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

Abstract

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.

Drug‐drug interaction of atazanavir on UGT1A1‐mediated glucuronidation of molidustat in human

“…Comparable effects were observed for C max of molidustat (twofold increase), although only a mild reduction in systemic exposure to the glucuronide M1 was found (−15%). The effects of UGT inhibition on EPO turnover were much less pronounced than on the PK of molidustat, confirming the exposure‐response relationship observed in other studies 2,48 . Molidustat administered concomitantly with atazanavir was well tolerated.…”

“…The effects of UGT inhibition on EPO turnover were much less pronounced than on the PK of molidustat, confirming the exposure-response relationship observed in other studies. 2,48 Molidustat administered concomitantly with atazanavir was well tolerated. Given that molidustat dosing will follow a haemoglobin-guided individual dose titration, molidustat may be administered together with atazanavir.…”

Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF‐PH inhibitors

“…Physicians should understand the pharmacologic profiles (Table 1) of each HIF-PHI based on clinical trial data, [8][9][10][11][12][13][14] initiate HIF-PHI at an appropriate dose, and adjust HIF-PHI to achieve the Hb target stipulated in the guidelines of each country.…”

Effect of iron supplementation in patients with heart failure and iron deficiency: A systematic review and meta-analysis

“…Moreover, hypoxia-inducible factor-prolyl hydroxylase (HIF-PF) inhibitors have emerged as beneficial therapeutic agents for the treatment of renal anemia. Lentini S. et al showed the potential benefit of combined intake of iron supplements and HIF-PF inhibitors in patients with renal anemia [38] . Therefore, iron therapy along with other agents like HIF-PF inhibitors in iron-deficient HF patients with concomitant renal anemia or CKD may prove to be helpful.…”