Relationship between the Dose of Urate Lowering Therapies and Serum Uric Acid in Healthy Volunteers and Gout Patients: A Model Based Meta-Analysis (MBMA)
Yi Sun1, Liang Li1, Scott Marshall2*, Wei Lu1, Rujia Xie3*
1Peking University/Pfizer PMx Education center, 2Pfizer, Sandwich, UK, 3Pfizer (China) Research and Development Center, China,*Employees and shareholders of Pfizer Inc
Objectives: The purpose of this model-based meta-analysis was to characterize the steady-state dose-response (DR) relationship for the reduction of sUA across compounds in different mechanism of action (Xanthine Oxidase Inhibitors (XOi), Urate transport (URAT1) inhibitors, and Purine nucleoside phosphorylase (PNP) inhibitor).
Methods: A comprehensive literature search was conducted for PNP inhibitor, XOi and URAT1 inhibitors administered alone or in combination to healthy volunteers (HV) or gout patients. Serum uric acid (sUA) data were extracted and the dose response relationship for sUA change from baseline (CFB) was analyzed using NONMEM v7.2. Summary level data of sUA CFB was available on 39 trials (153 unique arms) presenting 6946 gout patients and 395 healthy volunteers. The potential covariates (baseline sUA, population, race) were explored. Inter-trial and additive residual variability were estimated and the latter was weighted by sample size. The correlation among repeated measurements was investigated.
Results: The dose-response relationship for sUA CFB was adequately described by an Emax model and a floor effect was introduced that was set to 1mg/dL as the lowest boundary of sUA level. It was assumed that the compounds having the same mechanism of action had a common maximum effect (Emax) but different potency (ED50). The different effect between HV and patients could be explained by the differences of baseline. Emax for Chinese population having Febuxostat was significantly lower from other races. At baseline 9.2mg/dL, derived Emax for XOi was -7.12mg/dL (-6.34mg/dL for Chinese) and the ED50 of Allopurinol and Febuxostat were 320.5mg and 41.3mg, respectively. For URAT1 inhibitors, derived Emax was -6.84mg/dL and ED50s of Benzbromarone and Lesinurad were estimated to be 41.3mg and 492.7mg, respectively. Derived Emax of PNP inhibitor BCX4208 was -5.45mg/dL with ED50 of 68mg. The maximum effect of refractory population was about 66% of non-refractory population. The combination effect was less than additive among all the co-medication situations, suggesting it was less than the sum of their separate effect.
Conclusions: This model-based meta-analysis provided a broad overview and understanding of effect size of different classes of urate-lowering drugs in order to develop comparative product profiles, aid translation between different populations and predict potential combination effects in the drug development of novel Urate lowering agents.
