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Clinical Pharmacokinetics
Erschienen in:

11.09.2024 | Original Research Article

Integrated Population Pharmacokinetics of Daprodustat in Patients with Chronic Kidney Disease with Anemia

verfasst von: Kelly M. Mahar, Shuying Yang, Emir Mesic, Teun M. Post, Sebastiaan C. Goulooze

Erschienen in: Clinical Pharmacokinetics | Ausgabe 9/2024

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Abstract

Background and Objective

Daprodustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in the USA for treatment of anemia owing to chronic kidney disease (CKD) in dialysis-dependent adults and in Japan for treatment of CKD in dialysis- and non-dialysis dependent adults. This analysis characterized the population pharmacokinetics (PopPK) of daprodustat in adults with CKD and evaluated the influence of intrinsic and extrinsic factors.

Methods

This PopPK analysis included data from one phase 2B and four phase 3 studies comprising 707 CKD subjects dose titrated to prespecified target hemoglobin levels with daprodustat doses ranging from 1 to 24 mg once daily and 2 to 48 mg given three times a week (TIW). Model development leveraged a previous phase 1/2 PopPK model. Stepwise covariate analysis included 20 extrinsic and intrinsic factors. Model evaluation used standard goodness-of-fit and visual predictive checks.

Results

Daprodustat PopPK was adequately characterized using a three-compartment distribution model with first-order elimination. The absorption phase was described using five transit compartments. Oral clearance and volume of distribution was 24.6 L/h and 26.9 L, respectively. Body weight dependence (with fixed allometric coefficients) of clearance and volume terms was a statistically significant covariate. Concomitant use of clopidogrel (moderate CYP2C8 inhibitor) decreased oral clearance, resulting in higher area under the plasma concentration-time curve (AUC) ratio of 1.59 (90% CI: 1.39–1.82), subjects’ dialysis status (non-dialysis versus dialysis) had an effect on absorption, with Cmax ratio of 1.19 (90% CI: 1.09–1.30). None of the other investigated intrinsic or extrinsic covariates, including concomitant administration with phosphate binders, oral iron and acid reducing agents resulted in a significant change in daprodustat systemic exposure.

Conclusion

The PopPK of daprodustat in the CKD population with anemia was adequately characterized. Allometrically-scaled body weight on clearance and volume, dialysis status on absorption and clopidogrel on clearance were statistically significant covariates.
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Literatur
1.
2.
Yap DYH, McMahon LP, Hao C. Recommendations by the Asian pacific society of nephrology (apsn) on the appropriate use of hif-ph inhibitors. Nephrology. 2020;26:105–18.CrossRefPubMed
3.
Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a potential new treatment for anemia in patients with CKD. Am J Kidney Dis. 2017;69(6):815–26.CrossRefPubMed
4.
Akizawa T, Nangaku M, Yonekawa T, Okuda N, Kawamatsu S, Onoue T, et al. Efficacy and safety of daprodustat compared with darbepoetin alfa in Japanese hemodialysis patients with anemia: a randomized, double-blind, phase 3 trial. Clin J Am Soc Nephrol. 2020;15(8):1155–65.CrossRefPubMedPubMedCentral
5.
Meadowcroft AM, Cizman B, Holdstock L, Biswas N, Johnson BM, Jones D, et al. Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis. Clin Kidney J. 2019;12(1):139–48.CrossRefPubMed
6.
Mahar KM, Johnson BM. Population Kinetic/Pharmacodynamic (K/PD) Analyses of Daprodustat (Prolyl Hydroxylase Inhibitor) in Non-dialysis (ND) and Hemodialysis-Dependent (HDD) Anemia Patients with Chronic Kidney Disease (CKD). J Pharmacokinet Pharmacodyn. 2018;45(1):T-041.
7.
Mactier R, Davies S, Dudley C, Harden P, Jones C, Kanagasundaram S, et al. Summary of the 5th edition of the renal association clinical practice guidelines (2009–2012). Nephron Clin Pract. 2011;118(1):c27–70.CrossRefPubMed
8.
Mahar K, Mills R, Goyal N. Population Pharmacokinetic (POP-PK) Analysis of Daprodustat (GSK1278863) and its Metabolites in Non-dialysis (ND) and Hemodialysis-Dependent (HDD) Anemia Patients with Chronic Kidney Disease (CKD). J Pharmacokinet Pharmacodyn. 2018;45(S64):T040.
9.
Post T, Mahar K, Ashman M. Population pharmacokinetic analysis of daprodustat in healthy volunteers (HV), global phase 2 and Japanese phase 3 studies in chronic kidney disease patients with anemia following once daily (QD) or 3 times weekly (TIW) administration. Clin Pharm Ther. 2021;109:PI-031.
10.
Mahar KM, Caltabiano S, Andrews S, Ramanjineyulu B, Chen L, Young G, et al. Clinical pharmacokinetics of daprodustat: results of an absorption, distribution, and excretion study with intravenous microtracer and concomitant oral doses for bioavailability determination. Clin Pharmacol Drug Dev. 2021;10(12):1419–31 (2021-12-01).CrossRefPubMedPubMedCentral
11.
Caltabiano S, Cizman B, Burns O, Mahar KM, Johnson BM, Ramanjineyulu B, et al. Effect of renal function and dialysis modality on daprodustat and predominant metabolite exposure. Clin Kidney J. 2019;12(5):693–701.CrossRefPubMedPubMedCentral
12.
Hara K, Takahashi N, Wakamatsu A, Caltabiano S. Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects. Drug Metab Pharmacokinet. 2015;30(6):410–8.CrossRefPubMed
13.
Johnson BM, Stier BA, Caltabiano S. Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863. Clin Pharmacol Drug Dev. 2014;3(2):109–17.CrossRefPubMed
14.
Mahar KM, Shaddinger BC, Ramanjineyulu B, Andrews S, Caltabiano S, Lindsay AC, Cobitz AR. Pharmacokinetics of daprodustat and metabolites in individuals with normal and impaired hepatic function. Clin Pharmacol Drug Dev. 2022;11(5):562–75.CrossRefPubMedPubMedCentral
15.
Caltabiano S, Mahar KM, Lister K, Tenero D, Ravindranath R, Cizman B, Cobitz AR. The drug interaction potential of daprodustat when coadministered with pioglitazone, rosuvastatin, or trimethoprim in healthy subjects. Pharmacol Res Perspect. 2018;6(2):1–9.CrossRef
16.
Van den Berg P, Post T, Ahsman Mea. Population dose-response analysis of hemoglobin data from global phase 2 and Japanese phase 3 studies with daprodustat in chronic kidney disease patients with anemia following once daily (QD) or 3 times weekly (TIW) administration. Clin Pharmacol Ther. 2021;109.
17.
Food and Drug Administration. Bioanalytic method validation guidance for industry. US Department of Health and Human Services; 2018.
18.
Yamada M, Osamura M, Ogura H, Onoue T, Wakamatsu A, Numachi Y, et al. A single-dose, open-label, randomized, two-way crossover study in healthy Japanese participants to evaluate the bioequivalence and the food effect on the pharmacokinetics of daprodustat. Clin Pharmacol Drug Dev. 2020;9(8):978–84.CrossRefPubMedPubMedCentral
19.
Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008;35(4):401–21.CrossRefPubMed
20.
Lehr T, Staab A, Tillmann C, Trommeshauser D, Raschig A, Schaefer HG, Kloft C. Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer’s disease. Br J Clin Pharmacol. 2007;64(1):36–48.CrossRefPubMedPubMedCentral
21.
Nguyen TH, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC, et al. Model evaluation of continuous data pharmacometric models: metrics and graphics. CPT Pharmacometrics Syst Pharmacol. 2017;6(2):87–109.CrossRefPubMedPubMedCentral
22.
23.
Beal S, Boeckmann L, Bauer R, Sheiner L. NONMEM User’s Guides. (1989–2009). 2009.
24.
Lindbom L, Pihlgren P, Jonsson N. PsN-Toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79(3):241–57 (2005/09/01/).CrossRefPubMed
25.
Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Programs Biomed. 2004;75(2):85–94 (2004/08/01/).CrossRefPubMed
26.
R Core Team. R: A language and environment for statistical computing. Vienna, Austria. 2020.
27.
Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol. 2008;4(8):1065–74.CrossRefPubMedPubMedCentral
28.
Bi YA, Jordan S, King-Ahmad A, West MA, Varma MVS. Mechanistic determinants of daprodustat drug-drug interactions and pharmacokinetics in hepatic dysfunction and chronic kidney disease: significance of OATP1B-CYP2C8 interplay. Clin Pharmacol Ther. 2024;115(6):1336–45.CrossRefPubMed
29.
Bruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Sheiner LB. A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinet Biopharm. 1996;24(2):153–72.CrossRefPubMed
30.
Gisleskog PO, Karlsson MO, Beal SL. Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn. 2002;29(5–6):473–505.CrossRefPubMed
31.
Chan Kwong AHP, Calvier EAM, Fabre D, Gattacceca F, Khier S. Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine. J Pharmacokinet Pharmacodyn. 2020;47(5):431–46.CrossRefPubMedPubMedCentral
Metadaten
Titel
Integrated Population Pharmacokinetics of Daprodustat in Patients with Chronic Kidney Disease with Anemia
verfasst von
Kelly M. Mahar
Shuying Yang
Emir Mesic
Teun M. Post
Sebastiaan C. Goulooze
Publikationsdatum
11.09.2024
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 9/2024
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-024-01417-9

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