RESUMO
The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (2) and the URAT1 inhibitor probenecid (3), followed by structure-activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC50 = 35 nM; URAT1 IC50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.
Assuntos
Gota , Hiperuricemia , Transportadores de Ânions Orgânicos , Proteínas de Transporte de Cátions Orgânicos , Xantina Oxidase , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo , Hiperuricemia/tratamento farmacológico , Animais , Gota/tratamento farmacológico , Relação Estrutura-Atividade , Humanos , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Ratos , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Administração Oral , Ratos Sprague-Dawley , Masculino , Macaca fascicularis , Febuxostat/farmacologia , Febuxostat/farmacocinética , Febuxostat/uso terapêutico , Febuxostat/química , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Supressores da Gota/farmacocinética , Supressores da Gota/farmacologia , Supressores da Gota/uso terapêutico , Supressores da Gota/química , Supressores da Gota/síntese química , Disponibilidade Biológica , Probenecid/farmacologiaRESUMO
Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.
Assuntos
Supressores da Gota , Gota , Oxipurinol , Diálise Peritoneal , Ácido Úrico , Humanos , Ácido Úrico/sangue , Gota/tratamento farmacológico , Gota/sangue , Masculino , Oxipurinol/farmacocinética , Supressores da Gota/farmacocinética , Supressores da Gota/uso terapêutico , Pessoa de Meia-Idade , Feminino , Idoso , Alopurinol/uso terapêutico , Alopurinol/farmacocinética , Eliminação Renal , Meia-Vida , Soluções para Diálise/farmacocinéticaRESUMO
AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.