Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study

Whittaker, Andrew K.; Kragh, Åsa M.; Hartleib‐Geschwindner, Judith; Albayaty, Muna; Backlund, Anna; Greasley, Peter J.; Heijer, Maria; Kjaer, Magnus; Forte, Pablo; Unwin, Robert J.; Wernevik, Linda; Ericsson, Henrik

doi:10.1111/cts.12705

Cited by 21 publications

(18 citation statements)

References 34 publications

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“…This study suggested that aldosterone‐induced decrease in Na + /K + ratio is not affected by AZD9977. In a dose‐escalation study, AZD9977 did not alter the serum Na + /K + ratio in healthy volunteers (Whittaker et al, 2020). AZD9977 has different interaction patterns with MR, with differential cofactor recruitment, which is considered responsible for the renoprotective effect devoid of hyperkalemia (Bamberg et al, 2018).…”

Section: Hyperkalemia With Mr Antagonistmentioning

confidence: 99%

Role of mineralocorticoid receptor antagonists in kidney diseases

Patel

Joharapurkar

Jain

2020

Drug Development Research

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Mineralocorticoid receptor (MR) antagonists, for example, spironolactone and eplerenone, are in clinical use to treat hypertension. Increasing evidence suggests that mineralocorticoid receptor activation causes the pathogenesis and progression of chronic kidney disease. Aldosterone‐induced MR activation increases inflammation, fibrosis, and oxidative stress in the kidney. MR antagonists (MRAs) have demonstrated therapeutic actions in chronic kidney disease (CKD), diabetic nephropathy (DN), renal fibrosis, and drug‐induced renal injury in preclinical and clinical studies. We have summarized and discussed these studies in this review. The nonsteroidal MRA, esaxerenone, recently received approval for the treatment of hypertension. It has also shown a positive therapeutic effect in phase 3 clinical trials in patients with DN. Other nonsteroidal MRA such as apararenone, finerenone, AZD9977, and LY2623091 are in different clinical trials in patients with hypertension suffering from renal or hepatic fibrotic diseases. Hyperkalemia associated with MRA therapy has frequently led to the discontinuation of the treatment. The new generation nonsteroidal MRAs like esaxerenone are less likely to cause hyperkalemia at therapeutic doses. It appears that the nonsteroidal MRAs can provide optimum therapeutic benefit for patients suffering from kidney diseases.

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Section: Hyperkalemia With Mr Antagonistmentioning

confidence: 99%

Role of mineralocorticoid receptor antagonists in kidney diseases

Patel

Joharapurkar

Jain

2020

Drug Development Research

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“…Eplerenone, a second-generation MR blocker, had improved specificity for the MR, thus reducing the frequency of serious sex hormone-related adverse events [14][15][16]. More recently, the highly selective nonsteroidal MR blockers esaxerenone, finerenone, apararenone, and AZD9977 have been successively developed [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone

2020

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The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with uncomplicated grade I–III hypertension, hypertension with moderate renal dysfunction, hypertension with type 2 diabetes mellitus with albuminuria, and hypertension associated with primary aldosteronism. Hyperkalemia has long been recognized as a potential side effect occurring during treatment with MR blockers, but there is a lack of understanding and guidance about the appropriate management of hyperkalemia during antihypertensive therapy with MR blockers, especially in regard to the newer agent esaxerenone. In this article, we first highlight risk factors for hyperkalemia, including advanced chronic kidney disease, diabetes mellitus, cardiovascular disease, age, and use of renin-angiotensin-aldosterone system inhibitors. Next, we examine approaches to prevention and management, including potassium monitoring, diet, and the use of appropriate therapeutic techniques. Finally, we summarize the currently available data for esaxerenone and hyperkalemia. Proper management of serum potassium is required to ensure safe clinical use of MR blockers, including awareness of at-risk patient groups, choosing appropriate dosages for therapy initiation and dosage titration, and monitoring of serum potassium during therapy. It is critical that physicians take such factors into consideration to optimize MR blocker therapy in patients with hypertension.

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“…Pharmacodynamic and pharmacokinetic characteristics of non‐steroidal mineralocorticoid receptor antagonists and spironolactone. 1 Arai, Homma, et al (2015); 2 Yamada et al (2019); 3 Ito et al (2019); 4 Ito, Itoh, et al (2020); 5 Ito, Kashihara, et al (2020); 6 Bamberg et al (2018); 7 Whittaker et al (2020); 8 Nakamura and Kawaguchi (2021); 9 Wada et al (2021); 10 Bakris, Yang, and Pitt (2020); 11 Bakris et al (2021); 12 Pitt et al (2012); 13 Amazit et al (2015); 14 Grune et al (2018); 15 Heinig et al (2016); 16 Gerisch et al (2018); 17 Bakris et al (2015); 18 Bakris, Agarwal, et al (2020); 19 Pitt et al (2013); 20 Pitt et al (2021); 21 Gardiner et al (1989); 22 Karim et al (1976); 23 Karim (1978); 24 Agarwal et al (2019); 25 Weinberger et al (2002); 26 Williams et al (2015); 27 Bianchi et al (2006). 7α‐TMS, 7α‐thiomethylspirono‐lactone; CKD, chronic kidney disease; comp., comparison; DKD, diabetic kidney disease; HT, arterial hypertension; modest, ≤5‐mmHg SBP change; nsMRA, non‐steroidal MRA; rHT, uncontrolled/resistant hypertension; rHT‐CKD, uncontrolled/resistant hypertension and chronic kidney disease; robust, ≥10‐mmHg SBP change; SBP, systolic BP; sMRA, steroidal mineralocorticoid receptor antagonist; wCHF, worsening of chronic heart failure…”

Section: Novel Non‐steroidal Mrasmentioning

confidence: 99%

“…In clinical Phase I studies, AZD9977 was safe and well tolerated with a plasma half‐life after single dosing of 2–3 h and after 8‐day administration between 4 and 9 h (Erlandsson et al, 2018; Whittaker et al, 2020) (Figure 3); 24–37% of AZD9977 was excreted in the urine (Whittaker et al, 2020) (Figure 3). After a fludrocortisone challenge, a single dose of AZD9977 (200 mg) resulted in a significant increase of the urine Na + /K + ratio similarly to eplerenone (100 mg) (Erlandsson et al, 2018).…”

Section: Novel Non‐steroidal Mrasmentioning

confidence: 99%

Novel non‐steroidal mineralocorticoid receptor antagonists in cardiorenal disease

Kintscher

Bakris

Kolkhof

2022

British J Pharmacology

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Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline‐oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced ejection fraction and resistant hypertension. Currently available steroidal MRAs are efficacious in reducing morbidity and mortality; however, they can be associated with intolerable side effects including hyperkalaemia in everyday clinical practice. Recently, a new class of non‐steroidal MRAs (including esaxerenone, AZD9977, apararenone, KBP‐5074 and finerenone) have been developed with an improved benefit–risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non‐steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice. LINKED ARTICLES This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc

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Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study

Cited by 21 publications

References 34 publications

Role of mineralocorticoid receptor antagonists in kidney diseases

Role of mineralocorticoid receptor antagonists in kidney diseases

Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone

Novel non‐steroidal mineralocorticoid receptor antagonists in cardiorenal disease

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