Background/Purpose: Among the estimated 8.3 million adults in the US with gout, approximately 40% have coexistent chronic kidney disease (CKD).^1,2 Further, the presence of gout in CKD appears to confer an increased risk for progression to end-stage renal disease (ESRD).³ Thus, patients often proceed to dialysis with chronic gout, and some suffer from severe tophaceous gout. There has been little detailed study of the use of urate-lowering medications in the hemodialysis (HD) population. Pegloticase, a recombinant uricase conjugated to PEG, acts by converting urate to a soluble product (allantoin) that is readily excreted. Pegloticase is reserved for patients with chronic gout who are refractory to current oral urate-lowering treatments and does not require dose adjustment based on renal function. Here we present results from a Phase 1 pharmacokinetic (PK) / pharmacodynamic study of single-dose pegloticase in patients undergoing HD.

Methods: A single intravenous dose of pegloticase (8 mg) was administered over a 2-hour period to male or female (age 18-75 years) HD patients without gout (N=12), 3 hours prior to the Day 1 dialysis session; a second dialysis session was monitored on Day 4. Patients received prophylactic antihistamine and corticosteroid prior to pegloticase infusion. Blood samples were drawn predialysis and hourly over 4 hours postdialysis during the Day 1 and Day 4 sessions. The limit of detection for pegloticase was 0.6 μg/mL; all samples below this value were set to zero. Safety assessments included standard vital signs, laboratory testing, and adverse event (AE) determinations.

Results: Following a single dose of pegloticase started approximately 3 hours prior to HD, the mean C_max was 3.27 μg/mL (arterial) and 4.00 μg/mL (venous). Pegloticase AUC_3-7h was 9.86 h∙μg/mL (arterial) and 12.91 h∙μg/mL (venous) at the Day 1 dialysis and for the Day 4 dialysis AUC_72-76h was 7.93 h∙μg/mL (arterial) and 9.70 h∙μg/mL (venous). Mean arterial and venous pegloticase concentrations during the Day 1 and Day 4 dialysis sessions are shown in the figure. Baseline mean serum uric acid in this non-gout population was 5.98 mg/dL; by 3 hours postinfusion, serum uric acid was undetectable and remained so over the 72-hour sampling period. One patient reported an AE of headache that was possibly related to study drug.

Conclusion: In a small cohort of patients with ESRD and no evidence of gout, pegloticase concentration was not affected by a first HD session and displayed stable decline during a second HD session. Serum uric acid levels in this cohort fell to nondetectable levels 3 hours postinfusion confirming that patients with ESRD can achieve urate-lowering with pegloticase. Data presented here support the use of pegloticase in patients with chronic gout undergoing HD.

References:

1. Fuldeore et al. BMC Nephrol. 2011.

2. Zhu et al. Arthritis Rheum. 2011.

3. Yu et al. Arthritis Res Ther. 2012.