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

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

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

Methods: 24 participants were enrolled; 8 with moderate hepatic impairment and 6 with severe hepatic impairment were matched 1:1 with 10 participants with normal hepatic function. Each participant received a single oral dose of parsa 20 mg. Serial PK samples were collected pre dose and 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 AEs, performing physical examinations, and collecting vital signs, 12-lead ECGs, and clinical laboratory data.

Results: Hepatic impairment had a modest effect on absorption but a greater impact on the elimination of parsa, with increased AUC0-inf, longer t½, and decreased CL/F observed in participants with moderate and severe hepatic impairment compared with healthy participants. Median tmax was 0.5 h in participants with moderate and severe impairment and 1.0 h in healthy participants. Cmax increased by approximately 22-25% in participants with moderate and severe hepatic impairment compared with healthy participants; AUC0-inf increased by approximately 40% and 54% in participants with moderate and severe hepatic impairment, respectively. Plasma protein binding was similar in all participants. No parsa-related serious adverse events (AEs) were reported. One participant with severe hepatic impairment had 3 serious treatment-emergent AEs (TEAEs), determined as not related to parsa. Two grade 1 nonserious TEAEs were observed. All TEAEs resolved.

Conclusion: Single oral doses of parsa 20 mg were generally well tolerated by participants with normal hepatic function and moderate or severe hepatic impairment. No treatment-emergent safety concerns were identified. Parsa AUC in participants with moderate or severe hepatic impairment was increased relative to participants with normal hepatic function. The difference in parsa exposures between participants with moderate or severe hepatic impairment and participants with normal hepatic function is considered not to be clinically significant. Therefore, no dose adjustment is required for patients with moderate or severe hepatic impairment.