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

Autor: Kamel B; The George Institute for Global Health, Sydney, New South Wales, Australia.; St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia.; Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital and University of New South Wales Sydney, New South Wales, Australia.; School of Medical Sciences, University of New South Wales Sydney, New South Wales, Australia., Abuhelwa AY; College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.; College of Medicine and Public Health, Flinders University, South Australia, Australia.; Australian Centre for Precision Health, Clinical and Health Sciences, University of South Australia, South Australia, Australia., Foster D; Australian Centre for Precision Health, Clinical and Health Sciences, University of South Australia, South Australia, Australia., Duong JK; Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia., Graham GG; Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital and University of New South Wales Sydney, New South Wales, Australia.; School of Medical Sciences, University of New South Wales Sydney, New South Wales, Australia., Williams KM; Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital and University of New South Wales Sydney, New South Wales, Australia.; School of Medical Sciences, University of New South Wales Sydney, New South Wales, Australia., Pile KD; Department of Medicine, Western Sydney University, New South Wales, Australia.; Department of Rheumatology, Campbelltown Hospital, Sydney, New South Wales, Australia., Day RO; St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia.; Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital and University of New South Wales Sydney, New South Wales, Australia.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2022 Dec; Vol. 88 (12), pp. 5359-5368. Date of Electronic Publication: 2022 Jul 28.
DOI: 10.1111/bcp.15462
Abstrakt: 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.
(© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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