Acute kidney injury observed during phase 1 clinical trials of a novel xanthine oxidase/URAT1 dual inhibitor PF-06743649.
The objective of these clinical studies was to assess the safety and urate lowering activity of a novel urate transporter 1 (URAT1)/ xanthine oxidase (XO) inhibitor PF-06743649 in healthy subjects and gout patients. Escalating doses of PF-06743649 or placebo were given to healthy young subjects, healthy elderly subjects and gout patients. Serum uric acid (sUA) and urinary pharmacodynamic markers were assayed, and safety was assessed by collection of adverse events and assessment of safety labs, ECGs and vital signs. Administration of PF-06743649 led to rapid decrease in sUA in all cohorts; in gout patients, a change from baseline of 69 % was observed for the 40 mg dose. Urinary and serum biomarkers were consistent with inhibition of both URAT1 and XO. Although dosing was otherwise well tolerated, two subjects experienced serious adverse events of acute kidney injury. Both subjects exhibited increased serum creatinine and blood urea nitrogen in the first 3 days post first dose and were hospitalised. One subject exhibited oliguria for the first 24 h. Both subjects made a complete recovery with minimal intervention. PF-06743649 was effective at rapidly lowering sUA, but further development was terminated for an identified renal safety risk.
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge, CB21 6GS, UK.
Pinky
P
Dua
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge, CB21 6GS, UK.
Rachel
R
Gurrell
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge, CB21 6GS, UK.
Simon
S
Kirby
AdClinico Consulting Ltd, Hawks Barn, Dilnot Lane, Acol, CT7 0HW, UK.
Maria
M
Sudworth
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge, CB21 6GS, UK. peter.t.loudon@pfizer.com.
Peter T
PT
Loudon
D058186:Acute Kidney Injury / Q000139:chemically induced*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D004311:Double-Blind Method; D005260:Female; D006073:Gout / Q000188:drug therapy*; D006074:Gout Suppressants / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D033461:Hyperuricemia / Q000097:blood; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D014481:United States; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D055815:Young Adult
D015415:Biomarkers; D006074:Gout Suppressants; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014527:Uric Acid; D014969:Xanthine Oxidase
Acute kidney injury; Gout; URAT1; Xanthine oxidase