Effect of Mild or Moderate Hepatic Impairment on the Pharmacokinetics of Ozanimod

Introduction: Ozanimod (OZA) is approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis. A prior phase 1 study of single-dose OZA 0.23 mg showed a 31%–33% reduction of CC112273, the major active metabolite (MET) of OZA, in participants (ptps) with mild or moderate (MOD) hepatic impairment (HI) vs healthy ptps. That study was designed prior to identification of the 2 major METs of OZA: CC112273 and CC1084037. Due to their slow accumulation and elimination, a new multiple-dose study was designed with a long sampling schedule. Methods: This multicenter, open-label phase 1 study (NCT04639115) evaluated the effect of mild (Child-Pugh score 5–6) or MOD (Child-Pugh score 7–9) HI on the multiple-dose pharmacokinetics (PK) of OZA and its 2 major active METs. Eligible ptps with HI without active hepatitis were enrolled into the mild or MOD HI groups (8 ptps each). Healthy ptps with normal hepatic function (HF) were matched to HI ptps. All ptps received once-daily OZA for 8 d with dose titration: 0.23 mg on Days (D) 1–4, 0.46 mg on D5–7, and 0.92 mg thereafter. PK samples were collected on D1, D5, and D8, and up to D72. Analysis of variance fitted to the natural log-transformed PK parameters with HF group as the fixed effect and the matching pair as a random effect compared PK parameters between groups. Safety was assessed. Results: All dosed ptps (N=26) completed the study: 8 in each HI group and 10 with normal HF (6 matched to both mild and MOD HI ptps). Of the 16 HI ptps, 13 had documented hepatic cirrhosis. There were no clinically meaningful differences in total and unbound PK parameters for OZA and its major METs between healthy and HI ptps on D1, D5, or D8 (Table 1). The unbound area under the plasma concentration-time curve from D8, time 0 to the time of last quantifiable concentration (AUC0-last,u; up to 64 d after D8 dose) of both METs increased ∼2-fold in both mild and MOD HI ptps (Table 1). No correlation was observed between PK parameters for OZA or its major METs and measures of HF. No laboratory measures, vital signs, physical examination, or ECG results were reported as treatment-emergent adverse events. Conclusion: There was no clinically meaningful difference in exposure of OZA or its METs between HI and healthy ptps over the dose titration period. The systemic exposure (AUC0-last,u) of the major METs was doubled in HI ptps after accounting for protein binding. Multiple oral doses of OZA were safe and generally well tolerated. Table 1. - Ratio of geometric LS mean (90% CI) for unbound PK parameters in ptps with HI vs matched healthy ptps Group comparison PK parameter of interest OZA CC112273 CC1084037 Mild hepatic impairment (test) vs normal matched (reference) D1 Cmax 134.42 (108.51–166.52) 118.03 (77.19–180.47) NA D5 Cmax 135.60 (106.51–172.63) 135.50 (92.26–198.99) 141.26 (95.86–208.17) D8 Cmax 186.48 (103.75–335.19) 147.45 (87.15–249.47) 145.26 (90.38–233.45) D8 AUC0-last,u 182.53 (81.97–406.46) 221.43 (106.61–459.88) 229.74 (93.24–566.10) MOD hepatic impairment (test) vs normal matched (reference) D1 Cmax 136.12 (110.49–167.71) 113.96 (85.55–151.81) NA D5 Cmax 124.92 (93.42–167.04) 111.73 (80.73–154.61) 120.98 (96.42–151.80) D8 Cmax 168.91 (95.72–298.09) 133.71 (84.78–210.88) 135.77 (94.20–195.68) D8 AUC0-last,u 145.87 (68.28–311.64) 199.64 (119.55–333.37) 212.36 (118.15–381.70) The log-transformed PK parameters were analyzed using an ANOVA model with HF group as a fixed effect and matching pair as a random effect.Cmax, maximum observed plasma concentration; LS, least squares; NA, not applicable.