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Aims: 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., Methods: 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., Results: Mean midazolam values of maximum plasma concentration (C max ) 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 C max of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon., Conclusions: 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., (© 2024 AstraZeneca. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy., Methods and Results: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected., Conclusions: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

Objective: To assess the risk of haemorrhagic stroke at different baseline SBP levels in a primary care population with hypertension, atrial fibrillation and newly initiated oral anticoagulants (OACs)., Methods: We identified 3972 patients with hypertension, atrial fibrillation and newly initiated OAC in The Swedish Primary Care Cardiovascular Database of Skaraborg. Patients were followed from 1 January 2006 until a first event of haemorrhagic stroke, death, cessation of OAC or 31 December 2016. We analysed the association between continuous SBP and haemorrhagic stroke with a multivariable Cox regression model and plotted the hazard ratio as a function of SBP with a restricted cubic spline with 130 mmHg as reference., Results: There were 40 cases of haemorrhagic stroke during follow-up. Baseline SBP in the 145-180 mmHg range was associated with a more than doubled risk of haemorrhagic stroke, compared with a SBP of 130 mmHg., Conclusion: In this cohort of primary care patients with hypertension and atrial fibrillation, we found that baseline SBP in the 145-180 mmHg range, prior to initiation of OAC, was associated with a more than doubled risk of haemorrhagic stroke, as compared with an SBP of 130 mmHg. This suggests that lowering SBP to below 145 mmHg, prior to initiation of OAC, may decrease the risk of haemorrhagic stroke in patients with hypertension and atrial fibrillation., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The protective effect of lipid-lowering treatment for secondary prevention after coronary heart disease (CHD) has been well documented. Current guidelines recommend a target level for low-density lipoprotein cholesterol (LDL-C) of ≤1.8 mmol/L. The aim was to describe lipid-lowering treatment patterns and to provide an estimate of the potential reductions in cardiovascular disease (CVD) events with improved adherence to guidelines., Design: Cross-sectional., Setting: Primary care in a large Swedish region., Participants: 37 120 patients with CHD in a Swedish regional primary care quality register (QregPV), by 31 December 2015., Primary and Secondary Outcome Measures: Proportion of patients on statin treatment and proportion of patients achieving LDL-C ≤1.8 mmol/L. Estimated number of CVD events calculated for (1) current treatment, (2) improved treatment and (3) lowered LDL-C, based on applying rate reductions from meta-analyses of randomised trials to the potentially undertreated population. Risk estimation modelling was based on 52 042 patients in the same register on January 2011 followed for 5 years., Results: Of 37 120 patients, 18% reached LDL-C ≤1.8 mmol/L and 32% were not on statin treatment. Based on individual risks, the estimated number of CVD events in the study group over 5 years was 9209/37 120. If all patients without a statin or with less potent statin treatment were given atorvastatin 80 mg, an estimated reduction of CVD events by 14% (7901 vs 9209) was seen. If all patients achieved LDL-C ≤1.8 mmol/L, the number of events was estimated to be reduced by 18% (7577 vs 9209)., Conclusion: One-third of patients with CHD in primary care were not on lipid-lowering treatment. Based on the assumption that included patients would react to statin therapy the same way as the patients in randomised trials, improved adherence to treatment guidelines could lead to a substantial reduction in new CVD events., Competing Interests: Competing interests: SAE is employed by AstraZeneca since September 2019 but was affiliated to University of Gothenburg during the main part of the study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)