Effect of renal function and dialysis modality on daprodustat and predominant metabolite exposure

Stephen Caltabiano, Borut Cizman, Olivia Burns, Kelly M Mahar, Brendan M Johnson, Bandi Ramanjineyulu, Gulyeter Serbest, Alexander R Cobitz, Stephen Caltabiano, Borut Cizman, Olivia Burns, Kelly M Mahar, Brendan M Johnson, Bandi Ramanjineyulu, Gulyeter Serbest, Alexander R Cobitz

Abstract

Background: Current therapies for anemia of chronic kidney disease (CKD) include administration of supplemental iron (intravenous and/or oral), blood transfusions and replacement of erythropoietin through the administration of recombinant human erythropoietin (rhEPO) and rhEPO analogs, each with limitations. Daprodustat is an orally active, small molecule hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently in Phase 3 clinical studies. As it is well appreciated that the kidney represents a major route of elimination of many drugs, and daprodustat will be administered to patients with advanced CKD as well as patients with end-stage kidney disease, it is important to characterize the pharmacokinetic profile in these patient populations to safely dose this potential new medicine.

Methods: The primary objective of these studies, conducted under two separate protocols and with identical assessments and procedures, was to characterize the steady-state pharmacokinetics of daprodustat and the six predominant metabolites (i.e. metabolites present in the highest concentration in circulation) in subjects with normal renal function, anemic non-dialysis (ND)-dependent CKD subjects (CKD Stage 3/4) and anemic subjects on either hemodialysis (HD) or peritoneal dialysis (PD). All enrolled subjects were administered daprodustat 5 mg once daily for 14 days (all except HD subjects) or 15 days (for HD subjects). Blood, urine and peritoneal dialysate were collected at various times for measurement of daprodustat, predominant metabolite, erythropoietin and hepcidin levels.

Results: The pharmacokinetic properties of steady-state daprodustat peak plasma concentration (Cmax), area under the plasma daprodustat concentration-time curve (AUC) and the time of Cmax (tmax) were comparable between all cohorts in this study. In addition, there was no clinically relevant difference in these properties in the HD subjects between a dialysis and ND day. For CKD Stage 3/4, HD (dialysis day) and PD subjects, the AUC of all daprodustat metabolites assessed was higher, while the C max was slightly higher than that in subjects with normal renal function. Over the course of the 14 or 15 days of daprodustat administration, hemoglobin levels were seen to be relatively stable in the subjects with normal renal function, CKD Stage 3/4 and PD subjects, while HD subjects had a decrease of 1.9 gm/dL. All renally impaired subjects appeared to have similar erythropoietin responses to daprodustat, with approximately a 3-fold increase in these levels. In subjects with minimal to no change in hemoglobin levels, hepcidin levels remained relatively stable. Daprodustat, administered 5 mg once daily for 14-15 days, was generally well tolerated with a safety profile consistent with this patient population.

Conclusion: These studies demonstrated no clinically meaningful change in the pharmacokinetic properties of daprodustat when administered to subjects with various degrees of renal impairment, while for CKD Stage 3/4, HD (dialysis day) and PD subjects, the C max and AUC of all daprodustat metabolites assessed were higher than in subjects with normal renal function. Administration of daprodustat in this study appeared to be generally safe and well tolerated.

Keywords: anemia; chronic kidney disease; pharmacokinetics; prolyl hydroxylase inhibitor.

© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

FIGURE 1
FIGURE 1
The effect of daprodustat on hemoglobin (Hgb) levels. Hemoglobin levels were measured at various times during the study. Bars represent arithmetic mean ± SD.
FIGURE 2
FIGURE 2
Plasma erythropoietin (EPO) levels following administration of daprodustat. The plasma levels of EPO were measured at various times post-dose of daprodustat. Each point represents the mean±SD.
FIGURE 3
FIGURE 3
Plasma hepcidin levels following administration of daprodustat. The plasma levels of hepcidin were measured at various times post-dose of daprodustat. Each point represents the mean±SD.

References

    1. Koury MJ. Abnormal erythropoiesis and the pathophysiology of chronic anemia. Blood Rev 2014; 28: 49–66
    1. Fishbane S, Pollack S, Feldman HI. et al. Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988–2004. Clin J Am Soc Nephrol 2009; 4: 57–61
    1. Gill KS, Muntner P, Lafayette RA. et al. Red blood cell transfusion use in patients with chronic kidney disease. Nephrol Dial Transplant 2013; 28: 1504–1515
    1. Gobe GC, Endre ZH, Johnson DW.. Administration of erythropoietin and its derivatives in renal disease: advantages, mechanisms and concerns. Drug Discov Today Ther Strateg 2007; 4: 79–84
    1. Agarwal R, Kusek JW, Pappas MK.. A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney Int 2015; 88: 905–914
    1. Alves VM, Martins PRJ, Soares S. et al. Alloimmunization screening after transfusion of red blood cells in a prospective study. Rev Bras Hematol Hemoter 2012; 34: 206–211
    1. Szczech LA, Barnhart HX, Inrig JK. et al. Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes. Kidney Int 2008; 74: 791–798
    1. Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 2013; 27: 41–53
    1. Schmid H, Jelkman W.. Investigational therapies for renal disease-induced anemia. Exp Opin Invest Drugs 2016; 25: 901–916
    1. Holdstock L, Cizman B, Meadowcroft AM. et al. Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants with chronic kidney disease. Clin Kidney J 2019; 12: 129--138
    1. Meadowcroft AM, Cizman B, Holdstock L. et al. Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis. Clin Kidney J 2019; 12: 139--148
    1. Johnson BM, Stier BA, Caltabiano S.. Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863. Clin Pharm Drug Dev 2013; 3: 109–117
    1. Haase VH. Therapeutic targeting of the HIF oxygen-sensing pathway: lessons learned from clinical studies. Exp Cell Res 2017; 356: 160–165
    1. Koury MJ, Haase VJ.. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol 2015; 11: 394–410
    1. Miners JO, Yang X, Knights KM. et al. The role of the kidney in drug elimination: transport, metabolism, and the impact of kidney disease on drug clearance. Clin Pharm Therap 2017; 102: 436
    1. FDA. Guidance for Industry (Draft): Pharmacokinetics in Patients with Impaired Renal Function—Study Design, Data Analysis, and Impact on Dosing and Labeling, 2010; (20 June 2018, date last accessed)
    1. EMA. European Medicines Agency’s Guidance on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Decreased Renal Function, 2014; (20 June 2018, date last accessed)
    1. Zhang Y, Zhang L, Abraham S. et al. Assessment of the impact of renal impairment on systemic exposure of new molecular entities. Clin Pharmacol Ther 2009; 85: 305–311
    1. Dreisbach AW, Lertora JJL.. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol 2008; 4: 1065–1074
    1. Balafa O, Halbesma N, Struijk DG. et al. Peritoneal albumin and protein losses do not predict outcome in peritoneal dialysis patients. Clin J Am Soc Nephrol 2011; 6: 561–566
    1. Chang GWM, Kam PCA.. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia 1999; 54: 42–50
    1. FDA. Safety Testing of Drug Metabolites: Guidance for Industry, 2016. (20 June 2018, date last accessed)
    1. Basu M, Malhotra AS, Pal K. et al. Erythropoietin levels in lowlanders and high-altitude natives at 3450 m. Aviat Space Environ Med 2007; 78: 963–967
    1. Brockmoller J, Kochling J, Weber W. et al. The pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in haemodialysis patients Br J Clin Pharmacol 1992; 34: 499–508
    1. Ashby DR, Gale DP, Busbridge M. et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int 2009; 75: 976–981
    1. Mastrogiannaki M, Matak P, Mathieu JRR. et al. Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. Haematologica 2012; 97: 827–834

Source: PubMed

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