Jacob Leander, Joanna Parkinson, Susanne Johansson, Ulf Eriksson, Dinko Rekić
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Sweden
Objectives: Verinurad (also known as RDEA3170) is a novel URAT1 inhibitor currently in Phase II development for treatment of chronic kidney disease (CKD). Verinurad lowers serum uric acid (risk factor for CKD [1]), by inhibiting reabsorption of uric acid in proximal tubule [2]. Verinurad as mono therapy or combined with a xanthine oxidase inhibitor has been shown to lower serum uric acid in patients with recurrent gout and/or asymptomatic hyperuricemia [3][4][5][6].
In recent studies, verinurad has been administered as an oral extended release formulation that has higher bioavailability and no effect of food compared to the oral modified release formulation that was used in the Phase II studies in gout. In addition to difference in formulation, renal function and Asian origin has previously been identified to impact verinurad exposure [6][7].
The objective of this work was to integrate pharmacokinetic data from relevant verinurad studies and to build a fit-for-purpose population pharmacokinetic (popPK) model of verinurad capable of predicting exposure for the two formulations in different populations.
Methods: In total 12398 verinurad plasma concentration samples from 419 subjects (299 non-Asians and 120 Asians) were obtained from 12 studies (8 Phase I and 4 Phase II). Three of the studies included gout patients (n=144), one study included patients with albuminuria (n=27), one study was a renal impairment study (n=31), and 7 studies were done in healthy volunteers (n=217). The modified release formulation was used in 8 studies (n=316) while the extended release formulation was used in 4 studies (n=123). Renal function ranged from 12 to 138 mL/min in the pooled population. Subjects with at least one measurable PK concentration were included in the analysis.
Covariates included in the analysis were: renal function (estimated glomerular filtration rate (eGFR) using the CKD-EPI formula [9]), Asian origin, formulation, food status, body weight, and gout. The popPK model of verinurad was developed using non-linear mixed effect modelling as implemented in NONMEM 7.3.0 [10]. Covariates were investigated in a stepwise fashion as implemented in PsN 4.4.8 [11].
Results: The pharmacokinetics of verinurad was adequately described by two-compartmental linear disposition model. The absorption phase of verinurad required a complex absorption model with three parameters, of which formulation and food (for the modified release) was found to be highly significant covariates on the zero-order duration parameter D1. Additional covariates in the final model included eGFR, Asian origin, and body weight.
Simulations show that the typical Asian subject has a 1.45-fold higher AUC compared to a non-Asian subject after correcting for renal function and body weight. Subjects with moderate renal impairment (eGFR = 60 mL/min) were estimated to have 1.25-fold higher AUC compared with subjects with normal renal function (eGFR = 90 mL/min), while subjects with low body weight (60 kg) were estimated to have 1.47-fold higher exposure compared to those with high body weight (100 kg).
Conclusions: A population pharmacokinetic model was developed for verinurad, based on the wide range of data integrated from several studies (different patient populations and drug formulations). This allowed to simulate various dosing scenarios and was valuable to support dose selection during verinurad clinical development program.
References:
[1] R. Mohandas and R. J. Johnson, “Uric Acid Levels Increase Risk for New-Onset Kidney Disease,” J. Am. Soc. Nephrol., vol. 19, no. 12, pp. 2251–2253, 2008.
[2] I. A. Bobulescu and O. W. Moe, “Renal Transport of Uric Acid: Evolving Concepts and Uncertainties,” Adv Chronic Kidney Dis, vol. 19, no. 6, pp. 358–371, 2012.
[3] D. Fitz-Patrick et al., “Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials,” Mod. Rheumatol., pp. 1–11, 2018.
[4] R. Fleischmann et al., “Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with febuxostat in adults with gout: A phase IIa, Open-Label study,” RMD Open, vol. 4, no. 1, pp. 1–8, 2018.
[5] M. Shiramoto et al., “Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: A phase 2a, open-label study,” Rheumatol. (United Kingdom), vol. 57, no. 9, pp. 1602–1610, 2018.
[6] R. Fleischmann et al., “Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: A phase IIa, open-label study,” RMD Open, vol. 4, no. 1, pp. 1–9, 2018.
[7] W. B. Smith et al., “Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Verinurad, a Selective Uric Acid Reabsorption Inhibitor,” Clin. Drug Investig., vol. 38, no. 8, pp. 703–713, 2018.
[8] J. Hall et al., “Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy Japanese and non-Asian male subjects,” Drug Des. Devel. Ther., vol. 12, pp. 1799–1807, 2018.
[9] A. S. Levey et al., “A New Equation to Estimate Glomerular Filtration Rate,” vol. 150, no. 9, pp. 604–612, 2009.
[10] S. L. Beal and L. B. Sheiner, “NONMEM User’s Guides. (1989-2009).” Icon Development Solutions, Elliot City, MD, USA, 2009.
[11] L. Lindbom, J. Ribbing, and E. N. Jonsson, “Perl-speaks-NONMEM ( PsN )–— a Perl module for NONMEM related programming,” 2004.
Reference: PAGE 28 (2019) Abstr 8839 [www.page-meeting.org/?abstract=8839]
Poster: Drug/Disease Modelling - Other Topics