PII-029 - EFFECT OF RENAL FUNCTION IMPAIRMENT ON THE PHARMACOKINETICS (PK) OF PARSACLISIB, A SELECTIVE INHIBITOR OF PI3Kδ

K. Szeto¹, K. Rockich¹, J. Getsy¹, X. Gong¹, K. Madden¹, X. Liu¹, H. Overholt¹, P. Wang¹, X. Chen¹, N. Punwani¹; ¹Incyte Corporation, Wilmington, DE, USA.

Background: A phase 1, open-label, parallel-group study was conducted to evaluate the effect of renal impairment on the PK of parsaclisib (parsa).

Methods: 48 participants were enrolled: 8 each with mild, moderate, and severe renal impairment; 8 with end-stage renal disease (ESRD) maintained on hemodialysis (HD); and 16 healthy matched participants. Each participant received a single oral dose of parsa 20 mg. Serial PK samples were collected up to 96 h post dose. PK parameters were derived by noncompartmental analysis. Safety and tolerability were assessed by monitoring the frequency and severity of treatment-emergent adverse events (TEAEs), performing physical examinations, and collecting vital signs, 12-lead ECGs, and clinical laboratory data.

Results: Renal impairment had a modest effect on absorption but a greater impact on the elimination of parsa; participants with renal impairment had increased AUC0-inf, longer t½, and lower CL/F compared with healthy participants. Median tmax was 0.5-1.0 h in participants with mild, moderate, and severe impairment and healthy participants. In participants with ESRD before HD and after HD, median tmax was 1.0 and 1.5 h, respectively, and 0.5 h in healthy participants. Modest changes in Cmax were observed compared with healthy participants, ranging from a 25% decrease in participants with ESRD before HD to a 30% increase in participants with moderate impairment. While mild impairment did not significantly impact parsa AUCs, AUC0-inf values were increased by 64%, 107%, 35%, and 50% in participants with moderate impairment, severe impairment, ESRD before HD, and ESRD after HD, respectively. Plasma protein binding was similar across all participants. No fatal or serious TEAEs were reported and no TEAEs led to dose reduction, interruption, or discontinuation of parsa.

Conclusion: Single oral doses of parsa 20 mg were generally well tolerated by healthy participants and participants with varying degrees of renal impairment. Dose adjustments are not recommended for mild renal impairment. For moderate or severe renal impairment, or ESRD on HD, the increase in plasma exposure of parsa may be clinically significant and require dose adjustment. Final parsa dose recommendations will be determined based on cumulative clinical PK and safety data.