Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects

Hara, Katsutoshi; Takahashi, Naoki; Wakamatsu, Akira; Caltabiano, S

doi:10.1016/j.dmpk.2015.08.004

Cited by 38 publications

(34 citation statements)

References 12 publications

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Section: Pharmacokinetics (Pk)mentioning

confidence: 99%

“…Additionally, daprodustat decreased the concentration of ferritin at all doses, which signifies utilization of iron stores [15,16]. Surrogate markers of pharmacodynamic effects, including EPO, VEGF, and absolute reticulocyte counts, have also exhibited dose-ordered increases over a range of 10 to 100 mg in both Japanese and Caucasian ethnic populations [14].…”

Section: Pharmacodynamics (Pd)mentioning

confidence: 99%

“…Across the 10, 25, 50 and 100 mg doses, the mean terminal halflife (t 1/2 ) ranged from 1.1 to 2.3 hours and 0.9 to 1.9 hours, respectively [14]. Suggestively, higher exposure as determined by Cmax and AUCinf was observed in the Japanese group relative to the Caucasian group [14]. With regard to food, co-administration of a single dose of daprodustat with a high-fat/high calorie meal did not significantly change its plasma AUC; however, a mean reduction of 29% was observed for the Cmax (NCT01376232) [13].…”

Section: Pharmacokinetics (Pk)mentioning

confidence: 99%

“…In a phase I trial of daprodustat conducted in healthy volunteers, Japanese patients had a 1.3 to 1.5 fold higher plasma drug concentration [14]. This study sought to evaluate the Hb dose response and safety of daprodustat in Japanese participants [14,18].…”

Section: Phase II Therapeutic Trialsmentioning

confidence: 99%

“…Results from a study designed to characterize differences in PK/PD parameters between Japanese and Caucasian participants revealed rapid absorption of daprodustat with a median concentration peak time (t max ) between 1.3 to 2.5 hours and 1.0 to 2.0 hours in the Japanese group and Caucasian group, respectively (NCT02348372) [14]. Across the 10, 25, 50 and 100 mg doses, the mean terminal halflife (t 1/2 ) ranged from 1.1 to 2.3 hours and 0.9 to 1.9 hours, respectively [14].…”

Section: Pharmacokinetics (Pk)mentioning

confidence: 99%

See 4 more Smart Citations

An Emerging Treatment Alternative for Anemia in CKD Patients: A Review on Daprodustat

Becker¹,

Jj²

2017

J Kidney

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This review article informs the reader about daprodustat (GSK1278863), a novel oral therapeutic agent for the treatment of anemia currently in development by GlaxoSmithKline, inclusive of published and ongoing clinical trial information. Results from phase II studies have demonstrated a promising therapeutic alternative for chronic kidney disease (CKD) patients that may ultimately change future clinical practice.

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Section: Pharmacokinetics (Pk)mentioning

confidence: 99%

Section: Pharmacodynamics (Pd)mentioning

confidence: 99%

Section: Pharmacokinetics (Pk)mentioning

confidence: 99%

Section: Phase II Therapeutic Trialsmentioning

confidence: 99%

Section: Pharmacokinetics (Pk)mentioning

confidence: 99%

See 3 more Smart Citations

An Emerging Treatment Alternative for Anemia in CKD Patients: A Review on Daprodustat

Becker¹,

Jj²

2017

J Kidney

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Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study

Shaddinger

Mahar

Sprys

et al. 2023

Clinical Pharm in Drug Dev

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Daprodustat, an orally bioavailable hypoxia‐inducible factor–prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease. Part A of this 2‐part, randomized, double‐blind, single‐dose, cross‐over study (NCT04640311) compared pharmacokinetic properties of a single oral dose of daprodustat 4 mg tablets manufactured via twin‐screw wet granulation (process 1) to 2 sets of 4 mg tablets manufactured via high‐shear wet granulation (process 2), to assess the impact of different dissolution profiles on pharmacokinetics. Part B assessed the bioequivalence of daprodustat tablets manufactured via process 1 with tablets manufactured via process 2 at 5 different dose strengths (1, 2, 4, 6, and 8 mg). In part A, mean plasma concentrations of daprodustat were comparable over a 24‐hour period despite differences in manufacturing processes and dissolution profiles. In part B, the 90% confidence intervals of the ratios of the least squared means for area under the concentration‐time curve and maximum observed plasma concentration fell within the 0.8–1.25 bioequivalence range for all doses, except for maximum observed plasma concentration at 8 mg. A prespecified sensitivity analysis jointly assessing all doses showed bioequivalence for all doses tested. No new safety concerns for daprodustat were identified.

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Randomized Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Topical Daprodustat in Healthy Volunteers and in Patients With Diabetic Foot Ulcers

Olson

Mahar

Morgan

et al. 2019

Clinical Pharm in Drug Dev

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Daprodustat, a small‐molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia‐inducible factor (HIF), leading to increased transcription of HIF‐responsive genes. This randomized, placebo‐controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14‐day repeat‐dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness. Systemic absorption via topical application was limited across doses up to 1.0% at 100 mg/cm2 for 14 days. Systemic pharmacokinetics were quantifiable in a few samples from a few patients. Because only sporadic concentrations were observed versus pharmacokinetic profiles, pharmacokinetic parameters were not determined. Wound area, depth, and volume showed consistent but weak improvements in the treatment arm; however, the variability in response and small sample size of the standard‐of‐care and placebo arms limited the ability to assess trends in wound healing compared with the daprodustat arm. Overall, topically applied daprodustat was well tolerated, raised no safety concerns, and provided limited to nonquantifiable systemic exposures. The healing of DFUs will need to be evaluated in studies designed to test this hypothesis over a longer treatment duration.

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Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects

Cited by 38 publications

References 12 publications

An Emerging Treatment Alternative for Anemia in CKD Patients: A Review on Daprodustat

An Emerging Treatment Alternative for Anemia in CKD Patients: A Review on Daprodustat

Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study

Randomized Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Topical Daprodustat in Healthy Volunteers and in Patients With Diabetic Foot Ulcers

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