Background/Purpose: Results from a dose-ranging study of abatacept (ABA) in systemic lupus erythematosus (SLE) patients (pts) with active proliferative glomerulonephritis (PGN) showed a larger reduction in urinary protein:creatinine ratio (UPCR) in nephrotic pts treated with ABA versus placebo1. Limited studies have shown differences in exposure to biologics due to renal damage in non-lupus pts2,3; therefore, the relationship between proteinuria and ABA systemic exposure was examined. We describe the pharmacokinetics of IV ABA in pts with active PGN due to SLE and evaluate the association with baseline nephrotic status (UPCR >339 mg/mmoL).
Methods: In Study IM101075, lupus nephritis pts with active PGN (UPCR ≥50 mg/mmoL) were randomized to receive placebo (n=100) or one of two IV ABA regimens: either 3 mths of ABA 30 mg/kg followed by ABA ~10 mg/kg for 9 mths (30/10; n= 99), or ~10 mg/kg for the entire 12 mths (10/10; n= 99). Mean (standard deviation [SD]) glomerular filtration rates at screening were 85 ± 36, 92 ± 36, and 88 ± 31 mL/min and mean (SD) UPCR values were 446 ± 381, 483 ± 954, and 403 ± 329, for the ABA 30/10, ABA 10/10, and placebo groups. A validated enzyme-linked immunosorbant assay (ELISA) was used to determine serum ABA concentrations. Measures of systemic exposure to ABA (maximum observed concentration [Cmax], area under the concentration–time curve [AUC], and trough concentration [Cmin]) were derived by model-independent analysis.
Results: Systemic exposure to ABA was 3-fold higher for the first 3 mths in the 30/10 regimen group compared with the 10/10 regimen group, demonstrating linear pharmacokinetics. After transitioning from 30 mg/kg to 10 mg/kg on Day 57, systemic exposure in the 30/10 group was comparable to that of the 10/10 regimen group by Day 141. Pts who were nephrotic at baseline (34% of ABA-treated pts) had 2.2-fold lower geometric mean Cmin values at Day 57 (Figure) and 1.2-fold lower geometric mean AUC values than pts who were not nephrotic at baseline, suggesting that nephrotic pts clear ABA more rapidly. Cmax values were similar in nephrotic and non-nephrotic pts, suggesting that distribution volume was not affected by renal damage. Pts who were nephrotic at baseline, but had improvement in proteinuria, had corresponding increases in ABA Cmin values.
Conclusions: ABA systemic exposure is lower in nephrotic pts due to increased clearance secondary to active PGN. Nephrotic pts showed better improvement in UPCR compared with non-nephrotic pts despite having lower ABA exposure. Although these results were unexpected, they suggest that clinical response may be related to other factors besides ABA exposure in SLE pts with active PGN. Further investigation is needed to understand if this observation is due to different therapeutic trough levels or other factors.
1Furie R et al. ACR Abstract 2011
2Nagai Tet al. Transplant Proc 2005;37:879-80
3Joy M et al. Am J Kidney Dis 2011;55:50-60
Disclosure: M. Tagen, Bristol-Myers Squibb, 3 ; B. Vakkalagadda, Bristol-Myers Squibb, 1, Bristol-Myers Squibb, 3 ; N. Thanneer, Bristol-Myers Squibb, 3 ; S. Meadows-Shropshire, Bristol-Myers Squibb, 1, Bristol-Myers Squibb, 3 ; M. Ullmann, Bristol-Myers Squibb, 1, Bristol-Myers Squibb, 3 ; R. Wong, Bristol-Myers Squibb, 1, Bristol-Myers Squibb, 3 ; R. Aranda, Bristol-Myers Squibb [at time of study], 3, Bristol-Myers Squibb [at time of study], 1 ; B. Murthy, Bristol-Myers Squibb, 3 .