Seonghae Yoon, Jae-Yong Chung, Kyung-Sang Yu, In-Jin Jang
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: Gout is a common inflammatory arthropathy caused by elevated serum uric acid (hyperuricemia), usually due to reduced excretion [1]. There are several categories of drug to lower serum uric acid level, including a xanthine oxidase inhibitor like allopurinol or febuxostat. The aims of this study were 1) to characterize the population pharmacokinetics(PK) of a newly developed xanthine oxidase inhibitor in healthy volunteers, 2) to find an appropriate pharmacodynamic(PD) model to explain the metabolic process of uric acid, and 3) finally, to recommend an optimal dose of the drug to treat hyperuricemia or gout patients.
Methods: A population PK/PD analysis was performed in 124 healthy volunteers who received single or multiple doses of the drug (10 – 600mg, single dose; 100 – 800mg, multiple doses). For pharmacodynamic analysis, the concentrations of uric acid, xanthine and hypoxanthine of serum and urine were determined. A total of 3,116 drug concentration measurements and 2,590 measurements of PD markers were analyzed using the nonlinear mixed effect model (NONMEM V7.2) program.
Results: The population PK of the drug was well described by an oral, two-compartment model with first-order absorption and elimination from the central compartment. There was no significant covariate for clearance or volume of distribution. Uric acid formation at baseline was modeled using serum and urine compartments of 3 biomarkers based on known metabolic pathway of uric acid [2]. Indirect response model [3] was used to describe inhibition of xanthine oxidase that metabolizes hypoxanthine to xanthine, and xanthine to uric acid: PK parameters and parameters calculated in uric acid formation model at baseline[j1] were fixed in this model. To investigate the optimal dose of the drug in patient with gout or hyperuricemia, final PK/PD model was used simulate changes in uric acid levels after the drug administrations.
References:
[1] Neogi T. Clinical practice. Gout. The New England journal of medicine. 2011;364(5):443-52. doi:10.1056/NEJMcp1001124.
[2] Harzand A, Tamariz L, Hare JM. Uric acid, heart failure survival, and the impact of xanthine oxidase inhibition. Congest Heart Fail. 2012;18(3):179-82.
[3] Sharma A, Jusko WJ. Characteristics of indirect pharmacodynamic models and applications to clinical drug responses. British journal of clinical pharmacology. 1998;45(3):229-39.
Reference: PAGE 24 () Abstr 3500 [www.page-meeting.org/?abstract=3500]
Poster: Drug/Disease modeling - Other topics