Dinko Rekić, Jacob Leander, Susanne Johansson, and Ulf Eriksson
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit Biotech Unit, AstraZeneca, Gothenburg, Sweden
Objectives: Febuxostat is a xanthine oxidase inhibitor indicated for gout and hyperuricemia. Several clinical studies are completed or ongoing to investigate the effect of xanthine oxidase inhibitors and other uric acid lowering drugs on renal function in chronic kidney disease [1]. Xanthine oxidase inhibitors including febuxostat are titrated to a serum uric acid target in gout and hyperuricemia. Medical value of adjusting the dose of febuxostat to achieve a target serum uric acid for chronic kidney disease is unknown. This work investigates potential clinically relevant covariates for febuxostat dosing to support a fixed dose regimen in the chronic kidney disease indication.
Methods: Febuxostat plasma concentrations from 145 male subjects were obtained from 2 phase-2 studies in hyperuricemic/gout patients and 1 study in healthy volunteers. Subjects were administered febuxostat doses ranging from 10 to 80 mg. The pharmacokinetics of febuxostat were analyzed using non-linear mixed-effects modeling as implemented in NONMEM 7.3.0 [2]. The dataset consisted of racially diverse subjects, 40% being Japanese, 10% of unknown Asian origin, 39% Caucasian and 10% Black. Most subjects (n=92, 63%) had normal CrCL (90 mL/min), while 52 subjects (36%) had mild renal impairment (CrCL >60-<90) at baseline. Mean (±SD) bodyweight (BW) differed between Asian (78±12 kg) and Caucasian subjects (98±16 kg). The effect of disease state, BW, and time-dependent Creatinine clearance (CrCL) on febuxostat pharmacokinetics was investigated using stepwise covariate modeling as implemented in PsN 4.4.8 [3].
Results: Asian race (Japanese or of unknown Asian origin) was the only covariate resulting in potentially clinically important increase in febuxostat AUC (1.63-fold, 90%CI: [1.48;1.79]) compared to Caucasians. Difference in BW between Asian and Caucasian subjects did not explain the difference in febuxostat exposure. Febuxostat pharmacokinetics were well described by a 2-compartment model. Absorption was modeled as sequential first and zero order process with lag-time. Additive residual error was estimated separately for the absorption- and for the disposition phase on the log-scale.
Conclusions: In this pooled analysis of 3 studies, we show that Japanese subjects, or Asians of unknown origin, have 1.63-fold higher febuxostat exposure than Caucasians, independent of bodyweight or other investigated covariates. These findings may be of importance when selecting starting febuxostat doses in Asian patients.
References:
[1] Pisano, Anna, et al. “Xanthine Oxidase Inhibitors for Improving Renal Function in Chronic Kidney Disease Patients: An Updated Systematic Review and Meta-Analysis.” International journal of molecular sciences 18.11 (2017): 2283.
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[3] Lindbom, Lars, Pontus Pihlgren, and Niclas Jonsson. “PsN-Toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM.” Computer methods and programs in biomedicine 79.3 (2005): 241-257.
Reference: PAGE 28 (2019) Abstr 9039 [www.page-meeting.org/?abstract=9039]
Poster: Drug/Disease Modelling - Other Topics