Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout

Bishoy Kamel; Ahmad Y Abuhelwa; David Foster; Janna K Duong; Garry G Graham; Kenneth M Williams; Kevin D Pile; Richard O Day

doi:10.1111/bcp.15462

Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout

Br J Clin Pharmacol. 2022 Dec;88(12):5359-5368. doi: 10.1111/bcp.15462. Epub 2022 Jul 28.

Authors

Bishoy Kamel^{1

2

3

4}, Ahmad Y Abuhelwa^{5

6

7}, David Foster⁷, Janna K Duong⁸, Garry G Graham^{3

4}, Kenneth M Williams^{3

4}, Kevin D Pile^{9

10}, Richard O Day^{2

3}

Affiliations

¹ The George Institute for Global Health, Sydney, New South Wales, Australia.
² St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia.
³ Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital and University of New South Wales Sydney, New South Wales, Australia.
⁴ School of Medical Sciences, University of New South Wales Sydney, New South Wales, Australia.
⁵ College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
⁶ College of Medicine and Public Health, Flinders University, South Australia, Australia.
⁷ Australian Centre for Precision Health, Clinical and Health Sciences, University of South Australia, South Australia, Australia.
⁸ Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
⁹ Department of Medicine, Western Sydney University, New South Wales, Australia.
¹⁰ Department of Rheumatology, Campbelltown Hospital, Sydney, New South Wales, Australia.

Abstract

Aims: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug.

Methods: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model.

Results: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h^-1 , 32.8 l, 19.4 l, 3.6 h^-1 and 1.25 l h^-1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F.

Conclusions: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.

Keywords: clinical pharmacology; febuxostat; gout; hyperuricaemia; population pharmacokinetics; rheumatology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biological Availability
Febuxostat*
Gout* / drug therapy
Healthy Volunteers
Humans
Models, Biological

Substances

Febuxostat