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The breakthrough in erythropoietin-stimulating agents in the 1990s improved the prognosis and treatment of complications in chronic kidney disease patients and renal anemia. Discovery of the novel molecular mechanisms for hypoxia-inducible factor (HIF) transcription factor under hypoxic conditions has led to the development of oral drugs, HIF-Prolyl Hydroxylase inhibitors (HIF-PHIs), that constantly activate erythropoietin by inhibiting prolyl hydroxylase. HIF-PHIs have gained rapid approval in Asian countries, including Japan, with six distinct types entering clinical application. This article provides a comprehensive review of the latest literature, with a particular focus on the effectiveness and safety of vadadustat. A phase 3, randomized, open-label, clinical trial (PRO2TECT) demonstrated that vadadustat had the prespecified non-inferiority for hematologic efficacy as compared with darbepoetin alfa in non-dialysis-dependent patients not previously treated with ESA. However, vadadustat did not show non-inferiority in major adverse cardiovascular events in the non-US/non-Europe patients. It may partly because of imbalances of the baseline eGFR level in those countries. In dialysis-dependent patients, a phase 3 clinical trial (INNO2VATE) showed vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and maintenance of hemoglobin levels. Adverse events including cancer, retinopathy, thrombosis, and vascular calcification should be evaluated in future clinical studies. [ABSTRACT FROM AUTHOR]

Background: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease (CKD). The purpose of this post-hoc analysis was to investigate the factors affecting the responsiveness to vadadustat in anemia patients with nondialysis-dependent (NDD) or hemodialysis-dependent (HDD) CKD in two Japanese phase 3 studies. Methods: Of 151 and 162 patients enrolled in NDD-CKD and HDD-CKD studies, 136 and 140 patients, respectively, were included and divided into subgroups for the analysis. To assess vadadustat responsiveness, the resistance index was defined as the mean body weight-adjusted dose of vadadustat (mg/kg) at weeks 20–24 divided by the mean hemoglobin (g/dL) at weeks 20–24. Multivariate analysis was performed to identify the variables affecting the resistance index. Results: Independent factors identified as determinants for better response to vadadustat were as follows: high baseline hemoglobin, low baseline eGFR, high week-20–24 ferritin, and CKD not caused by autoimmune disease/glomerulonephritis/vasculitis in NDD-CKD; and male sex, high baseline C-reactive protein, and low baseline erythropoiesis-stimulating agent resistance index (ERI) in HDD-CKD. Conclusions: In this post-hoc analysis, several factors were identified as affecting the response to vadadustat. These results may provide useful information leading to an appropriate dose modification for vadadustat. Clinical trial registration: NCT03329196 (MT-6548-J01) and NCT03439137 (MT-6548-J03). [ABSTRACT FROM AUTHOR]

Abstract Background Our case is the first report showing the development of hypoglycemia following the administration of vadadustat in a patient with chronic kidney disease being treated with mitiglinide and sitagliptin, possibly due to drug–drug interaction between vadadustat and sitagliptin under the administration of mitiglinide. Case presentation A 72-year-old man with type 2 diabetes mellitus had received sitagliptin 50 mg once daily and mitiglinide 10 mg three times daily over the last 3 years. He initiated vadadustat 300 mg once daily orally on day X owing to renal anemia (hemoglobin A1c: 7.4% and estimated glomerular filtration rate: 28.0 mL/min/1.73 m2). On day 23, he developed hypoglycemia with a blood glucose level of 67 mg/dL. The mean blood glucose level ± standard deviation was lower in the first 24 days of co-administration of vadadustat (before breakfast: 94 ± 14 mg/dL, before lunch: 109 ± 24 mg/dL, and before dinner: 126 ± 39 mg/dL) than in the last 2 weeks (before breakfast: 108 ± 14 mg/dL, before lunch: 122 ± 24 mg/dL, and before dinner: 158 ± 39 mg/dL). Considering the timing of the concomitant administration of vadadustat, hypoglycemia may have been caused by the drug–drug interaction between sitagliptin and vadadustat, and he discontinued treatment with vadadustat. The mean blood glucose levels improved two weeks after the discontinuation of vadadustat (before breakfast: 121 ± 25 mg/dL, before lunch: 147 ± 38 mg/dL, and before dinner: 161 ± 36 mg/dL). The drug interaction probability scale was classified as "Probable" (5 points). Conclusions Hypoglycemia was observed when sitagliptin, mitiglinide, and vadadustat were concomitantly administered, which may have resulted in a drug–drug interaction between vadadustat and sitagliptin via OAT3 inhibition in the renal tubules.

Background: Our case is the first report showing the development of hypoglycemia following the administration of vadadustat in a patient with chronic kidney disease being treated with mitiglinide and sitagliptin, possibly due to drug–drug interaction between vadadustat and sitagliptin under the administration of mitiglinide. Case presentation: A 72-year-old man with type 2 diabetes mellitus had received sitagliptin 50 mg once daily and mitiglinide 10 mg three times daily over the last 3 years. He initiated vadadustat 300 mg once daily orally on day X owing to renal anemia (hemoglobin A1c: 7.4% and estimated glomerular filtration rate: 28.0 mL/min/1.73 m2). On day 23, he developed hypoglycemia with a blood glucose level of 67 mg/dL. The mean blood glucose level ± standard deviation was lower in the first 24 days of co-administration of vadadustat (before breakfast: 94 ± 14 mg/dL, before lunch: 109 ± 24 mg/dL, and before dinner: 126 ± 39 mg/dL) than in the last 2 weeks (before breakfast: 108 ± 14 mg/dL, before lunch: 122 ± 24 mg/dL, and before dinner: 158 ± 39 mg/dL). Considering the timing of the concomitant administration of vadadustat, hypoglycemia may have been caused by the drug–drug interaction between sitagliptin and vadadustat, and he discontinued treatment with vadadustat. The mean blood glucose levels improved two weeks after the discontinuation of vadadustat (before breakfast: 121 ± 25 mg/dL, before lunch: 147 ± 38 mg/dL, and before dinner: 161 ± 36 mg/dL). The drug interaction probability scale was classified as "Probable" (5 points). Conclusions: Hypoglycemia was observed when sitagliptin, mitiglinide, and vadadustat were concomitantly administered, which may have resulted in a drug–drug interaction between vadadustat and sitagliptin via OAT3 inhibition in the renal tubules. [ABSTRACT FROM AUTHOR]

Background Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. Methods We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24–36). Results Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n  = 152; darbepoetin alfa, n  = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was −0.10 g/dL (95% CI −0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. Conclusions In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa. [ABSTRACT FROM AUTHOR]

Abstract Background Rhabdomyolysis is a potentially life-threatening disease caused by melting or necrosis of skeletal muscle cells and leakage of muscle components into the bloodstream. It has been reported that the interaction of the HMG-CoA reductase inhibitor rosuvastatin with the renal anemia drug vadadustat increases the blood concentration of rosuvastatin in vitro. In this study, we report a case of suspected rhabdomyolysis caused by the drug interaction of rosuvastatin and vadadustat in clinical practice. Case presentation A 62-year-old male with medical records of hypertension, myocardial infarction, chronic renal failure, renal anemia, dyslipidemia, and alcoholic liver disease. The patient had been diagnosed with chronic kidney disease (CKD) at the Department of Nephrology, and treated by outpatient care with renal support therapy for the past two years. On X-63 day, his prescription was rosuvastatin (10 mg/day) and a continuous erythrocyte-stimulating agent, epoetin beta pegol (genetical recombination, 100 μg). X-Day 0, blood tests revealed creatine phosphokinase (CPK) 298 U/L, serum creatinine (SCr) 5.26 mg/dL, and hemoglobin (Hb) 9.5 g/dL; thus, the prescription was changed from epoetin beta pegol 100 μg to vadadustat 300 mg/day. On X + day 80, a prescription for a diuretic (azosemide 15 mg/day) was added for swelling of the lower extremities. On X + day 105, we found CPK 16,509 U/L, SCr 6.51 mg/dL, and Hb 9.5 g/dL. The patient was diagnosed as rhabdomyolysis and hospitalized. After hospitalization, rosuvastatin and vadadustat were discontinued and we administered intravenous fluids. Thereafter, CPK and SCr values of the patient improved. On X + day 122, CPK improved to 29 U/L, SCr to 2.6 mg/dL, and Hb to 9.6 g/dL, and he was discharged on X + day 124. At discharge, rosuvastatin 2.5 mg/day was resumed. A blood test on X + day 133 showed CPK 144 U/L and SCr 4.2 mg/dL. Conclusion We experienced a case of rhabdomyolysis caused by drug interactions between rosuvastatin and vadadustat.

Background: Rhabdomyolysis is a potentially life-threatening disease caused by melting or necrosis of skeletal muscle cells and leakage of muscle components into the bloodstream. It has been reported that the interaction of the HMG-CoA reductase inhibitor rosuvastatin with the renal anemia drug vadadustat increases the blood concentration of rosuvastatin in vitro. In this study, we report a case of suspected rhabdomyolysis caused by the drug interaction of rosuvastatin and vadadustat in clinical practice. Case presentation: A 62-year-old male with medical records of hypertension, myocardial infarction, chronic renal failure, renal anemia, dyslipidemia, and alcoholic liver disease. The patient had been diagnosed with chronic kidney disease (CKD) at the Department of Nephrology, and treated by outpatient care with renal support therapy for the past two years. On X-63 day, his prescription was rosuvastatin (10 mg/day) and a continuous erythrocyte-stimulating agent, epoetin beta pegol (genetical recombination, 100 μg). X-Day 0, blood tests revealed creatine phosphokinase (CPK) 298 U/L, serum creatinine (SCr) 5.26 mg/dL, and hemoglobin (Hb) 9.5 g/dL; thus, the prescription was changed from epoetin beta pegol 100 μg to vadadustat 300 mg/day. On X + day 80, a prescription for a diuretic (azosemide 15 mg/day) was added for swelling of the lower extremities. On X + day 105, we found CPK 16,509 U/L, SCr 6.51 mg/dL, and Hb 9.5 g/dL. The patient was diagnosed as rhabdomyolysis and hospitalized. After hospitalization, rosuvastatin and vadadustat were discontinued and we administered intravenous fluids. Thereafter, CPK and SCr values of the patient improved. On X + day 122, CPK improved to 29 U/L, SCr to 2.6 mg/dL, and Hb to 9.6 g/dL, and he was discharged on X + day 124. At discharge, rosuvastatin 2.5 mg/day was resumed. A blood test on X + day 133 showed CPK 144 U/L and SCr 4.2 mg/dL. Conclusion: We experienced a case of rhabdomyolysis caused by drug interactions between rosuvastatin and vadadustat. [ABSTRACT FROM AUTHOR]

Objective: As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD). Methods: Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs). Results: Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) − 0.19, [95% confidence interval (CI), − 0.21 to − 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = − 0.06, [95% CI, − 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20–36 weeks (MD = 0.02, [95% CI, − 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively). Conclusion: Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value. [ABSTRACT FROM AUTHOR]

Vadadustat is an investigational oral hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitor to treat anemia due to chronic kidney disease (CKD). Some studies suggest that HIF activation promotes tumorigenesis by activating angiogenesis downstream of vascular endothelial growth factor, while other studies suggest that elevated HIF activity may produce an antitumor phenotype. To evaluate the potential carcinogenicity of vadadustat in mice and rats, we dosed CByB6F1/Tg.rasH2 hemizygous (transgenic) mice orally by gavage with 5 to 50 mg/kg/d of vadadustat for 6 months and dosed Sprague-Dawley rats orally by gavage with 2 to 20 mg/kg/d for approximately 85 weeks. Doses were selected based on the maximally tolerated dose established for each species in previous studies. The tumors that were identified in the studies were not considered to be treatment-related for statistical reasons or within the historical control range. There was no carcinogenic effect attributed to vadadustat in mice or rats. [ABSTRACT FROM AUTHOR]

Introduction: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production, with fewer excursions of hemoglobin concentrations above the target range.Methods: To comprehensively analyze the safety profile of vadadustat in patients with CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n=7373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm.Results: In patients randomized to vadadustat vs darbepoetin alfa, rates of TEAEs (88.9% vs 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events.Discussion/conclusion: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa. [ABSTRACT FROM AUTHOR]

Rationale & Objective: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative erythropoiesis-stimulating agents (ESA) for the treatment of anemia in the setting of CKD. To investigate the efficacy and safety of conversion from long-acting erythropoiesis-stimulating agent (ESA) methoxy polyethylene glycol-epoetin beta (MPG-EPO) to the oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) vadadustat 3-times-weekly versus maintenance on MPG-EPO., Study Design: Phase 3b, open-label, noninferiority trial., Setting & Participants: Multicenter study in United States; 456 patients adults with anemia and dialysis-dependent chronic kidney disease., Intervention: Participants were randomized 1:1:1 either to vadadustat (starting dose: 600 mg thrice weekly), vadadustat (starting dose: 900 mg thrice weekly), or MPG-EPO, for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination., Outcomes: Primary and secondary efficacy endpoints were the mean change in hemoglobin from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75 g/dL for the difference in mean change in hemoglobin from baseline. Other efficacy endpoints were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). Primary safety endpoints were any treatment-emergent and serious adverse events (AEs)., Results: After combining the vadadustat groups (600 mg and 900 mg thrice weekly, n=304), vadadustat was noninferior to MPG-EPO (n=152) for both primary (least squares mean treatment difference, -0.33; 95% CI, -0.53 to -0.13) and secondary efficacy endpoints (-0.33; -0.56 to -0.09). Mean hemoglobin concentrations were stable for all groups, except for an initial slight decline in the vadadustat 600 mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups., Limitations: Potential errors in attribution of AEs as drug related., Conclusions: Three-times-weekly vadadustat was noninferior to MPG-EPO on their effect on hemoglobin levels without detectable differences in AEs., (Copyright © 2024. Published by Elsevier Inc.)

Vadadustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open‐label, single‐arm study evaluated the efficacy and safety of vadadustat in 24 Japanese patients with CKD‐associated anemia on hemodialysis who were not receiving erythropoiesis‐stimulating agents (ESAs). Patients received vadadustat for 24 weeks; the starting dose was 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 10.0–12.0 g/dL. The least squares mean of average Hb at Weeks 20 and 24 (95% confidence interval) was 10.75 g/dL (10.35, 11.14). The most common adverse event was shunt stenosis (25.0%). Adverse drug reactions (diarrhea and vomiting) occurred in two patients (8.3%) and the severity was mild. Vadadustat increased and maintained Hb levels within the target range and was generally well‐tolerated in Japanese patients with anemia on hemodialysis not receiving ESAs. [ABSTRACT FROM AUTHOR]

Performance‐enhancing substances and methods have become a serious problem in competitive sports. The hypoxia‐inducible factor (HIF) stabilizers can enhance the organism's capacity for molecular oxygen transport and are likely to be abused as performance‐enhancing agents in sports. This paper describes the metabolic conversion of the popular hypoxia inducible factor‐prolyl hydroxylase (HIF‐PH) inhibitors, namely, daprodustat, desidustat, and vadadustat using equine liver microsomes, determined on a QExactive high‐resolution mass spectrometer. During this study, a total of 10 metabolites for daprodustat (all are Phase I), 10 metabolites for desidustat (five each for Phase I and Phase II), and 15 metabolites for vadadustat (six for Phase I and nine for Phase II) were detected. The important findings of the current research are as follows: (1) All the three HIF‐PH inhibitor drug candidates are prone to oxidation, which results in corresponding hydroxylated metabolites; (2) in desidustat, hydrolysis and dissociation of oxime linkage also observed; (3) the glucuronic acid conjugate (except daprodustat) of the parent drugs as well as the monohydroxylated analogs were observed; (4) sulfonic acid conjugated metabolites were observed only for vadadustat. [ABSTRACT FROM AUTHOR]

Background: Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia. Methods: PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach. Results: Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included (n = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; p < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; p < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: −54.95 to −18.30; p < 0.001) and ferritin (MD −56.24; 95% CI: −77.37 to −35.11; p < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; p < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke. Conclusion: Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events. [ABSTRACT FROM AUTHOR]

Background: Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia.Methods: PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach.Results: Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included (n = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; p < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; p < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: −54.95 to −18.30; p < 0.001) and ferritin (MD −56.24; 95% CI: −77.37 to −35.11; p < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; p < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke.Conclusion: Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.

Background Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. Methods Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0–23), maintenance (Weeks 24–52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24–36). Results A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. Conclusions The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population. [ABSTRACT FROM AUTHOR]

Vadadustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open‐label, 24‐week single‐arm study evaluated the efficacy and safety of vadadustat in 42 Japanese CKD patients with anemia undergoing peritoneal dialysis. Patients received oral vadadustat for 24 weeks, initiated at 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 11.0‐13.0 g/dL. Least squares mean of average Hb at weeks 20 and 24 was 11.35 g/dL, which was within the target range. The most frequent adverse events were catheter site infections (23.8%), which were not related to vadadustat treatment. Vadadustat was generally well tolerated and effective in controlling Hb levels within the target range, indicating the usefulness of vadadustat for treating anemia in Japanese CKD patients undergoing peritoneal dialysis. [ABSTRACT FROM AUTHOR]

Background Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. Methods The efficacy and safety of vadadustat, compared with darbepoetin alfa, was determined in a Phase 3 double-blind study in Japanese anemic patients on hemodialysis. Patients receiving erythropoiesis-stimulating agents (ESAs) were randomized and switched to either vadadustat or darbepoetin alfa for 52 weeks. Doses were adjusted to maintain a hemoglobin (Hb) level of 10.0–12.0 g/dL. The primary endpoint was average Hb level at Weeks 20 and 24. Results Of the 323 randomized patients, 120 and 135 completed the 52-week treatment period in the vadadustat and darbepoetin alfa groups, respectively. The average Hb levels at Weeks 20 and 24 [least square mean (LSM) and 95% confidence interval (CI)] were 10.61 (10.45–10.76) and 10.65 (10.50–10.80) g/dL in the vadadustat and darbepoetin alfa groups, respectively, demonstrating vadadustat's noninferiority to darbepoetin alfa (difference: −0.05 g/dL; 95% CI −0.26 to 0.17). In both groups, the mean Hb levels were maintained within the target range for 52 weeks. Furthermore, irrespective of patient backgrounds, the LSMs of Hb at Week 52 were within the target range. The most common adverse events were nasopharyngitis, diarrhea and shunt stenosis, which occurred at similar frequencies in both groups. No new safety concerns were identified. Conclusions Vadadustat was as well-tolerated and effective as darbepoetin alfa in maintaining Hb levels within the target range. The findings suggest that vadadustat can be an alternative to ESA in the management of anemia in Japanese hemodialysis patients receiving ESA (ClinicalTrials.gov, NCT03439137). [ABSTRACT FROM AUTHOR]

Vadadustat is a hypoxia‐inducible factor prolyl hydroxylase inhibitor in development for the treatment of anemia of chronic kidney disease. This phase 1, open‐label, parallel‐group, single‐dose study evaluated the pharmacokinetics of 450‐mg vadadustat in adults with moderate hepatic impairment (Child‐Pugh class B) vs those with normal hepatic function. Primary end points were area under the plasma concentration–time curve (AUC) from dosing to last concentration and to infinity, as well as maximum concentration (Cmax); additional pharmacokinetic parameters included time to Cmax (Tmax) and half‐life. Safety and tolerability were also assessed. All enrolled participants (n = 16) completed the study. Demographics were similar in both groups (overall, 100% White; 62.5% female; mean age, 59.2 years). Vadadustat plasma exposure was higher in the moderate hepatic impairment group, whereas maximum concentration was similar between groups. Point estimates of the hepatic impairment : normal geometric mean ratios (90% confidence interval) for AUC from dosing to last concentration, AUC from dosing to infinity, and Cmax were 1.05 (0.82‐1.35), 1.06 (0.82‐1.36), and 1.02 (0.79‐1.32), respectively. Mean elimination half‐life was 5.8 and 7.8 hours in the normal and hepatic impairment groups, respectively. Treatment‐emergent adverse events were mostly mild in severity, and vadadustat was generally well tolerated. In conclusion, moderate hepatic impairment did not significantly impact vadadustat systemic exposure, and mild hepatic impairment is unlikely to alter vadadustat exposure. [ABSTRACT FROM AUTHOR]

What is known and objective: Previous studies based on small‐sample clinical data proved that short‐term use of hypoxia‐inducible factor prolyl hydroxylase (HIF‐PHD) inhibitors increased haemoglobin levels in anaemic patients with chronic kidney disease (CKD). However, these studies reached conflicting conclusions on iron parameters and adverse event profiles. Our meta‐analysis aimed to evaluate the long‐term efficacy and safety of HIF‐PHD inhibitors in renal anaemia. Methods: Randomized controlled trials comparing treatment with HIF‐PHD inhibitors versus placebo or erythropoiesis‐stimulating agents (ESAs) were thoroughly searched in the PubMed, Embase, Cochrane Library and international clinical trial registries. Meta‐analysis was performed on main outcomes with random effects models. Results and discussion: A total of 30 studies comprising 13,146 patients were included. The HIF‐PHD inhibitors used included roxadustat, daprodustat, vadadustat, molidustat, desidustat and enarodustat. HIF‐PHD inhibitors significantly increased haemoglobin levels in comparison with placebo [weighted mean difference (WMD) 1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to 0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding capacity and transferrin levels were increased in the HIF‐PHD inhibitor group versus those in placebo or ESAs group. Additionally, HIF‐PHD inhibitors medication was associated with cholesterol‐lowering effects. As for safety, the risk of serious adverse events in the HIF‐PHD inhibitor group was increased in comparison with placebo group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group (RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32, 1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76). Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65), headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63). What is new and conclusion: HIF‐PHD inhibitors treatment effectively increased haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and they were well tolerated for long‐term use. In order to avoid unfavourable effects of excessive iron consumption, it was appropriate to administer HIF‐PHD inhibitors in combination with iron supplements for long‐term treatment. [ABSTRACT FROM AUTHOR]

The review analyzes the potential advantages and problems associated with using HIF prolyl hydroxylase inhibitors as a treatment for COVID-19. HIF prolyl hydroxylase inhibitors are known to boost endogenous erythropoietin (Epo) and activate erythropoiesis by stabilizing and activating the hypoxia inducible factor (HIF). Recombinant Epo treatment has anti-inflammatory and healing properties, and thus, very likely, will be beneficial for moderate to severe cases of COVID-19. However, HIF PHD inhibition may have a significantly broader effect, in addition to stimulating the endogenous Epo production. The analysis of HIF target genes reveals that some HIF-targets, such as furin, could play a negative role with respect to viral entry. On the other hand, HIF prolyl hydroxylase inhibitors counteract ferroptosis, the process recently implicated in vessel damage during the later stages of COVID-19. Therefore, HIF prolyl hydroxylase inhibitors may serve as a promising treatment of COVID-19 complications, but they are unlikely to aid in the prevention of the initial stages of infection.

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome’s interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

Studies in the field of oxygen-dependent regulation of erythropoiesis provided new data on the pathogenesis of anemia associated with chronic kidney disease, which led to the development of therapeutic agents for treatment. A new class of agents for the treatment of anemia in chronic kidney disease are prolyl hydroxylase inhibitors, which stabilize hypoxia-inducible factor that is the key regulator of erythropoiesis and iron metabolism. Currently, drugs such as roxadustat (FG-4592), vadadustat (AKB-6548), daprodustat (GSK1278863) are undergoing phase III clinical trials, and molidustat (BAY 85-3934) — phase II.

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously. [ABSTRACT FROM AUTHOR]

Background Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease. Methods In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7–8) and end-of-trial (Weeks 15–16) and was analyzed using available data (no imputation). Results Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations—analyzed using available data—remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat. Conclusions Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis. [ABSTRACT FROM AUTHOR]

The therapeutic potential of mesenchymal stromal cells (MSCs) is largely attributed to their immunomodulatory properties, which can be further improved by hypoxia priming. In this study, we investigated the immunomodulatory properties of MSCs preconditioned with hypoxia-mimetic Vadadustat (AKB-6548, Akebia). Gene expression analysis of immunomodulatory factors was performed by real-time polymerase chain reaction (real-time PCR) on RNA isolated from six human bone-marrow derived MSCs populations preconditioned for 6 h with 40 μM Vadadustat compared to control MSCs. The effect of Vadadustat preconditioning on MSCs secretome was determined using Proteome Profiler and Luminex, while their immunomodulatory activity was assessed by mixed lymphocyte reaction (MLR) and Culturex transwell migration assays. Real-time PCR revealed that Vadadustat downregulated genes related to immune system: IL24, IL1B, CXCL8, PDCD1LG1, PDCD1LG2, HIF1A, CCL2 and IL6, and upregulated IL17RD, CCL28 and LEP. Vadadustat caused a marked decrease in the secretion of IL6 (by 51%), HGF (by 47%), CCL7 (MCP3) (by 42%) and CXCL8 (by 40%). Vadadustat potentiated the inhibitory effect of MSCs on the proliferation of alloactivated human peripheral blood mononuclear cells (PBMCs), and reduced monocytes-enriched PBMCs chemotaxis towards the MSCs secretome. Preconditioning with Vadadustat may constitute a valuable approach to improve the therapeutic properties of MSCs.

Rationale & Objective: In the PRO 2 TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO 2 TECT trials., Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial., Setting & Participants: A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD., Intervention: 1:1 randomization to receive vadadustat or darbepoetin alfa., Outcomes: The primary safety end point was the time to first MACE., Results: At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90 U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of ≥10 g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P  = 0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups., Limitations: Several analyses are exploratory., Conclusions: In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group., Funding: Akebia Therapeutics, Inc., Trial Registration: ClinicalTrials.gov identifier: NCT02680574., (© 2023 The Authors.)

Rationale & Objective: Prespecified analyses of the PRO 2 TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO 2 TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents., Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial., Setting and Participants: Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD., Intervention: Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa., Outcomes: The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis)., Results: In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m 2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m 2 and who may not have had access to dialysis., Limitations: Different regional treatment patterns of patients with NDD-CKD., Conclusions: The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths., (© 2023 The Authors.)

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome's interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions. [ABSTRACT FROM AUTHOR]

Anemia is common in CKD and increases the risk of developing heart disease. Although ESAs relieve the symptoms of anemia, they have adverse effects and do not reduce the adverse outcomes associated with anemia. This evaluation is of the phase 3 ASCEND clinical trials of the hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor daprodustat versus ESAs in subjects with CKD undergoing dialysis or not. Daprodustat was non-inferior to ESAs in increasing hemoglobin, and in the incidence of cardiovascular events and adverse effects. Daprodustat is effective in subjects who are hyporesponsive to ESAs, and this is one circumstance when daprodustat may be preferred to ESAs. However, to become a widely used medicine in subjects with CKD responsive to ESAs, daprodustat needs to be well tolerated, used by a high percentage of subjects over a long time, and be superior to ESAs in improving clinical outcomes. As this may not be the case, there is not a strong basis for recommending daprodustat over ESAs. The other 'dustats' (roxadustat, vadadustat) have also not been shown to be superior to the ESAs, and none have been approved by the FDA to date.

Background: Vadadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor, is a substance which carries a lifetime ban in both horse racing and equestrian competition. A comprehensive metabolic study of vadadustat in horses has not been previously reported., Objective: Metabolism and elimination profiles of vadadustat in equine plasma and urine were studied for the purpose of doping control., Methods: A nasoesophageal administration of vadadustat (3 g/day for 3 days) was conducted on three thoroughbred mares. Potential metabolites were comprehensively detected by differential analysis of full-scan mass spectral data obtained from both in vitro studies with liver homogenates and post-administration samples using liquid chromatography high-resolution mass spectrometry. The identities of metabolites were further substantiated by product ion scans. Quantification methods were developed and validated for the establishment of the excretion profiles of the total vadadustat (free and conjugates) in plasma and urine., Results: A total of 23 in vivo and 14 in vitro metabolites (12 in common) were identified after comprehensive analysis. We found that vadadustat was mainly excreted into urine as the parent drug together with some minor conjugated metabolites. The elimination profiles of total vadadustat in post-administration plasma and urine were successfully established by using quantification methods equipped with alkaline hydrolysis for cleavage of conjugates such as methylated vadadustat, vadadustat glucuronide, and vadadustat glucoside., Conclusion: Based on our study, for effective control of the misuse or abuse of vadadustat in horses, total vadadustat could successfully be detected for up to two weeks after administration in plasma and urine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production., Methods: To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm., Results: In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events., Discussion/conclusion: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa., (© 2022 The Author(s). Published by S. Karger AG, Basel.)