Molidustat for the treatment of renal anaemia in patients with dialysis-dependent chronic kidney disease: design and rationale of three phase III studies

Akizawa, Tadao; Taguchi, Megumi; Matsuda, Yoshinobu; Iekushi, Kazuma; Yamada, Takashi; Yamamoto, Hiroyasu

doi:10.1136/bmjopen-2018-026602

Cited by 19 publications

(46 citation statements)

References 36 publications

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“…Although PK and PD (effect on EPO) parameters of molidustat in healthy volunteers were affected by oral administration of iron(II) sulphate or iron(II) glycine sulphate immediately before molidustat, these effects were reduced by temporal separation of drug intake. This is currently being investigated in ongoing phase 3 clinical trials [8,9]. Calcium supplement (investigated as calcium acetate) co-administration had no relevant effect on the pharmacokinetics or pharmacodynamics of molidustat.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of HIF-PH results in stabilization of HIF, which leads to endogenous production of EPO and, ultimately, stimulation of erythropoiesis [7]. Molidustat is an orally bioavailable HIF-PH inhibitor being investigated in phase 3 clinical trials in patients with renal anaemia, including patients receiving dialysis treatment [8,9]. The phase 2 DIALOGUE (DaIly orAL treatment increasing endOGenoUs Erythropoietin) programme, which included three studies with a 16week treatment duration and two extension studies, assessed the safety and efficacy of molidustat in different populations of patients with renal anaemia [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF–PH inhibitor for the treatment of renal anaemia

Lentini

Kaiser

Kapsa

et al. 2020

Eur J Clin Pharmacol

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Purpose The present studies assessed the drug-drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD). Methods Forty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12-15 participants per study). Molidustat AUC and C max were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics. Results Depending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and C max by 50-75% and 46-84%, respectively, and EPO AUC (0-24) and C max by 31-44% and 36-48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and C max of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and C max by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated. Conclusions In contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF–PH inhibitor for the treatment of renal anaemia

Lentini

Kaiser

Kapsa

et al. 2020

Eur J Clin Pharmacol

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“…In preclinical studies, molidustat restored renal EPO production with minor stimulation of hepatic EPO [121,123]. Moreover, it heightened plasma EPO and EPO mRNA in the kidney prevented the reduction in hematocrit and corrected Hb level [121].…”

Section: New Strategies Of Anemia Treatmentmentioning

confidence: 96%

The Influence of Inflammation on Anemia in CKD Patients

Gluba-Brzózka

Franczyk

Olszewski

et al. 2020

IJMS

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Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient’s life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a chronic inflammatory state which is related to a vast range of underlying factors. The results of studies have demonstrated that persistent inflammation may contribute to the variability in Hb levels and hyporesponsiveness to erythropoietin stimulating agents (ESA), which are frequently observed in CKD patients. The understanding of the impact of inflammatory cytokines on erythropoietin production and hepcidin synthesis will enable one to unravel the net of interactions of multiple factors involved in the pathogenesis of the anemia of chronic disease. It seems that anti-cytokine and anti-oxidative treatment strategies may be the future of pharmacological interventions aiming at the treatment of inflammation-associated hyporesponsiveness to ESA. The discovery of new therapeutic approaches towards the treatment of anemia in CKD patients has become highly awaited. The treatment of anemia with erythropoietin (EPO) was associated with great benefits for some patients but not all.

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“…PHD2 knockdown did not affect the formation of MBL oligomers further supporting that prolyl hydroxylation of collagen-like domain of MBL as well as oligomerization of MBL is CP4H dependent and PHD independent. Finally, we used several PHD inhibitors which are currently undergoing phase III clinical trials 21,34 (roxadustat, vadadustat and molidustat) at concentrations which stabilize HIF1α in a robust manner. Crystallography studies by Yeh et al 35 showed that the mechanism of action for these drugs was via chelation to the active site iron.…”

Section: Discussionmentioning

confidence: 99%

Mannose Binding Lectin Is Hydroxylated by Collagen Prolyl-4-hydroxylase and Inhibited by Some PHD Inhibitors

et al. 2020

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Background Mannose binding lectin (MBL) is an important component of innate immune defence. MBL undergoes oligomerization to generate high molecular weight (HMW) forms which act as pattern recognition molecules to detect and opsonize various microorganisms. Several post-translational modifications including prolyl hydroxylation are known to affect the oligomerization of MBL. Yet, the enzyme(s) which hydroxylate proline in the collagen-like domain residues have not been identified and the significance of prolyl hydroxylation is incompletely understood. Methods To investigate post-translational modifications of MBL, we stably expressed Myc-DDK tagged MBL in HEK293S cells. We used pharmacological and genetic inhibition of 2-oxoglutarate dependent dioxygenases (2OGDD) to identify the enzyme required for prolyl hydroxylation of MBL. We performed mass spectrometry to determine the effects of various inhibitors on MBL modifications. Results Secretion of HMW MBL was impaired by inhibitors of the superfamily of 2OGDD, and was dependent on prolyl-4-hydroxylase subunit alpha 1. Roxadustat and vadadustat, but not molidustat, led to significant suppression of hydroxylation and secretion of HMW forms of MBL. Conclusions These data suggest that prolyl hydroxylation in the collagen-like domain of MBL is mediated by collagen prolyl 4 hydroxylase. Reduced MBL activity is likely to be an off-target effect of some, but not all PHD inhibitors. There may be advantages in selective PHD inhibitors that would not interfere with MBL production.

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Molidustat for the treatment of renal anaemia in patients with dialysis-dependent chronic kidney disease: design and rationale of three phase III studies

Cited by 19 publications

References 36 publications

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF–PH inhibitor for the treatment of renal anaemia

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF–PH inhibitor for the treatment of renal anaemia

The Influence of Inflammation on Anemia in CKD Patients

Mannose Binding Lectin Is Hydroxylated by Collagen Prolyl-4-hydroxylase and Inhibited by Some PHD Inhibitors

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