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AZD5718 is a first‐in‐class small‐molecule anti‐inflammatory drug with the potential to reduce the residual risk of cardiovascular events after myocardial infarction in patients receiving lipid‐lowering statin therapy. Leukotrienes are potent proinflammatory and vasoactive mediators synthesized in leukocytes via 5‐lipoxygenase and 5‐lipoxygenase‐activating protein (FLAP). AZD5718 is a FLAP inhibitor that dose‐dependently reduced leukotriene biosynthesis in a first‐in‐human study. We enrolled 12 healthy men in a randomized, open‐label, crossover, single‐dose phase 1 pharmacokinetic study of AZD5718 to investigate a potential drug‐drug interaction with rosuvastatin, and the effects of formulation and food intake (ClinicalTrials.gov identifier: NCT02963116). Rosuvastatin (10 mg) were absorbed more rapidly when coadministered with AZD5718 (200 mg), probably owing to weak inhibition of hepatic statin uptake, but relative bioavailability was unaffected (geometric least‐squares mean ratio [GMR], 100%; 90% confidence interval [CI], 86%‐116%). AZD5718 pharmacokinetics were unaffected by coadministration of rosuvastatin. AZD5718 (200 mg) was absorbed less rapidly when formulated as tablets than oral suspension, with reduced relative bioavailability (GMR, 72%; 90%CI, 64%‐80%). AZD5718 absorption was slower when 200‐mg tablets were taken after a high‐fat breakfast than after fasting, but relative bioavailability was unaffected (GMR, 96%; 90%CI, 87%‐106%). In post hoc pharmacodynamic simulations, plasma leukotriene B4 levels were inhibited by >90% throughout the day following once‐daily AZD5718, regardless of formulation or administration with food. AZD5718 was well tolerated, with no severe or serious adverse events. These data supported the design of a phase 2a efficacy study of AZD5718 in patients with coronary artery disease. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5‐lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single‐blind, placebo‐controlled, first‐in‐human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4) production in whole blood and endogenous leukotriene E (LTE4) in urine. No clinically relevant safety and tolerability findings were observed. The AZD5718 was rapidly absorbed and plasma concentrations declined biphasically with a mean terminal half‐life of 10–12 h. Steady‐state levels were achieved after ∼3 days. After both SADs and MADs, a dose/concentration‐effect relationship between both LTB4 and LTE4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC50) values in the lower nM range. Based on obtained result, AZD5718 is considered as a suitable drug candidate for future evaluation in patients with coronary artery disease (CAD). [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate the pharmacodynamics, pharmacokinetics and safety of the glucokinase activator AZD6370 after 1day of administration under fed and fasted conditions in patients with type 2 diabetes mellitus (T2DM). Methods: This was a two-part study. In Part A, patients received a single oral dose of AZD6370 (20, 60 or 180mg) or placebo in the fasted or fed states (both n =8). In Part B, patients (n =8) received placebo and a total dose of AZD6370 180mg given in one, two or four divided doses. Plasma glucose, insulin and C-peptide changes versus placebo were assessed. Results: AZD6370 provided dose-dependent reductions in plasma glucose of up to 30% versus placebo in both fasted and fed patients (p <0.001 at 60 and 180mg doses). Insulin secretion increased with dose, but absolute increases were relatively small in the fasted versus fed state (0–4h). Dosing AZD6370 twice or four-times over 1day gave a smoother 24-h glucose profile than single-dose. AZD6370 was rapidly absorbed. Pharmacokinetics of AZD6370 were dose-independent and unaffected by food. AZD6370 was generally well tolerated. Conclusions: AZD6370 produced dose-dependent glucose reductions and increased glucose-stimulated insulin secretion in patients with T2DM. [Copyright &y& Elsevier]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Tesaglitazar, is predominantly metabolized (to an acyl glucuronide of the parent compound) and 20% of given dose is found unchanged in the urine. • Acyl glucuronides are know to be unstable and can become hydrolysed back to parent compound, a phenomena called interconversion. WHAT THIS STUDY ADDS • A likely mechanism (interconversion) for the cause of the increased exposure of tesaglitazar in subjects with impaired renal function. • A possible modelling framework to evaluate interconversion without dosing of the metabolite based on the simultaneous analysis of plasma and urine data from a group of subjects with varying renal function. • A mechanistic understanding of the pharmacokinetic properties of tesaglitazar and its metabolite. AIMS To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function. METHODS Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar ( n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation. RESULTS The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h−1) and metabolic (1.9 l h−1) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, Vmax = 0.19 μmol l−1 and K m = 0.04 μmol l−1) and nonrenal clearances (1.2 l h−1), biliary secretion (12 h−1) to the gut, where interconversion and reabsorption (0.8 h−1) of tesaglitazar occurred. CONCLUSION A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite. [ABSTRACT FROM AUTHOR]

The article summarizes an international collaborative study on the development of reference methods and provision of information and recommendations to improve the performance of antimicrobial sensitivity tests. The methods used in the study included broth and agar dilution methods, as well as an agar diffusion method. Findings indicated that broth and agar dilution tests are recommended as routine methods.

A technique for modeling contaminant transport based on Markov process theory is developed. Transport is quantified by summing the first two moments of independent random displacements and applying the central limit theorem (CLT) to obtain solute distributions of a Gaussian nature. For non-uniform flow fields the CLT is applied in a streamfunction/equi-travel time space and transforms are used to give concentrations in Cartesian coordinates. Simulations in uniform, radially converging and circular flow fields show the method to be two to three orders of magnitude faster than modeling with the advection-dispersion equation, using a control volume technique. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre‐clinical profiling suggests that time‐dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co‐administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time‐/dose‐dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity.Open‐label, fixed‐sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug–drug interaction.Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co‐administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co‐administrations with two predicted therapeutically relevant doses of Atuliflapon.Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs. [ABSTRACT FROM AUTHOR]

Mitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non‐alcoholic steatohepatits and chronic obstructive pulmonary disease. We aimed to assess the risk of QT‐interval prolongation with mitiperstat using concentration–QT (C‐QT) modeling. Healthy male volunteers were randomized to receive single oral doses of mitiperstat 5, 15, 45, 135, or 405 mg (n = 6 per dose) or matching placebo (n = 10) in a phase 1 study (NCT02712372). Time‐matched pharmacokinetic and digital electrocardiogram data were collected at the baseline (pre‐dose) and at 11 time‐points up to 48 h post‐dose. C‐QT analysis was prespecified as an exploratory objective. The prespecified linear mixed effects model used baseline‐adjusted QT interval corrected for the heart rate by Fridericia's formula (ΔQTcF) as a dependent variable and plasma mitiperstat concentration as an independent variable. Initial exploratory analyses indicated that all model assumptions were met (no effect on heart rate; appropriate use of QTcF; no hysteresis; linear concentration–response relationship). Model‐predicted mean baseline‐corrected and placebo‐adjusted ΔΔQTcF was +0.73 ms (90% confidence interval [CI]: −1.73, +3.19) at the highest anticipated clinical exposure (0.093 μmol/L) during treatment with mitiperstat 5 mg once daily. The upper 90% CI was below the established threshold of regulatory concern. The 16‐fold margin to the highest observed exposure was high enough to mean that a positive control was not needed. Mitiperstat is not associated with risk of QT‐interval prolongation at expected therapeutic concentrations. [ABSTRACT FROM AUTHOR]

Aims: Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity‐induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b–3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF. Methods: In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6‐min walk distance (6MWD) of 30–400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ‐TSS. The sample size provides 85% power to detect placebo‐adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ‐TSS at overall two‐sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo. Conclusion: ENDEAVOR is the first phase 2b–3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF. [ABSTRACT FROM AUTHOR]

Aims: Myeloperoxidase activity can contribute to impaired vascular endothelial function and fibrosis in chronic inflammation‐related cardiovascular disease. Here, we investigated the safety, tolerability and pharmacokinetics of the myeloperoxidase inhibitor, AZD4831. Methods: In this randomized, single‐blind, placebo‐controlled, phase I, first‐in‐human study, healthy men in five sequential cohorts were randomized 3:1 to receive a single oral dose of AZD4831 (5, 15, 45, 135 or 405 mg) or placebo, after overnight fasting. After at least 7 days' washout, one cohort additionally received AZD4831 45 mg after a high‐calorie meal. Results: Forty men participated in the study (eight per cohort: AZD4831, n = 6; placebo, n = 2). AZD4831 distributed rapidly into plasma, with a half‐life of 38.2–50.0 hours. The area under the plasma concentration–time curve (AUC) increased proportionally with dose (AUC0–∝ slope estimate 1.060; 95% confidence interval [CI] 0.9943, 1.127). Increases in maximum plasma concentration were slightly more than dose proportional (slope estimate 1.201; 95% CI 1.071, 1.332). Food intake reduced AZD4831 absorption rate but did not substantially affect overall exposure or plasma half‐life (n = 4). Serum uric acid concentrations decreased by 71.77 (95% CI 29.15, 114.39) and 84.42 (58.90, 109.94) μmol L−1 with AZD4831 135 mg and 405 mg, respectively. Maculopapular rash (moderate intensity) occurred in 4/30 participants receiving AZD4831 (13.3%). No other safety concerns were identified. Conclusions: AZD4831 was generally well tolerated, rapidly absorbed, had a long plasma half‐life and lowered uric acid concentrations after single oral doses in healthy men. These findings support the further clinical development of AZD4831. [ABSTRACT FROM AUTHOR]

Background and Objective: AZD5718, a 5-lipoxygenase-activating protein (FLAP) inhibitor, is in clinical development for treatment of coronary artery disease (CAD) and chronic kidney disease (CKD). This study evaluated AZD5718 pharmacokinetics, pharmacodynamics, and tolerability in healthy male Japanese subjects. Methods: Four cohorts of eight Japanese subjects were randomized to receive oral doses of AZD5718 (60, 180, 360, and 600 mg) or matching placebo administered as a single dose on Day 1 and as once-daily doses from Day 3 to Day 10 in fasted conditions. Pharmacokinetic, pharmacodynamic, and safety data were collected. Results: The pharmacokinetics characteristics of AZD5718 in Japanese male subjects were similar to those reported in a previous study, and the pharmacokinetics were characterized as rapid absorption with median time to reach maximum concentration (Tmax) of 1–2 h Creatine-normalized urine maximum concentration (Cmax) with mean half-lives ranging from 8 to 21 h, and supra-proportional increase in exposure over the 60–600 mg dose range evaluated. Also, an increase in steady-state area under the concentration-time curve (AUC) compared to the first dose was observed. After both single and multiple doses of AZD5718, a clear dose/concentration-effect relationship was shown for urinary leukotriene E4 (LTE4) versus AZD5718 exposure with > 80 % inhibition at plasma concentrations in the lower nM range. No clinically relevant safety and tolerability findings were observed. Conclusions: The observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD. [ABSTRACT FROM AUTHOR]

We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single‐blind, placebo‐controlled study, following once‐daily multiple ascending dosing to steady‐state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half‐life of ~ 60 hours. A dose/concentration‐effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady‐state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration‐dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Excessive activation of the mineralocorticoid receptor (MR) underlies the pathophysiology of heart failure and chronic kidney disease. Hyperkalemia risk limits the therapeutic use of conventional MR antagonists. AZD9977 is a nonsteroidal, selective MR modulator that may protect nonepithelial tissues without disturbing electrolyte balance. This phase I study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AZD9977 in healthy volunteers. Twenty‐seven male participants aged 23–45 years were randomized 3:1 to receive oral AZD9977 or placebo for 8 days (with twice‐daily dosing on days 2–7), in dose cohorts of 50, 150, and 300 mg (AZD9977, n = 6 per cohort; placebo, n = 3 per cohort). Adverse events occurred in 4 of 18 participants receiving AZD9977 (22.2%) and 6 of 9 receiving placebo (66.7%), all of mild or moderate severity; none were serious or led to withdrawal. AZD9977 was rapidly absorbed, with median time of maximum concentration of 0.50–0.84 hours across dose groups. Area under the curve and maximum concentration were approximately dose proportional but elimination and accumulation terminal half‐life increased with dose. Steady‐state was reached after 3–4 days, with dose‐dependent accumulation of 1.2–1.7‐fold. Renal clearance was 5.9–6.5 L/hour and 24–37% of AZD9977 was excreted in the urine. Serum aldosterone levels increased dose dependently from days −1 to 7 in participants receiving AZD9977, but serum potassium levels and urinary electrolyte excretion were unchanged. AZD9977 was generally well‐tolerated with no safety concerns. Exploratory outcomes suggested reduced hyperkalemia risk compared with MR antagonists. These findings support further clinical development of AZD9977. [ABSTRACT FROM AUTHOR]

Aims/Hypothesis: GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients. Methods: We determined the drive on PGD2 secretion by glucose and IL-1beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro. To test if metabolic control would be improved by antagonizing a hyperglycemia-driven increased PGD2 tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m2). The randomized, double-blind, placebo-controlled cross-over study consisted of two three-day treatment periods (AZD1981 or placebo) separated by a three-day wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose infusion (GGI) was performed at start and end of each treatment period. Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, GLP-1, and PGD2 pathway biomarkers were performed. Results: We found (1) that PGD2 is produced in human islet in response to high glucose or IL-1beta, but likely by stellate cells rather than endocrine cells; (2) that PGD2 suppresses both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. However, AZD1981 had no impact on neither glucose nor incretin dependent insulin secretion in humans (GGI AUC C-peptide 1-2h and MMTT AUC Glucose 0-4h LS mean ratios vs placebo of 0.94 (80% CI of 0.90–0.98, p = 0.12) and 0.99 (90% CI of 0.94–1.05, p = 0.45), despite reaching the expected antagonist exposure. Conclusion/Interpretation: Pharmacological inhibition of the PGD2-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Aims: AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977. Methods: A first‐in‐human trial explored doses from 5 to 1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross‐over four‐period clinical trial was performed. Twenty‐three healthy volunteers were administered fludrocortisone alone or in combination with AZD9977, eplerenone or both. AZD9977/eplerenone combination was given to assess if AZD9977 can attenuate eplerenone induced natriuresis. Results: AZD9977 at doses from 5 to 1200 mg was safe and well tolerated and pharmacokinetics were compatible with further development. AZD9977 exhibited similar effects on urinary ln [Na+]/[K+] as eplerenone when using fludrocortisone as mineralocorticoid receptor agonist, and the combination had an additive effect on ln [Na+K+]. Conclusions: The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients. [ABSTRACT FROM AUTHOR]