INCB 00928-109 hepatic impairment study

20 evidence topics · 2 sources

Objective

Effect of hepatic impairment on zilurgisertib pharmacokinetics

“Here are the results of two separate Phase I, open‐label, parallel‐group studies (INCB 00928‐108; INCB 00928‐109) assessing the effect of renal and hepatic impairment, respectively, on zilurgisertib exposure.” (opens the source at this quote in a new tab)

Location and study date

Study sites

“These studies were undertaken at seven overlapping study sites in the United States (renal impairment study four sites, hepatic impairment study five sites).” (opens the source at this quote in a new tab)

Study design

Open-label, parallel-group design with matched controls

“Participants with normal renal or hepatic function, were enrolled and matched on a 1:1 basis with participants with impaired renal/hepatic function respectively, according to age (±10 years), sex and body mass index (±20%).” (opens the source at this quote in a new tab)

Child-Pugh groups and the omitted mild impairment cohort

“Hepatic function was assessed at screening (2–28 days before zilurgisertib administration) based on Child–Pugh score, then reassessed for consistency on the day of admission before dosing. Participants with normal hepatic function were assigned to Group 4, those with severe hepatic impairment (Child–Pugh score of 10–14 points) to Group 1, and those with moderate impairment (7–9 points) to Group 2” (opens the source at this quote in a new tab)
“Following a pre‐specified interim analysis of PK results, it was determined that an additional cohort with mild hepatic impairment (Group 3; 4–6 points) was unnecessary as zilurgisertib exposure was similar between participants with normal and moderate hepatic impairment.” (opens the source at this quote in a new tab)

Eligibility criteria

Age, body mass index, and excluded conditions and medications

“Eligible participants were adults (18–82 years, renal impairment study, 18–80 years, hepatic impairment study), with body mass index of 18–40 and 18–44 kg/m2 in the renal and hepatic impairment studies, respectively.” (opens the source at this quote in a new tab)
“In both studies, participants with unstable or clinically significant comorbidities were excluded” (opens the source at this quote in a new tab)
“Use of medications known to be potent inhibitors or potent/moderate inducers of CYP3A4 (hepatic study) and medications known to affect CYP3A4 or P‐glycoprotein (renal study) for the longer of 30 days or five half‐lives prior to dosing was prohibited.” (opens the source at this quote in a new tab)

Treatment

Single 200 mg oral dose

“Zilurgisertib was administered as a single 200‐mg dose (8 × 25 mg tablets) in both studies.” (opens the source at this quote in a new tab)
“Participants refrained from food for 8 h before and 4 h after dosing.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using plasma cmax, AUC0-t, and AUC0-inf as the primary endpoints

Pharmacokinetic parameters derived in both studies

“For both studies, the following PK parameters were calculated: maximum plasma drug concentration (Cmax); area under the plasma or serum concentration–time curve from time 0 to the last measurable concentration at time t (AUC0–t); total AUC extrapolated to infinity (AUC0–∞)” (opens the source at this quote in a new tab)

Hepatic clearance as the basis for a hepatic impairment study

“Similarly, plasma exposure can be influenced by liver diseases via altered hepatic metabolism/biliary excretion.” (opens the source at this quote in a new tab)
“PK studies should also be performed in patients with hepatic impairment where the condition is likely to significantly alter the PK of the drug and/or its metabolites, e.g., where hepatic metabolism/excretion accounts for >20% of the elimination of the parent/metabolite absorbed drug, and for drugs that may have a narrow therapeutic index.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Planned group sizes and their basis

“Up to eight participants could be enrolled into each renal/hepatic impairment group, to allow six or more participants per group to complete the study. The normal renal/hepatic function groups could consist of ≤ 16 participants. The sample size for these respective cohorts was based upon other PK studies of a similar nature and was not based on power calculations.” (opens the source at this quote in a new tab)

Participants enrolled by hepatic function group

“Twenty‐eight participants were enrolled in the hepatic impairment study: normal hepatic function n = 12; moderate impairment n = 9; severe impairment n = 7.” (opens the source at this quote in a new tab)

Description of analysis sets

Safety and pharmacokinetic populations

“All participants who received zilurgisertib were included in the safety population; those with at least one measurable PK sample collected were included in the PK population.” (opens the source at this quote in a new tab)
“To evaluate the effect of renal/hepatic impairment on zilurgisertib PK, log‐transformed PK parameters (Cmax, AUC0–t, AUC0–∞) were compared between participants with renal/hepatic impairment and matched participants with normal renal/hepatic function using a one‐way analysis of variance (ANOVA) with a fixed factor for renal/hepatic function group and a random factor for participant.” (opens the source at this quote in a new tab)

Results

Participant disposition

Completion

“All participants completed the study and were included in the safety and PK populations.” (opens the source at this quote in a new tab)

Baseline characteristics

Demographics and liver function by group

Characteristic	Normal function (n = 12)	Moderate impairment (n = 9)	Severe impairment (n = 7)
Age, median (range), years	“57.5 (40–64)”	“59.0 (40–69)”	“54.0 (48–61)”
Male, n (%)	“7 (58)”	“7 (78)”	“3 (43)”
White/Caucasian, n (%)	“7 (58)”	“8 (89)”	“6 (86)”
BMI, median (range), kg/m2	“32.1 (27.2–37.8)”	“32.8 (24.4–35.7)”	“32.1 (25.8–42.8)”
Albumin, median (range), g/dL	“4.2 (3.5–4.4)”	“3.9 (3.2–4.5)”	“2.4 (1.3–3.1)”
Bilirubin, median (range), mg/dL	“0.5 (0.15–0.8)”	“1.0 (0.3–9.0)”	“3.0 (0.6–6.3)”

Efficacy results

Geometric mean ratios versus matched participants with normal hepatic function

“Among participants with hepatic impairment, values were as follows: moderate, 1.06 (0.80–1.42) and 1.13 (0.93–1.38); severe: 1.36 (1.05–1.76) and 1.25 (1.06–1.48), respectively.” (opens the source at this quote in a new tab)

Moderate hepatic impairment

“GMRs for zilurgisertib exposure among participants with normal hepatic function versus those with moderate hepatic impairment were 1.06, 1.09 and 1.13 for Cmax, AUC0–t and AUC0–∞, respectively, with 90% CIs including unity for all parameters.” (opens the source at this quote in a new tab)

Severe hepatic impairment

“Zilurgisertib plasma AUC0–t and AUC0–∞ were 22% and 25% higher in participants with severe hepatic impairment, respectively, than in participants with normal hepatic function. Cmax was similar in participants with severe hepatic impairment and those with normal hepatic function (GMR: 1.36, p = 0.0585). Lower geometric mean CL/F (16.0 vs. 20.1 L/h, p = 0.0347) and earlier median tmax (1.0 vs. 2.0 h, p = 0.0208) were observed in participants with severe hepatic impairment versus normal hepatic function.” (opens the source at this quote in a new tab)

Plasma protein binding across hepatic function groups

“Plasma protein binding was independent of both renal and hepatic function; hence, PK analysis was not performed on the unbound fraction.” (opens the source at this quote in a new tab)

Label statement of hepatic impairment results

“The zilurgisertib Cmax and AUC in patients with moderate hepatic impairment was comparable to healthy subjects with normal hepatic function. In patients with severe hepatic impairment, zilurgisertib AUC was 25% higher and Cmax was similar to that in subjects with normal hepatic function.” (opens the prescribing information at this quote)

Health-related quality of life and patient-reported outcomes

Not applicable.

Safety results

Treatment-emergent adverse events in the hepatic impairment study

“In the hepatic impairment study, four TEAEs occurred in two of 28 participants (7.1%) none of which were considered treatment‐related. One participant with severe hepatic impairment experienced TEAEs of vomiting (Grade 1) and nausea (Grade 2), and one participant with moderate hepatic impairment reported TEAEs of diarrhoea and headache (both Grade 1); all TEAEs resolved on the day of onset.” (opens the source at this quote in a new tab)

Study limitations

Summary: limitations of the hepatic impairment study

The study gave one 200 mg dose to 28 adults (12 with normal hepatic function, 9 with moderate impairment, and 7 with severe impairment), with group sizes not based on power calculations. The mild impairment group was not enrolled after an interim analysis found similar exposure with moderate impairment, so no exposure data exist for mild hepatic impairment. The study describes neither steady-state exposure at the 100 mg daily dose nor exposure in adolescents. No registry record or study dates were located for this study.