rigid inclusion/exclusion criteria there is still a substantial percentage of values above ULN 24h and 0h predose. INSERT TABLE - image 4 AST and γGT values are less affected. Conclusion: A 24h predose lab sample may help to confirm inclusion/exclusion criteria and reduce the number of HVs with abnormal lab values entering the trial. A 0 hour sample should be mandatory to interpret abnormal values under treatment. Acknowledgements no Keywords: variability, Phase I, Healthy male subjects, Clinical chemistry parameters, prior drug administration Conference: EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017. Presentation Type: Poster Topic: EUFEMED 2017 CONFERENCE Citation: Wensing G (2019). Variability in clinical chemistry parameters in healthy male volunteers prior to drug administration, an overview of Bayer in-house phase I trials from 2000 - 2013 INSERT TABLE AST and γGT values are less affected. Conclusion: A 24h predose lab sample may. Front. Pharmacol. Conference Abstract: EUFEMED 2017. doi: 10.3389/conf.fphar.2017.62.00018 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Aug 2017; Published Online: 25 Jan 2019. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Georg Wensing Google Georg Wensing Google Scholar Georg Wensing PubMed Georg Wensing Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A high variability of clinical chemistry parameters was previously reported for healthy male volunteers (HV) who volunteered to participate in early Phase I studies (Artmeier-Brandt et al, 2005). In the present meta-analysis, we extended the investigation from 2005 to all BAYER HV trials performed at the Institute of Clinical Pharmacology (Wuppertal) and ClinPharm Cologne between 2000 and 2013. In addition to previously measured screening values, laboratory parameters at follow-up examinations and during the treatment periods both on active drug and placebo were included. In total, more than 35712 blood samples from 4300 healthy male subjects (aged 18-70 years) were investigated. Key parameters of interest were: AST, ALT, GLDH, γGT, total bilirubin, CK, Amylase, lipase, creatinine. All volunteers were judged as healthy based on clinical investigations and additional laboratory parameters. Nevertheless, a wide variability of laboratory parameters exceeding the upper limit of normal at screening and in HVs with normal values at screening and receiving placebo during the study were observed confirming our previous observations. Increases of about more than 3x above the upper limit of normal were observed for all a parameters except creatinine. During the course of the study, most values of the investigated parameters remained within the normal ranges. For AST, γGT, total bilirubin and AP, only 2 % of the values exceeded the upper limit normal. Values for CK (7.8%), creatinine (7.5%), ALT (5.7%), lipase (5.0%), amylase (2.4%) and GLDH (2.0%) showed higher variability. Laboratory increases of 3 times upper limit of normal or more were observed for CK (0.40%), lipase (0.31%), GLDH (0.15%), ALT (0.10%), AST (0.03%) and amylase (0.03%). Generally, the results confirmed our previous observations (2000-2005) demonstrating a high variability in laboratory values of potentially healthy volunteers. Care should be taken when interpreting laboratory values. Most stable parameters appear to be AST, γGT, total bilirubin and amylase.

Event Abstract Back to Event First in Human (FiH) studies in healthy volunteers – a 10 years review David -. Jung1*, Wolfgang -. Mueck1 and Georg -. Wensing1 1 Bayer AG, Department of Clinical Pharmacology CV/HEM, Germany Background: The tragic incident of Rennes, in which a healthy volunteer died in a FiH study, led to a European draft guideline on “Strategies to identify and mitigate risks in FiH and early clinical trials” including recommendations for starting doses, dose escalation, and maximum doses for FiH trials. Methods: We reviewed all Bayer cardiovascular FiH trials from 2006 – 2016 with respect to the proposed dosing recommendations. Results: 24 FiH studies (22 NCEs, 2 biologicals) were performed. 7 compounds were stopped during or after FiH (insufficient PK n=5, lack of tolerability n=2; hypotension). 20 NCEs started below and 2 (well-known mechanism) with or above the anticipated minimum effective dose (MED). For biologics MABEL approach was used. Ratios of actual vs predicted exposure for the first dose were within 3-fold for > 70% of compounds. Doses were escalated up to a factor of 3 (low doses) and 2 (higher doses). PK and PD were measured at all dose steps. No MTD approach was used. For NCEs highest doses planned exceeded start doses by a mean of about 100 fold (equaling about 8 dose steps) and MED of about 50 fold. Due to the MABEL approach higher increases above starting doses were planned for biologics. Maximum doses administered exceeded the anticipated MED by a mean of 30 fold (NCEs and biologics). Conclusion: Major components of the guideline apply already now; starting doses were chosen higher for known MoA. Maximum doses exceeded the anticipated therapeutic dose to cover for potential variability in patient exposure/response. Acknowledgements no Keywords: Safety, prediction, Dose, escalation, First in human, FIH Conference: EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017. Presentation Type: Poster Topic: EUFEMED 2017 CONFERENCE Citation: Jung D-, Mueck W- and Wensing G- (2019). First in Human (FiH) studies in healthy volunteers – a 10 years review. Front. Pharmacol. Conference Abstract: EUFEMED 2017. doi: 10.3389/conf.fphar.2017.62.00002 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Aug 2017; Published Online: 25 Jan 2019. * Correspondence: Dr. David - Jung, Bayer AG, Department of Clinical Pharmacology CV/HEM, Wuppertal, Germany, david.jung@bayer.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers David - Jung Wolfgang - Mueck Georg - Wensing Google David - Jung Wolfgang - Mueck Georg - Wensing Google Scholar David - Jung Wolfgang - Mueck Georg - Wensing PubMed David - Jung Wolfgang - Mueck Georg - Wensing Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

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.

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.

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.

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 [ t max ]: 0.500–1.00 h), exhibited dose‐linear pharmacokinetics and was rapidly eliminated from plasma (geometric mean terminal half‐life [ t ½ ]: 1.70–2.83 h). Finerenone IR tablets demonstrated similar pharmacokinetics (median t max : 0.750–2.50 h; geometric mean t ½ : 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 [ C max ]). 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.

D, L-lysine acetylsalicylate (ASA) glycine (LASAG, Aspirin i.v.®) has antiviral activity including resistant viral strains: inhalation of nebulized LASAG leads to dose-dependent lung virus titer reduction in mice, decreases disease severity and weight loss. Mortality is reduced dose-dependently. Proof-of-concept (PoC) is planned by measuring viral load and clinical symptoms after Influenza infection in patients.

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.

Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An excess of HNE activity has been implicated in the pathogenesis of inflammatory pulmonary diseases, e.g. bronchiectasis (BE), COPD, and pulmonary hypertension. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic target. BAY 85-8501 is a novel, selective and reversible HNE inhibitor with activity in the picomolar concentration range, which reveals target inhibition in the lung and ameliorates pulmonary inflammation in preclinical models. This First-in-Man study evaluated BAY 85-8501 in a Single-Dose-Escalation (SDE) design with 0.05, 0.1, 0.2, 0.5 or 1.0 mg as oral liquid formulation in 37 healthy male subjects (27 active, 10 placebo). The single dose treatments were safe and well tolerated without serious or severe adverse events and without any hints for mode of action or drug substance related adverse effects. All clinical safety parameters (BP, HR, ECG) and clinical laboratory parameters were in the normal range for single doses up to 1 mg. Drug absorption was fast, max. concentration (C) reached after 1 h, mean drug half-life was up to 145 - 175 h, allowing once daily dosing. Max. C and Area under Curve (0-24) increased in a dose-proportional way. Renal elimination of the unchanged drug is a minor pathway of elimination ( 4%). SDE up to 1 mg BAY 85-8501 was safe and well tolerated with pharmacokinetics that allow once daily dosing. Drug candidate is adequate for further clinical evaluation in studies in chronic anti-inflammatory treatment of lung diseases.

Background: The pharmacology of single doses of acetylsalicylic acid (ASA) administered intravenously (250 or 500 mg) or orally (100, 300, or 500 mg) was evaluated in a randomized, placebo-controlled, crossover study.Methods: Blood and urine samples were collected before and up to 24 hours after administration of ASA in 22 healthy volunteers. Pharmacokinetic parameters and measurements of platelet aggregation were determined using validated techniques.Results: A comparison between administration routes showed that the geometric mean dose-corrected peak concentrations (C-max/D) and the geometric mean dose-corrected area under the curve (AUC(0-infinity)/D) were higher following intravenous administration of ASA 500 mg compared with oral administration (estimated ratios were 11.23 and 2.03, respectively). Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous ASA doses, reflecting a rapid onset of inhibition that was not observed with oral dosing. At 5 minutes after administration, the mean reduction in arachidonic acid-induced thromboxane B-2 synthesis ex vivo was 99.3% with ASA 250 mg intravenously and 99.7% with ASA 500 mg intravenously. In exploratory analyses, thromboxane B2 synthesis was significantly lower after intravenous versus oral ASA 500 mg (P<0.0001) at each observed time point up to the first hour after administration. Concentrations of 6-keto-prostaglandin(1 alpha) at 5 and 20 minutes after dosing were also significantly lower with ASA 500 mg intravenously than with ASA 500 mg orally.Conclusion: This study demonstrates that intravenous ASA provides more rapid and consistent platelet inhibition than oral ASA within the first hour after dosing.

Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An excess of HNE activity has been implicated in the pathogenesis of inflammatory pulmonary diseases, e.g. bronchiectasis, COPD and pulmonary hypertension. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic option. BAY 85-8501 is a novel, selective and reversible HNE inhibitor with activity in the picomolar concentration range, which reveals target inhibition in the lung and ameliorates pulmonary inflammation in preclinical models. Relative bioavailability of 0.1 and 0.5 mg BAY 85-8501 immediate release tablets (tbl) and influence of concomitant food intake on 0.5 mg tbl was investigated in a 4-fold crossover study in 12 healthy male subjects. Treatments were single doses of tbl 0.1 and 0.5 and oral liquid 0.5 mg fasted and tbl 0.5 mg with food. All treatments were safe and well tolerated, no changes of clinical safety (BP, HR, ECG) and clinical laboratory parameters occurred. Tablet formulations of 0.5 and 0.1 mg revealed a comparable dose-normalized exposure, however, absorption rate was nearly halved for the tablet. Intake of American breakfast reduced the absorption rate (max. concentration (40 %) reached after 4 h), but not its extent. Terminal half-life after 0.5 mg ranged from 110 to 121 h. Bioavailability in terms of AUC was comparable between solution and tablet. Food intake decreased absorption rate, but not absorption extent. Tablets have favorable PK and are safe for further treatment in clinical studies.

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.

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.

Background Activation of the mineralocorticoid receptor (MR) by aldosterone is known to promote the retention of sodium by the kidney and has an important role in the pathophysiology of heart failu...