A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis
Abstract Background Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-10-01
|
| Series: | BMC Nephrology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12882-019-1547-z |
| _version_ | 1818158764841238528 |
|---|---|
| author | Christine K. Bailey Stephen Caltabiano Alexander R. Cobitz Chun Huang Kelly M. Mahar Vickas V. Patel |
| author_facet | Christine K. Bailey Stephen Caltabiano Alexander R. Cobitz Chun Huang Kelly M. Mahar Vickas V. Patel |
| author_sort | Christine K. Bailey |
| collection | DOAJ |
| description | Abstract Background Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule. Methods 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days. Results Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population. Conclusions These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen. Trial registration ClinicalTrials.gov Identifier: NCT02689206; date registered: 02/11/2016. |
| first_indexed | 2024-12-11T15:35:17Z |
| format | Article |
| id | doaj.art-27bc2670a74349538c5d727bfabca1f7 |
| institution | Directory Open Access Journal |
| issn | 1471-2369 |
| language | English |
| last_indexed | 2024-12-11T15:35:17Z |
| publishDate | 2019-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Nephrology |
| spelling | doaj.art-27bc2670a74349538c5d727bfabca1f72022-12-22T00:59:57ZengBMCBMC Nephrology1471-23692019-10-0120111210.1186/s12882-019-1547-zA randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysisChristine K. Bailey0Stephen Caltabiano1Alexander R. Cobitz2Chun Huang3Kelly M. Mahar4Vickas V. Patel5R&D, Clinical Sciences, GlaxoSmithKlineR&D, GlaxoSmithKlineR&D, Clinical Sciences, GlaxoSmithKlineR&D, Clinical Statistics, GlaxoSmithKlineR&D, Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKlineR&D, Discovery Medicine, GlaxoSmithKlineAbstract Background Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule. Methods 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days. Results Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population. Conclusions These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen. Trial registration ClinicalTrials.gov Identifier: NCT02689206; date registered: 02/11/2016.http://link.springer.com/article/10.1186/s12882-019-1547-zAnemiaHemodialysisThree-times weekly (TIW)Dose responseBayesianEfficacy |
| spellingShingle | Christine K. Bailey Stephen Caltabiano Alexander R. Cobitz Chun Huang Kelly M. Mahar Vickas V. Patel A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis BMC Nephrology Anemia Hemodialysis Three-times weekly (TIW) Dose response Bayesian Efficacy |
| title | A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis |
| title_full | A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis |
| title_fullStr | A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis |
| title_full_unstemmed | A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis |
| title_short | A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis |
| title_sort | randomized 29 day dose ranging efficacy and safety study of daprodustat administered three times weekly in patients with anemia on hemodialysis |
| topic | Anemia Hemodialysis Three-times weekly (TIW) Dose response Bayesian Efficacy |
| url | http://link.springer.com/article/10.1186/s12882-019-1547-z |
| work_keys_str_mv | AT christinekbailey arandomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT stephencaltabiano arandomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT alexanderrcobitz arandomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT chunhuang arandomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT kellymmahar arandomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT vickasvpatel arandomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT christinekbailey randomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT stephencaltabiano randomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT alexanderrcobitz randomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT chunhuang randomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT kellymmahar randomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis AT vickasvpatel randomized29daydoserangingefficacyandsafetystudyofdaprodustatadministeredthreetimesweeklyinpatientswithanemiaonhemodialysis |