Cardiovascular risk of veterans' football: An observational cohort study with follow-up.

BACKGROUND: The cardiac stress for veteran football players during match is considerable. In this specific elderly population, the kinetics of exercise-induced cardiac troponin I (cTnI) and B-Type natriuretic peptide (BNP) could potentially be related to cardiovascular risk factors (CVRF) and cardiovascular disease and are therefore be investigated for their usefulness as an complement to established screening measures. METHODS: cTnI and BNP was measured in 112 veteran football players (age: 51 ± 10 years) within 30 minutes pre- and post-match. Players with elevated cTnI (cTnI-positive) and a control group (out of the 112 veteran players) with normal cTnI (cTnI-negative) underwent cardiac follow-up 4.2 ± 3.5 months post-match, comprising history, resting and stress ECG (including 30 minutes pre- and post cTnI and BNP), and echocardiography. RESULTS: In 33 players (29%) cTnI and in 6 players BNP (5%) exceeded the upper range limit for increased risk of myocardial damage (cTnI ≥ 5 ng/l) and myocardial wall stress (BNP ≥ 100 pg/ml) post-match, respectively. No correlation was observed between Δ cTnI (pre- vs. post-match) and the number of CVRF (r = -0.06, p = 0.50). Follow-up was conducted in 62 players (31 cTnI-positive and 31 cTnI-negative players) of which 6 (10%, 3 cTnI positive and 3 cTnI negative players) had cardiac abnormalities (hypertrophic cardiomyopathy n = 2, coronary artery disease n = 2, coronary artery anomaly n = 1, hypertensive heart disease n = 1). CONCLUSION: Veterans' football matches elicit increases in BNP and particularly cTnI in a considerable number of players. However, these biochemical alterations do not indicate acute cardiac damage as evidenced by follow-up. Routine determination of cardiac biomarkers is unlikely to improve cardiovascular screening in veteran football players.

First-in-human study of eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: Tolerability, safety and pharmacokinetics.

AIMS: Neuronal hypersensitisation due to adenosine triphosphate-dependent P2X3 receptor signalling plays a significant role in several disorders including chronic cough and endometriosis. This first-in-human study of eliapixant (BAY 1817080) investigated the tolerability, safety and pharmacokinetics (PK) of single doses of eliapixant, including the effect of food and coadministration with a CYP3A inhibitor on eliapixant relative bioavailability. METHODS: In this randomised, double-blind phase I study (NCT02817100), 88 healthy male subjects received single ascending doses of immediate-release eliapixant (10-800 mg) tablets or placebo under fasted conditions, with food (low-fat continental or high-fat American breakfast) or with itraconazole (fasted state). PK parameters, dose proportionality, adverse events and taste assessments (taste strips; dysgeusia questionnaire) were evaluated. RESULTS: Eliapixant had a long half-life (23.5-58.9 h [fasted state]; 32.8-43.8 h [high-fat breakfast]; 38.9-46.0 h [low-fat breakfast]). Less than dose-proportional increases in maximum plasma concentrations (Cmax ) and area under the concentration-time curve from time 0 to infinity (AUC[0-inf] ) were observed with ascending eliapixant doses. We observed a pronounced food effect with the high-fat breakfast (4.1-fold increased Cmax ; 2.7-fold increased AUC[0-inf] ), a smaller food effect with the low-fat breakfast and a mild-to-moderate effect of itraconazole coadministration on eliapixant (1.1-1.2-fold increased Cmax ; 1.7-fold increased AUC from 0 to 72 h). Eliapixant was well tolerated with minimal impact on taste perception. CONCLUSION: The PK profile, particularly the long half-life, and favourable tolerability with no taste-related adverse events, supports the further development of eliapixant in disorders with underlying P2X3 receptor-mediated neuronal hypersensitisation.

BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans.

BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in preventing COVID-191. Here we extend a previous phase-I/II trial report2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNγ+ or IL-2+ CD8+ and CD4+ T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8+ T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.

Desmethyl bosentan displays a similar in vitro interaction profile as bosentan.

The endothelin-1 receptor antagonists bosentan and ambrisentan used for the treatment of pulmonary arterial hypertension remarkably differ in their potential to act as perpetrators in pharmacokinetic drug-drug interactions. So far, it is not clear whether the metabolites of bosentan and ambrisentan contribute to the extent of drug interactions. We therefore investigated the effects of 4-hydroxymethyl ambrisentan, hydroxy bosentan, desmethyl bosentan, and hydroxy desmethyl bosentan on targets which are inhibited or induced by the parent compounds. The hydroxylated metabolites of ambrisentan and bosentan neither induced any of the genes investigated at the mRNA level, nor inhibited P-glycoprotein (P-gp) measured by calcein assay in L-MDR1 cells, and only weakly inhibited organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 measured by 8-fluorescein-cAMP uptake in HEK-OATP1B1 and HEK-OATP1B3 cells. In contrast, desmethyl bosentan induced mRNA expression of cytochrome P450 3A4 (CYP3A4, about 6-fold at 50 µM), ABCB1 (P-gp, about 4.5-fold at 50 µM), and ABCG2 (breast cancer resistance protein, about 2-fold at 50 µM), whereas CYP2C19, ABCB11, and ABCC2 (multidrug resistance-associated protein 2) were not induced in LS180 cells. In a reporter gene assay, desmethyl bosentan activated pregnane X receptor with the highest potency of all metabolites tested. Whereas desmethyl bosentan did not inhibit P-gp, it inhibited OATP1B1 with an IC50 of 3.8 µM (1.9-7.6) (geometric mean, 95% CI) and OATP1B3 with an IC50 of 7.4 µM (2.6-21.52). In conclusion, our data demonstrate that desmethyl bosentan exhibits a similar pharmacokinetic interaction profile as bosentan and might contribute to the inducing effects of the parent compound.

Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial.

Chemotherapy-induced nausea and vomiting is ranked among the worst side effects of chemotherapy. NEPA is an oral fixed-dose combination antiemetic under development, consisting of netupitant 300 mg, a highly selective NK1 receptor antagonist (RA), and palonosetron 0.5 mg, a pharmacologically and clinically distinct 5-HT3 RA. Although palonosetron is not associated with relevant ECG effects, this study evaluated cardiovascular safety of netupitant in combination with palonosetron, as well as its tolerability. This randomised, placebo- and positively controlled study in 197 subjects included 4 treatment groups: placebo, 200 mg netupitant + 0.5 mg palonosetron (NEPA200/0.5), 600 mg netupitant + 1.5 mg palonosetron (NEPA600/1.5, a supratherapeutic dose), and 400 mg moxifloxacin. Assessments included a 24-h baseline ECG recording, followed by a single dose of treatment and ECG measurements for 2 days. Mean placebo-corrected time-averaged changes from baseline were similar in NEPA200/0.5 and NEPA600/1.5 groups primarily for individually heart rate-corrected QT interval (QTcI: +4.7 and +3.6 ms, respectively) and for heart rate (HR: -3.3 bpm and -3.0 bpm), PR interval (-0.4 ms and 0.2 ms), and QRS interval (1 ms and 0.5 ms). The time-matched analysis showed no upper confidence interval >10 ms, with no suggestion of a QTc effect by pharmacokinetic-pharmacodynamic modeling for parent/metabolites. Moxifloxacin showed the expected placebo-corrected change from baseline (+8.4 ms time average) and the expected profile to establish assay sensitivity. No new morphologic changes of clinical relevance were observed. Treatment-related adverse events were comparable among groups. This study showed that NEPA treatments produced no significant effects on QTcI, HR, PR interval, QRS interval, and cardiac morphology relative to placebo, even at supratherapeutic doses.

Inhalation of a dry powder ciprofloxacin formulation in healthy subjects: a phase I study.

BACKGROUND: Oral and intravenous formulations of ciprofloxacin have established efficacy and safety profiles in respiratory infections. A dry powder for inhalation (DPI) that uses Novartis' PulmoSphere™ technology has been developed to deliver high concentrations of ciprofloxacin to the lung with low systemic exposure using a portable and convenient passive dry powder inhaler (Novartis' T-326 inhaler). OBJECTIVES: The primary objective was to investigate the safety and tolerability of ciprofloxacin DPI in healthy male subjects, with a secondary objective to investigate the pharmacokinetics of ciprofloxacin after ciprofloxacin DPI administration. METHODS: This was a phase I, single-dose, single-site, randomized, single-blind, placebo-controlled, crossover study conducted in the hospital setting. Subjects were followed up for safety for approximately 2 weeks. Six healthy male subjects, aged 27-42 years with no history of pulmonary disease, repeated bronchitis or respiratory allergies were enrolled. In randomized order and separated by a 1-week washout period, subjects inhaled a single dose of ciprofloxacin DPI 32.5 mg or placebo from the T-326 inhaler. Primary safety parameters included vital signs, electrocardiogram, laboratory tests, adverse events and lung function (total specific resistance, thoracic gas volume and forced expiratory volume in 1 s). Plasma concentration-time data were used to calculate pharmacokinetic parameters. RESULTS: Ciprofloxacin DPI was well tolerated with no clinically relevant adverse effects on lung function. Estimates of lung deposition derived from physiology-based pharmacokinetic modelling suggest that approximately 40 % of the total dose of ciprofloxacin DPI reached the trachea/bronchi and alveolar space. Systemic ciprofloxacin was detected soon after inhalation [peak concentration in plasma (C(max)) 56.42 µg/L, median time to C max 0.625 h], but total systemic exposure was minimal (area under the plasma concentration-time curve 354.4 µg·h/L). Terminal elimination half-life (9.5 h), apparent total clearance from plasma after non-intravenous administration (91.7 L/h) and apparent volume of distribution (1,262 L) data suggest that elimination from the respiratory tract was prolonged. CONCLUSIONS: In healthy subjects, ciprofloxacin DPI was well tolerated, delivered ciprofloxacin to the lungs and resulted in minimal systemic exposure, allowing further investigation of its clinical use for the management of specific, chronic infections in pulmonary diseases.

An innovative phase I population pharmacokinetic approach to investigate the pharmacokinetics of an intranasal fentanyl spray in healthy subjects.

BACKGROUND: Intranasal Fentanyl Spray (INFS) was developed for the treatment of breakthrough pain (BTP) in cancer patients using a new route of administration. Dose strengths of 50, 100, and 200 µg INFS (Instanyl®) are currently on the market, however, some adult cancer patients with BTP may require higher doses up to 400 µg INFS. OBJECTIVE: As pharmacokinetic (PK) samples from cancer patients with BTP are hard to obtain, PK of 400 µg INFS was investigated in healthy volunteers. Using prior knowledge from an available population PK (PopPK) model, a PK trial design was derived which aimed for short study duration and reduced trial costs without jeopardizing trial readout. METHODS: Different trial designs to investigate the systemic exposure of 400 µg INFS were simulated using the available PopPK model. Parameters with strong influence on Cmax and AUC, i.e., clearance (CL), absorption rate constant (KA), central volume (V2) and bioavailability (F1), were estimated, while other parameters were fixed to previous model estimates. The concentration-time data obtained from the applied trial design was subjected to a PopPK analysis. From the final individual parameter estimates, single-dose concentration-time profiles with wash-out were simulated, and AUC and Cmax values were calculated as for a classical trial design. RESULTS: The final trial design was a two-sequence, three period, and three-treatment cross-over design with no wash-out intervals between treatments. 20 subjects received three doses of INFS. Four hours after a single dose of 200 µg INFS (Treatment A), subjects received either a single dose of 400 µg INFS (Treatment B) or two single doses (10 minutes apart) of 400 µg INFS (Treatment C). At t = 24 hours subjects received either Treatment B or Treatment C as cross-over. Plasma samples were taken up to 72 hours. The study duration per subject was less than 4 days. PopPK analysis and validation were performed successfully. The estimated primary PK parameters were F1 = 59%, CL=33.5 l/h, V2 = 68.8 l and KA = 12.8 1/h. The ratio analysis of the least square geometric means of dose normalized AUC∞ values resulted in point estimates of 97 - 104%, indicating dose proportionality in the investigated dose range of 200 µg - 2 × 400 µg. CONCLUSION: The implementation of a PopPK approach in the planning and analysis of this trial yielded an innovative, cost- and time-saving trial design that successfully delivered the required information about the PK of the 400 µg dose strength within this small clinical study.

Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers.

PURPOSE: To evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate. METHODS: This was an open-label trial in healthy male subjects. In part 1 (pilot, n = 8) and part 3 (n = 12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran. RESULTS: Bioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUC(τ,ss) were 135% (90% CI 107-169%) and 132% (90% CI 112-156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUC(τ,ss) ratio test/reference: 91.9%, 90% CI 78.7-107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC(0-24) was 103%; 90% CI 80.3-131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation. CONCLUSIONS: When given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent.