Effect of renal impairment and hemodialysis on zilurgisertib pharmacokinetics

“A Phase 1 Study to Evaluate the Pharmacokinetics, Safety, and Pharmacodynamics of INCB000928 in Participants With Impaired Renal Function and Hemodialysis” (opens the source at this quote in a new tab)

“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)

Registry status and dates

Registry field	Quoted record
Sponsor protocol number	“INCB 00928-108”
Overall status	“Completed”
Start date, actual	“2021-12-14”
Primary completion, actual	“2023-02-19”
Study completion, actual	“2023-02-27”
Enrollment, actual	“48”

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)

Open-label, parallel-group design with matched controls

“This is a multicenter, open-label parallel-group to evaluate single oral doses of INCB000928 in participants with varying level of renal function or impairment.” (opens the source at this quote in a new tab)

“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)

Renal function groups assigned by estimated glomerular filtration rate

“Renal function was assessed at screening (2–28 days before administration of zilurgisertib) based on estimated glomerular filtration rate (eGFR) score, calculated via the isotope dilution mass spectrometry (IDMS)‐traceable 4‐variable Modification of Diet in Renal Disease (MDRD‐4‐IDMS) formula, and on the requirement for haemodialysis.” (opens the source at this quote in a new tab)

Dosing before and after hemodialysis in end-stage renal disease

“Group 5 participants were admitted on two separate occasions. During their first visit, zilurgisertib was administered per Groups 1–4 and 3 h before the start of haemodialysis. Blood and dialysate samples were collected during the 4‐day stay in the unit following dosing. On visit 2 (5–7 days after the end of their first visit), zilurgisertib was administered 1 h after the end of haemodialysis.” (opens the source at this quote in a new tab)

Inclusion criteria

“Age 18 to 82 years (inclusive) at the time of signing the ICF.” (opens the source at this quote in a new tab)
“Participants eligible for Group 5 with ESRD have received HD for at least 3 months prior to screening.” (opens the source at this quote in a new tab)
“Body mass index within the range 18.0 to 40.0 kg/m2 (inclusive) at screening.” (opens the source at this quote in a new tab)

Exclusion criteria

“Evidence of rapidly deteriorating renal function.” (opens the source at this quote in a new tab)
“Participants who have a current, functioning organ transplant or have a scheduled organ transplant within 6 weeks after check-in.” (opens the source at this quote in a new tab)
“Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) of study drug administration with strong or moderate inducer or inhibitor of CYP3A4 or P-gp” (opens the source at this quote in a new tab)

Single 200 mg oral dose

“INCB000928 200 mg will be administered on Day 1 of each treatment period.” (opens the source at this quote in a new tab)

“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)
“Following an 8‐h fast, Groups 1–4 participants received a single 200 mg oral dose in the morning of Day 1 and were confined to the unit for 4 days.” (opens the source at this quote in a new tab)

Registered primary outcome measures

“PK for plasma of INCB000928: Cmax” (opens the source at this quote in a new tab)
“PK for plasma of INCB000928: AUC0-t” (opens the source at this quote in a new tab)
“Defined as area under the single-dose plasma or serum concentration-time curve extrapolated to time of infinity, this test will assess the effect of renal impairment and hemodialysis on the exposure of single oral doses of INCB00928.” (opens the source at this quote in a new tab)

Renal impairment can alter exposure to drugs cleared by non-renal pathways

“The potential impact of renal impairment on the PK of drugs cleared by non‐renal pathways (including intestinal and hepatic drug metabolism and transport) is well established.” (opens the source at this quote in a new tab)
“As such, drugs with minimal renal clearance may still need dose adjustments in individuals with renal impairment, as reflected in current US Food and Drug Administration (FDA) guidance.” (opens the source at this quote in a new tab)

Choice of the MDRD equation for group assignment

“was selected because, of the three standard methods available (MDRD‐4‐IDMS, Cockroft‐Gault and Chronic Kidney Disease Epidemiology Collaboration [CKD‐EPI]), it shows the greatest accuracy in estimation of renal clearance across difference stages of renal impairment.” (opens the source at this quote in a new tab)

Truncated AUC as a supporting exposure measure

“Recent guidance from the US Food & Drug Administration supports the use of truncated AUCs (e.g., AUC0–72) as the primary exposure metrics for IR drugs with long half‐lives.” (opens the source at this quote in a new tab)
“Therefore, AUC0–72 represents a robust and interpretable measure of systemic exposure across renal function groups; AUC0–∞ should be interpreted with caution in this population.” (opens the source at this quote in a new tab)

Hemodialysate bioanalytical method

“INCB000928 in hemodialysate exhibited strong nonspecific binding to polypropylene containers. In the presence of 10% isopropyl alcohol, the loss of INCB000928 was fully recovered, regardless of pre- or post-addition of the solvent.” (opens the source at this quote in a new tab)

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 renal function group

“Forty‐eight participants were enrolled in the renal impairment study: normal renal function n = 16; mild impairment n = 7; moderate impairment n = 8; severe impairment n = 8; end‐stage renal disease (ESRD) n = 9.” (opens the source at this quote in a new tab)

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)

Matched comparison by analysis of variance

“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)
“Summary statistics are presented for both excluding (n = 6) and including (n = 7) one participant with mild renal impairment who lacked a healthy‐matched participant with normal renal function. This participant was excluded from the ANOVA test.” (opens the source at this quote in a new tab)

Completion and exclusion from the pharmacokinetic population

“All participants completed the study and were included in the safety population; one participant with ESRD was excluded from the PK population because zilurgisertib was mistakenly administered before haemodialysis during their second visit.” (opens the source at this quote in a new tab)

Demographics and renal function by group

Characteristic	Normal function (n = 16)	Mild impairment (n = 7)	Moderate impairment (n = 8)	Severe impairment (n = 8)	ESRD (n = 9)
Age, median (range), years	“58.5 (34–75)”	“65.0 (63–79)”	“71.0 (48–76)”	“72.5 (38–80)”	“54.0 (44–67)”
Male, n (%)	“11 (69)”	“4 (57)”	“5 (63)”	“5 (63)”	“9 (100)”
White/Caucasian, n (%)	“15 (94)”	“5 (71)”	“5 (63)”	“8 (100)”	“5 (56)”
BMI, median (range), kg/m2	“29.0 (22.2–35.6)”	“27.1 (21.1–33.1)”	“30.0 (26.4–36.5)”	“32.0 (25.4–39.4)”	“28.0 (22.5–39.4)”
eGFR, median (range), mL/min/1.73 m2	“99.2 (76.5–114.0)”	“63.9 (53.3–82.0)”	“48.3 (33.0–65.0)”	“19.5 (15.5–28.0)”	“6.7 (2.9–11.0)”

Geometric mean ratios versus matched participants with normal renal function

Renal function group	Cmax GMR (90% CI)	AUC0-inf GMR (90% CI)
Mild impairment	“0.92 (0.64–1.34)”	“0.98 (0.77–1.24)”
Moderate impairment	“1.22 (0.92–1.63)”	“1.64 (1.28–2.10)”
Severe impairment	“1.00 (0.74–1.35)”	“1.70 (1.33–2.16)”
ESRD, dosed before hemodialysis	“1.17 (0.91–1.49)”	“1.47 (1.15–1.88)”
ESRD, dosed after hemodialysis	“1.32 (1.00–1.75)”	“1.68 (1.29–2.19)”

Half-life and apparent clearance in moderate and severe renal impairment

“Zilurgisertib plasma exposure was 45% higher in participants with moderate renal impairment versus normal renal function when determined by AUC0–t (GMR: 1.45, p = 0.0073) and 64% higher based on AUC0–∞ (GMR: 1.64, p = 0.0031); geometric mean terminal t½ (35.6 vs. 25.1 h, p = 0.0031; Table 2) was longer and geometric mean CL/F (12.3 vs. 20.2 L/h, p = 0.0031) was lower in participants with moderate renal impairment.” (opens the source at this quote in a new tab)
“Geometric mean terminal t½ (39.0 vs. 26.4 h, p = 0.0376; Table 2) was longer and geometric mean CL/F (11.0 vs. 18.7 L/h, p = 0.0017) was lower in participants with severe renal impairment, compared with those with normal renal function.” (opens the source at this quote in a new tab)

End-stage renal disease and timing of hemodialysis

“Overall, changes in zilurgisertib exposure in participants with ESRD were similar to those seen in participants with moderate and severe renal impairment.” (opens the source at this quote in a new tab)
“Exposure was also increased by 30%–68% in participants with ESRD; notably, comparison of data obtained before and after haemodialysis demonstrate that zilurgisertib PK was not affected by the timing of dosing relative to this procedure.” (opens the source at this quote in a new tab)

Renal and dialysate clearance

“In participants with normal renal function, the GMR of renal clearance of zilurgisertib was 4.4 L/h, dropping to 3.9, 2.1 and 1.4 L/h in participants with mild, moderate and severe renal impairment, respectively. Similarly, the fraction of dose eliminated in urine as unchanged drug dropped from 19% in participants with normal renal function to 18%, 12% and 9% in participants with mild, moderate and severe renal impairment, respectively” (opens the source at this quote in a new tab)
“The geometric mean dialysate clearance among participants with ESRD was 1.3 L/h and the geometric mean fraction excreted in dialysate was 1.0%.” (opens the source at this quote in a new tab)

Plasma protein binding across renal function groups

“Average fraction unbound was 32%, 36%, 30%, 30% and 30% in participants with normal renal function, mild, moderate and severe renal impairment, and ESRD, respectively” (opens the source at this quote in a new tab)

Label statement of renal impairment results

“No significant difference in the exposure of zilurgisertib was observed in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2, MDRD) compared to healthy subjects with normal renal function.” (opens the prescribing information at this quote)
“Zilurgisertib exposure (AUC0-∞) was approximately 64% higher in patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), approximately 70% higher in” (opens the prescribing information at this quote)
“patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), and approximately 47% and 68% higher in patients with end-stage renal disease before and after hemodialysis (eGFR <15 mL/min/1.73 m2), respectively, than in healthy subjects with normal renal function.” (opens the prescribing information at this quote)

Treatment-emergent adverse events in the renal impairment study

“Overall, all TEAEs were of Grade 1 or 2 severity and resolved before the end of the studies; no serious or fatal TEAEs were observed. In the renal impairment study, five TEAEs occurred in three of 48 participants (6%), with four TEAEs in two participants with normal renal function considered treatment‐related by the study investigators.” (opens the source at this quote in a new tab)
“The second participant reported a treatment‐related TEAE of alopecia (Grade 1) on Day 5, which resolved by Day 7 without treatment. One participant with severe renal impairment experienced skin abrasion (Grade 1) that was not considered treatment‐related.” (opens the source at this quote in a new tab)

Summary: limitations of the renal impairment study

The study gave one 200 mg dose to 48 adults with a median age of 54.0 to 72.5 years across groups, with 7 to 16 participants per group; group sizes were not based on power calculations, and it does not describe steady-state exposure at the 100 mg daily dose or exposure in adolescents. One participant with mild impairment had no matched control and was excluded from the comparison, and one participant with end-stage renal disease was excluded from the pharmacokinetic population after a dosing error. In moderate or worse impairment, sampling to 72 hours covered less than two half-lives, and the authors state that AUC0-inf should be interpreted with caution in this population. The label reports the 64% to 70% increases in AUC0-inf in its pharmacokinetics section and gives no dose adjustment for renal or hepatic impairment; the authors note that dosing recommendations were to be informed by the therapeutic index from the pivotal trial. The publication reports four renal study sites, while the registry record lists five locations.