Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer's disease

Leithold, Leonie H. E.; Jiang, Nan; Post, Julia; Niemietz, Nicole; Schartmann, Elena; Ziehm, Tamar; Kutzsche, Janine; Shah, N. Jon; Breitkreutz, Jörg; Langen, Karl‐Josef; Willuweit, Antje; Willbold, Dieter

doi:10.1016/j.ejps.2016.04.016

Cited by 25 publications

(29 citation statements)

References 22 publications

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“…Description of the pharmacokinetics and disposition of other d ‐amino acid peptides is limited in the literature. The disposition (distribution, biotransformation, and excretion) of etelcalcetide and its biotransformation products have been characterized in an in vitro hemodialysis model, in rats, in healthy volunteers, and in patients with CKD and secondary hyperparathyroidism on hemodialysis .…”

Section: Distribution Biotransformation and Excretion Of Etelcalcetidementioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Etelcalcetide, a Novel Calcimimetic for Treatment of Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease on Hemodialysis

Melhem

Subramanian

et al. 2018

The Journal of Clinical Pharma

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Etelcalcetide, a d-amino acid peptide, is an intravenous calcimimetic approved for the treatment of secondary hyperparathyroidism. Etelcalcetide binds the calcium-sensing receptor and increases its sensitivity to extracellular calcium, thereby decreasing secretion of parathyroid hormone (PTH) by chief cells. Etelcalcetide and its low-molecular-weight transformation products are rapidly cleared by renal excretion in healthy subjects, but clearance is substantially reduced and dependent on hemodialysis in end-stage renal disease. The effective half-life is 3-5 days in patients undergoing hemodialysis 3 times a week. A clinical study using a single microtracer intravenous dose of [ C]etelcalcetide indicated that 60% of the administered dose was eliminated in dialysate. Etelcalcetide undergoes reversible disulfide exchange with serum albumin to form a serum albumin peptide conjugate that is too large (67 kDa) to be dialyzed, until a subsequent exchange forms etelcalcetide or a low-molecular-weight transformation product. This exchange from albumin is apparent after hemodialysis, when it partially restores etelcalcetide concentrations in plasma. Etelcalcetide has no known risks for drug-drug interactions. In phase 3 studies, 74%-75% of hemodialysis patients with secondary hyperparathyroidism who received etelcalcetide achieved a >30% PTH reduction from baseline versus 8%-10% of patients who received placebo. The pharmacokinetics and pharmacodynamics of etelcalcetide in hemodialysis patients supports a 5-mg starting dose administered after hemodialysis and uptitration in 2.5- or 5-mg increments every 4 weeks to a maximum dose of 15 mg 3 times a week.

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Section: Distribution Biotransformation and Excretion Of Etelcalcetidementioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Etelcalcetide, a Novel Calcimimetic for Treatment of Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease on Hemodialysis

Melhem

Subramanian

et al. 2018

The Journal of Clinical Pharma

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“…The advantage of D-peptides over L-peptides is their higher protease resistance, resulting in slower degradation and longer half-life (31,32). For A␤(1-42)directed D-peptides, high stability in media simulating the route of orally administered drugs (33) and enhanced proteolytic stability in murine plasma and organ homogenates were shown (34). The lead compound of these D-peptides, D3, had been selected by mirror-image phage display (26,35).…”

mentioning

confidence: 99%

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

Rösener

Gremer

Reinartz

et al. 2018

Journal of Biological Chemistry

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. One AD hallmark is the aggregation of β-amyloid (Aβ) into soluble oligomers and insoluble fibrils. Several studies have reported that oligomers rather than fibrils are the most toxic species in AD progression. Aβ oligomers bind with high affinity to membrane-associated prion protein (PrP), leading to toxic signaling across the cell membrane, which makes the Aβ-PrP interaction an attractive therapeutic target. Here, probing this interaction in more detail, we found that both full-length, soluble human (hu) PrP(23-230) and huPrP(23-144), lacking the globular C-terminal domain, bind to Aβ oligomers to form large complexes above the megadalton size range. Following purification by sucrose density-gradient ultracentrifugation, the Aβ and huPrP contents in these heteroassemblies were quantified by reversed-phase HPLC. The Aβ:PrP molar ratio in these assemblies exhibited some limited variation depending on the molar ratio of the initial mixture. Specifically, a molar ratio of about four Aβ to one huPrP in the presence of an excess of huPrP(23-230) or huPrP(23-144) suggested that four Aβ units are required to form one huPrP-binding site. Of note, an Aβ-binding all-d-enantiomeric peptide, RD2D3, competed with huPrP for Aβ oligomers and interfered with Aβ-PrP heteroassembly in a concentration-dependent manner. Our results highlight the importance of multivalent epitopes on Aβ oligomers for Aβ-PrP interactions and have yielded an all-d-peptide-based, therapeutically promising agent that competes with PrP for these interactions.

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“…For example, serum proteins such as albumin and α1-acid glycoprotein bind CARPs, providing a reservoir of the peptide that prolongs serum half-life and potentially extending peptide therapeutic duration [203,206,207]. Furthermore, various peptide structural modifications such as cyclization and use of D-enantiomer amino acids can enhance resistance to serum proteases, and thus improve serum stability [206,208,209]. With regards to tissue targeting, CARPs and CARP-conjugates generally exhibit preferential distribution in kidney, liver, spleen, lung and to a lesser extent brain [203,204,[210][211][212][213][214][215][216].…”

Section: Pharmacokinetics Of Carpsmentioning

confidence: 99%

Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

MacDougall

Anderton

Mastaglia

et al. 2019

Neurobiology of Disease

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Stroke is the second leading cause of death globally and represents a major cause of devastating long-term disability. Despite sustained efforts to develop clinically effective neuroprotective therapies, presently there is no clinically available neuroprotective agent for stroke. As a central mediator of neurodamaging events in stroke, mitochondria are recognised as a critical neuroprotective target, and as such, provide a focus for developing mitochondrial-targeted therapeutics. In recent years, cationic arginine-rich peptides (CARPs) have been identified as a novel class of neuroprotective agent with several demonstrated mechanisms of action, including their ability to target mitochondria and exert positive effects on the organelle. This review provides an overview on neuronal mitochondrial dysfunction in ischaemic stroke pathophysiology and highlights the potential beneficial effects of CARPs on mitochondria in the ischaemic brain following stroke.

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Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer's disease

Cited by 25 publications

References 22 publications

Clinical Pharmacokinetics and Pharmacodynamics of Etelcalcetide, a Novel Calcimimetic for Treatment of Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease on Hemodialysis

Clinical Pharmacokinetics and Pharmacodynamics of Etelcalcetide, a Novel Calcimimetic for Treatment of Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease on Hemodialysis

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

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