Abstract
Futibatinib is a covalently binding FGFR1–4 inhibitor that received US Food and Drug Administration approval for the treatment of patients with previously treated, advanced intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements. This phase I trial evaluated the pharmacokinetics (PKs), safety, and tolerability of futibatinib in subjects with impaired hepatic function and matched healthy volunteers. Twenty‐two subjects with hepatic impairment (8 mild [Child‐Pugh 5–6], 8 moderate [7–9], and 6 severe [10–15]) and 16 matched healthy control subjects received a single oral dose of futibatinib 20 mg. Futibatinib PKs were compared between subjects with mild/moderate/severe hepatic impairment and each corresponding control cohort and the overall control cohort. Relationships between futibatinib PKs and Child‐Pugh scores and liver function tests were examined via scatter/regression plots. Compared with matched controls, the area under the plasma concentration–time curve from time zero to infinity increased by 21%/20%/18% and the maximum plasma concentration (C max) increased by 43%/15%/10% in subjects with mild/moderate/severe hepatic impairment, respectively. Changes were not considered clinically relevant: geometric mean ratios were within 80%–125%, except for C max in subjects with mild hepatic impairment (143%). No obvious trends were observed among futibatinib PK parameters versus Child‐Pugh scores, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase (all p > 0.05). Futibatinib was well‐tolerated, with only four grade 1 treatment‐emergent adverse events (mild hepatic impairment = 2 and control = 2). The results demonstrate that futibatinib dose adjustments due to mild/moderate/severe hepatic impairment are not necessary in patients receiving futibatinib 20 mg daily.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Futibatinib, a covalently binding inhibitor of FGFR, is approved for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other re‐arrangements.
WHAT QUESTION DID THIS STUDY ADDRESS?
The pharmacokinetics (PKs), safety, and tolerability of futibatinib after a single 20 mg dose were assessed in participants with varying degrees of hepatic impairment.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Futibatinib exposure increased by 21%–43%, 15%–20%, and 10%–18% for participants with mild, moderate, and severe mild hepatic impairment, respectively, versus healthy matched controls. There were no clinically relevant trends between severity of hepatic impairment and changes in futibatinib exposure or in changes in futibatinib PK parameters. Futibatinib was well‐tolerated across all groups.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The results demonstrated that no dose adjustment is necessary for individuals with mild, moderate, or severe hepatic impairment receiving futibatinib 20 mg once daily for intrahepatic cholangiocarcinoma and provide the first dosing recommendation for an FGFR inhibitor in patients with cancer and severe hepatic impairment.
INTRODUCTION
Genomic alterations (amplifications, translocations, fusions, and activating point mutations) of fibroblast growth factor receptor (FGFR) are common in various cancers and are associated with tumorigenesis and disease progression. 1 , 2 Almost all tumor types are reported to have FGFR alterations, but those with the highest frequency include urothelial carcinoma, cholangiocarcinoma (CCA), endothelial cancer, and glioma. 1 , 3 Selective small‐molecule FGFR inhibitors have shown clinical efficacy in patients with tumors harboring FGFR pathway aberrations; however, most are reversible adenosine triphosphate (ATP)–competitive inhibitors, for which the emergence of acquired resistance mutations in the FGFR kinase domain is a major challenge. 4 , 5 , 6 , 7
Futibatinib (TAS‐120) is a novel and highly selective inhibitor of all four FGFR subtypes that, via covalent binding, results in the irreversible inhibition of downstream FGF/FGFR signaling. Futibatinib has shown broad antiproliferative activity in FGFR‐deregulated cell lines and xenograft models. 8 , 9 , 10 Furthermore, futibatinib is active against cell lines with distinct FGFR kinase domain mutations leading to resistance against reversible FGFR inhibitors, and prolonged treatment with futibatinib is associated with the appearance of fewer drug‐resistant clones compared with reversible—ATP‐competitive inhibitors. 2 , 10 On September 30, 2022, the US Food and Drug Administration granted accelerated approval of futibatinib for adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic CCA harboring FGFR2 gene fusions or other re‐arrangements. 11 Approval was based on the results of a multicenter, open‐label, phase I/II trial of futibatinib in patients with advanced solid tumors (NCT02052778). 12 Among 103 patients with advanced intrahepatic CCA harboring FGFR2 gene fusions or re‐arrangements who received the recommended phase II dose of futibatinib 20 mg once daily, 13 , 14 the objective response rate by independent review according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (primary end point) was 42%, with a median duration of response of 9.7 months. 12
Futibatinib pharmacokinetics (PKs) in patients with cancer and healthy subjects have been well‐characterized. 11 , 13 Dose‐proportional exposure increases were observed up to 80 mg, with no accumulation after repeat once daily doses. Futibatinib was quickly absorbed after administration, with a time to maximum plasma concentration (T max) of ~2 h. The mean half‐life was ~3 h. A phase I food effect study found that futibatinib bioavailability was 11.2% lower and median T max was significantly delayed (4.0 vs. 1.5 h) under fed versus fasted conditions. 15 However, these changes in bioavailability were not considered to have a clinically meaningful impact on safety and efficacy, and the US label recommends that futibatinib is administered with or without food. 11
In a phase I mass balance study in healthy male adults, the total amount of unchanged futibatinib in urine and feces was negligible, indicating that metabolism is the predominant elimination pathway for futibatinib. 16 More than 90% of radioactivity was recovered in feces, demonstrating that the renal route plays a minimal role in futibatinib elimination. Despite an in vitro study suggesting that cytochrome P450 (CYP450)–related metabolism contributed to ~50% of the overall metabolism, the major metabolite (>10% of total exposure of futibatinib‐related compounds) was a derivative of glutathione conjugate. 17
The results of phase I drug–drug interaction studies suggest that futibatinib has no impact on the PKs of CYP3A substrates. Furthermore, although futibatinib exposure increased by 40%–50% and decreased by 50%–60% when co‐administered with itraconazole and rifampin (dual P‐glycoprotein and strong CYP3A perpetrators), respectively, the impact on futibatinib half‐life was limited, indicating that the observed drug–drug interaction effect was likely due to the contribution of both CYP3A and P‐glycoprotein. 18 The relative contribution of intestinal and hepatic CYP3A to futibatinib metabolism is unknown.
As the primary elimination pathway for futibatinib is hepatic metabolism, it is important to understand the impact of hepatic impairment (HI) on futibatinib elimination. Here, we present the results of a phase I study conducted to assess the PKs, safety, and tolerability of single‐dose oral futibatinib in healthy subjects with normal and impaired hepatic function.
METHODS
Study design and participants
This was an open‐label, nonrandomized, single‐dose, phase I trial conducted at two sites in the United States. The study enrolled adults (≥18 years) with a body mass index (BMI) greater than or equal to 18.0 and less than or equal to 40.0 kg/m2. All participants were required to be nonsmokers or moderate smokers (≤10 cigarettes/day or equivalent). Participants with impaired hepatic function—categorized as mild (Child‐Pugh score, 5–6), moderate (7–9), or severe (10–15) hepatic impairment at screening (day −1)—were enrolled first, with planned recruitment of at least eight participants in each cohort. Participants in the hepatic impairment cohorts were required to have a diagnosis of chronic (>6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology. Control subjects with normal hepatic function were recruited to match participants in each of the three hepatic impairment cohorts according to age, BMI, and sex, where possible, with a planned sample size of eight to 16. Control subjects matched to a participant in one hepatic impairment cohort could also be matched to a participant fitting the same demographic criteria in another hepatic impairment cohort rather than enrolling an additional subject. Participants in the healthy control group were excluded if their liver function tests, including alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin, were greater than the upper limit of normal and/or had phosphorus greater than 1.5 × the upper limit of normal at screening and check‐in. Aside from hepatic impairment in the test cohorts, all participants were required to be sufficiently healthy for study participation based upon medical history, physical examination, vital signs, electrocardiograms, and screening clinical laboratory profiles. Exclusion criteria for all cohorts included a positive coronavirus disease 2019 (COVID‐19) polymerase chain reaction test or symptoms, major surgery within the previous 4 weeks, hypersensitivity/idiosyncratic reaction to futibatinib or related compounds, positivity for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus, seated blood pressure less than 90/40 mmHg or greater than 155/95 mmHg, and seated heart rate less than 40 bpm or greater than 99 bpm.
Participants were admitted to the Clinical Research Unit on the day prior to dosing (day −1) and discharged after the 72‐h blood draw and/or study procedures on day 4. On day 1, all participants received a single dose of futibatinib 20 mg, administered orally with ~240 mL of water, following an overnight fast for greater than or equal to 10 h prior to dosing; participants continued to fast for greater than or equal to 4 h after dosing.
The use of xanthines/caffeine (except for small amounts of caffeine derived from normal foodstuffs), alcohol, and grapefruit/Seville orange was prohibited for 24 h, 48 h, and 14 days, respectively, prior to dosing and throughout the period of PK sample collection. Details on the use of concomitant medications are provided in the Supplementary Methods.
The study was performed in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The trial protocol and all study documents were approved by the Advarra Institutional Review Board and IntegReview (now Advarra) prior to study initiation, and all patients provided written informed consent before enrollment.
Bioanalytical methods
Blood samples for assessment of futibatinib plasma PK were collected on day 1 before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 h after dosing, and on day 2 (24 and 36 h after dosing), day 3 (48 h after dosing), and day 4 (72 h after dosing). Blood sampling was also conducted predose and at 2 and 12 h postdose for evaluation of futibatinib protein binding. Plasma total and unbound concentrations of futibatinib were determined using high performance liquid chromatography–tandem mass spectrometry methods, as described previously. 15 The analytical ranges (lower limit of quantitation–upper limit of quantitation) for plasma futibatinib and unbound plasma futibatinib were 0.500–250 and 0.050–25.0 ng/mL, respectively.
Pharmacokinetic and statistical analysis
Pharmacokinetic parameters assessed included maximum plasma concentration (C max), T max, area under the plasma concentration versus time curve (AUC) to the last measurable concentration (AUC0–t), AUC from time 0 to 24 h after dosing (AUC0–24), AUC from time 0 to infinity (AUC0–inf), apparent terminal elimination half‐life (t 1/2), apparent total clearance after extravascular administration (CL/F), and apparent volume of distribution during the terminal elimination phase after extravascular administration. Noncompartmental PK parameters were calculated from plasma futibatinib concentration–time data using Phoenix WinNonlin (Certara) version 8.3.4, and descriptive statistics for plasma futibatinib concentrations and PK parameters were generated using SAS version 9.4.
Summary statistics and geometric means for exposure parameters (AUC0–inf, AUC0–t, and C max) for each hepatic impairment cohort were compared with the associated matched healthy control cohort and with the overall healthy control cohort using an analysis of variance (ANOVA) of log‐transformed data, with the hepatic function group as a fixed effect. The geometric least squares mean (LSM) values reported in statistical comparisons were the exponentiated LSMs from the ANOVA. The geometric mean ratio (GMR) was calculated from the exponentiated difference between the cohort LSMs and expressed as a percentage relative to the healthy control cohort. The 90% confidence intervals (CIs) for the ratios were derived by exponentiation of the CIs obtained for the difference between the cohort LSMs and expressed as a percentage relative to the healthy control cohort.
Additionally, the relationship between plasma futibatinib PKs and hepatic impairment was examined graphically via scatter/regression plots of plasma futibatinib PK parameters (AUC0–inf, Cmax, and CL/F) versus the Child‐Pugh score, bilirubin levels, albumin levels, international normalized ratio (INR), and AST at baseline.
Safety assessments
Safety was monitored through day 4 of the study by repeated clinical and laboratory evaluations. In addition, all participants who received futibatinib (including those who terminated the study early) were contacted ~14 days after futibatinib administration to determine if any adverse events (AEs) had occurred since the last study visit. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 and were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI‐CTCAE) version 5.0. A treatment‐emergent AE (TEAE) was defined as an AE that started or worsened at the time of or after study drug administration.
RESULTS
Participants
A total of 38 participants were enrolled, including 22 with hepatic impairment (mild = 8; moderate = 8; and severe = 6) and 16 healthy controls. All participants completed the study and were included in the PK and safety populations. Baseline characteristics are summarized in Table 1. Demographics were generally similar across all hepatic impairment and healthy control groups.
TABLE 1.
Baseline demographics.
| Healthy control cohort | Hepatically impaired cohorts | |||||||
|---|---|---|---|---|---|---|---|---|
| Characteristic | Healthy control–mild HI (n = 8) a | Healthy control–moderate HI (n = 8) a | Healthy control–severe HI (n = 8) a | Overall healthy control (n = 16) a | Mild HI (n = 8) | Moderate HI (n = 8) | Severe HI (n = 6) | Overall HI (n = 22) |
| Median (range) age, years | 61.0 (54–68) | 60.5 (54–73) | 59.0 (34–68) | 60.5 (34–73) | 61.5 (51–66) | 61.5 (54–76) | 55.5 (41–69) | 59.5 (41–76) |
| Sex | ||||||||
| Male | 0 | 4 (50.0) | 1 (16.7) | 5 (31.3) | 0 | 4 (50.0) | 1 (16.7) | 5 (22.7) |
| Female | 8 (100) | 4 (50.0) | 5 (83.3) | 11 (68.8) | 8 (100) | 4 (50.0) | 5 (83.3) | 17 (77.3) |
| Race | ||||||||
| Asian | 0 | 0 | 0 | 0 | 1 (12.5) | 0 | 0 | 1 (4.5) |
| Black/African American | 3 (37.5) | 3 (37.5) | 2 (33.3) | 5 (31.3) | 2 (25.0) | 0 | 0 | 2 (9.1) |
| White | 5 (62.5) | 5 (62.5) | 4 (66.7) | 11 (68.8) | 5 (62.5) | 8 (100) | 6 (100) | 19 (86.4) |
| Ethnicity | ||||||||
| Hispanic or Latino | 4 (50.0) | 4 (50.0) | 3 (50.0) | 9 (56.3) | 4 (50.0) | 4 (50.0) | 3 (50.0) | 11 (50.0) |
| Not Hispanic or Latino | 4 (50.0) | 4 (50.0) | 3 (50.0) | 7 (43.8) | 4 (50.0) | 4 (50.0) | 3 (50.0) | 11 (50.0) |
| Mean (SD) weight, kg | 85.7 (11.5) | 86.3 (12.1) | 81.3 (16.2) | 85.4 (13.2) | 83.6 (17.2) | 91.3 (16.3) | 71.3 (9.8) | 83.0 (16.6) |
| Mean (SD) height, cm | 172.1 (7.1) | 169.9 (9.3) | 173.4 (10.0) | 171.8 (9.2) | 170.9 (9.1) | 170.4 (11.1) | 167.7 (11.7) | 169.8 (10.2) |
| Mean (SD) BMI, kg/m2 | 29.1 (4.6) | 30.1 (5.0) | 26.8 (2.9) | 28.9 (4.3) | 28.9 (6.9) | 31.5 (4.7) | 25.4 (3.2) | 28.9 (5.6) |
Note: Values are n (%) unless indicated otherwise.
Abbreviations: BMI, body mass index; HI, hepatic impairment; SD, standard deviation.
Healthy control subjects matched to a participant in one HI group could also be matched to a participant fitting the same demographic criteria (age, BMI, and sex) in another HI group. Three control subjects were matched to a participant in each of the mild and moderate HI groups, and three control subjects were matched to a participant in each of the mild and severe HI groups.
Futibatinib pharmacokinetics
Mean futibatinib plasma concentration–time profiles in participants with mild, moderate, and severe mild hepatic impairment and those with normal hepatic function are shown in Figures 1 and 2, with corresponding figures for individual hepatic impairment groups provided in Figure S1. The concentration–time profiles of futibatinib were generally well‐characterized (mean percentage of AUC0–inf extrapolated, <2% in all groups). Peak mean futibatinib concentrations were reached at ~1 h after dosing in participants with mild and moderate hepatic impairment and at ~2 h after dosing in participants with severe hepatic impairment and in healthy control participants (Figures 1 and 2; Table 2). The post‐peak decline of mean futibatinib concentrations was similar for each hepatic function group, with slightly lower mean futibatinib concentrations in those with mild hepatic impairment compared with participants with moderate or severe hepatic impairment and healthy control participants.
FIGURE 1.
Mean plasma concentration–time profiles for total futibatinib following a single oral dose of 20 mg futibatinib in participants with mild, moderate, and severe HI and matched participants with normal hepatic function. (a) linear scale; (b) semi‐log scale. HI, hepatic impairment.
FIGURE 2.
Mean plasma concentration–time profiles for total futibatinib following a single oral dose of 20 mg futibatinib in participants with mild, moderate, and severe HI and the overall healthy control cohort. (a) linear scale; (b) semi‐log scale. HI, hepatic impairment.
TABLE 2.
Summary of plasma futibatinib PK parameters following a single oral dose of 20 mg futibatinib.
| PK parameter | Hepatically impaired participants | ||
|---|---|---|---|
| Mild HI, (n = 8) | Moderate HI, (n = 8) | Severe HI, (n = 6) | |
| AUC0–24 (ng*h/mL) | 356.8 (47.5) | 507.5 (107.5) | 488.5 (66.9) |
| AUC0–t (ng*h/mL) | 352.0 (47.2) | 502.1 (108.6) | 490.0 (68.7) |
| AUC0–inf (ng*h/mL) | 357.2 (47.7) | 510.8 (108.2) | 494.4 (68.6) |
| C max (ng/mL) | 123.0 (40.5) | 127.8 (51.1) | 127.6 (29.9) |
| T max (h) | 1.000 (1.00, 2.50) | 1.250 (0.67, 3.00) | 1.750 (0.67, 3.00) |
| t ½ (h) | 1.759 (41.4) | 2.808 (54.9) | 2.712 (86.3) |
| CL/F (L/h) | 55.99 (47.7) | 39.16 (108.2) | 40.45 (68.6) |
| Vz/F (L) | 142.1 (29.8) | 158.6 (46.0) | 158.3 (33.1) |
| Healthy control cohorts | ||||
|---|---|---|---|---|
| Healthy control–mild HI, (n = 8) a | Healthy control–moderate HI, (n = 8) a | Healthy control–severe HI, (n = 6) a | Overall healthy control, (n = 16) a | |
| AUC0–24 (ng*h/mL) | 294.5 (71.7) | 424.3 (116.5) | 417.9 (85.5) | 415.3 (98.5) |
| AUC0–t (ng*h/mL) | 292.0 (72.2) | 421.8 (117.5) | 411.5 (86.5) | 411.5 (99.3) |
| AUC0–inf (ng*h/mL) | 295.7 (72.1) | 427.0 (117.2) | 418.2 (85.7) | 417.0 (99.0) |
| C max (ng/mL) | 86.3 (34.7) | 111.2 (50.3) | 116.4 (66.7) | 108.4 (53.3) |
| T max (h) | 1.750 (1.00, 2.00) | 1.750 (0.67, 4.00) | 2.000 (1.00, 6.00) | 2.000 (0.67, 6.00) |
| t ½ (h) | 2.054 (54.7) | 2.432 (57.9) | 1.924 (20.7) | 2.117 (50.0) |
| CL/F (L/h) | 67.63 (72.1) | 46.84 (117.2) | 47.83 (85.7) | 47.96 (99.0) |
| Vz/F (L) | 200.4 (65.8) | 164.3 (76.7) | 132.8 (71.3) | 146.5 (67.4) |
Note: AUCs, C max, t 1/2, and CL/F are presented as geometric mean (geometric coefficient of variation %). T max is presented as median (min, max).
Abbreviations: AUC0–24, area under the plasma concentration–time curve from time 0 to 24 hours after dosing; AUC0–inf, AUC from time 0 to infinity; AUC0–t, AUC from time 0 to time t after dosing; CL/F, apparent total clearance after extravascular administration; C max, maximum plasma concentration; HI, hepatic impairment; PK, pharmacokinetic; SD, standard deviation; t ½, apparent terminal elimination half‐life; T max, time to maximum plasma concentration; Vz/F, apparent volume of distribution during the terminal elimination phase after extravascular administration.
Healthy control subjects matched to a participant in one HI group could also be matched to a participant fitting the same demographic criteria (age, body mass index, and sex) in another HI group. Three control subjects were matched to a participant in each of the mild and moderate HI groups, and three control subjects were matched to a participant in each of the mild and severe HI groups.
Following a single 20 mg dose of futibatinib, the geometric mean AUC0–24, AUC0–t, AUC0–inf, and C max were greater (~17%–21% for AUC and ~10%–43% for C max) in participants with hepatic impairment compared with the corresponding matched healthy control group (Table 3). Results were similar when the hepatic impairment groups were compared with the overall healthy control group, with GMRs ranging from 85.9% to 122.5% for AUC and 113.5% to 117.9% for C max (Table 4). There was no obvious trend between the severity of hepatic impairment and the extent of exposure increase. Interindividual variability was generally higher in the matched healthy control groups compared with the three hepatic impairment groups (Table 4). Other PK parameters were largely comparable among the three hepatic impairment groups and the corresponding healthy control group, albeit with some interindividual variability, including one outlier for t 1/2 in the severe hepatic impairment group and one outlier for CL/F in the moderate hepatic impairment group (Figure S2).
TABLE 3.
Statistical comparisons of futibatinib plasma PK parameters AUC0–24, AUC0–inf, and C max in participants with hepatic impairment versus matched participants with normal hepatic function.
| HI (test) | Healthy control (reference) a | Cohort Inter‐subject CV% | |||||
|---|---|---|---|---|---|---|---|
| Geometric LSMs | n | Geometric LSMs | n | GMR (90% CI), % | HI | Healthy control | |
| Mild HI | |||||||
| AUC0–24 (ng*h/mL) | 356.8 | 8 | 294.5 | 8 | 121.19 (74.27–197.74) | 47.51 | 71.68 |
| AUC0–inf (ng*h/mL) | 357.2 | 8 | 295.7 | 8 | 120.79 (73.89–197.47) | 47.65 | 72.08 |
| C max (ng/mL) | 123.0 | 8 | 86.3 | 8 | 142.53 (103.42–196.44) | 40.45 | 34.72 |
| Moderate HI | |||||||
| AUC0–24 (ng*h/mL) | 507.5 | 8 | 424.3 | 8 | 119.62 (54.08–264.61) | 107.49 | 116.48 |
| AUC0–inf (ng*h/mL) | 510.8 | 8 | 427.0 | 8 | 119.61 (53.90–265.45) | 108.17 | 117.16 |
| C max (ng/mL) | 127.8 | 8 | 111.2 | 8 | 114.85 (75.38–175.00) | 51.10 | 50.27 |
| Severe HI | |||||||
| AUC0–24 (ng*h/mL) | 488.5 | 6 | 417.9 | 6 | 116.91 (57.52–237.60) | 66.87 | 85.54 |
| AUC0–inf (ng*h/mL) | 494.4 | 6 | 418.2 | 6 | 118.23 (57.79–241.87) | 68.57 | 85.67 |
| C max (ng/mL) | 127.6 | 6 | 116.4 | 6 | 109.64 (66.62–180.44) | 29.89 | 66.68 |
Note: GMR = 100 × (test/reference).
Abbreviations: AUC0–24, area under the plasma concentration–time curve from time 0 to 24 h after dosing; AUC0–inf, area under the plasma concentration–time curve from time 0 to infinity; CI, confidence interval; C max, maximum plasma concentration; CV, coefficient of variation; GMR, geometric mean ratio; HI, hepatic impairment; LSM, least squares mean; PK, pharmacokinetic.
Healthy control subjects matched to a participant in one HI group could also be matched to a participant fitting the same demographic criteria (age, body mass index, and sex) in another HI group. Three control subjects were matched to a participant in each of the mild and moderate HI groups, and three control subjects were matched to a participant in each of the mild and severe HI groups.
TABLE 4.
Statistical comparisons of futibatinib plasma PK parameters AUC0–24, AUC0–inf, and C max in participants with hepatic impairment versus the overall healthy control cohort.
| HI (test) | Healthy control (reference) a | GMR (90% CI), % | Cohort, Inter‐subject CV% | ||||
|---|---|---|---|---|---|---|---|
| Geometric LSMs | n | Geometric LSMs | n | HI | Healthy control | ||
| Mild HI | |||||||
| AUC0–24 (ng*h/mL) | 356.8 | 8 | 415.3 | 16 | 85.92 (54.94–134.38) | 47.51 | 98.51 |
| AUC0–inf (ng*h/mL) | 357.2 | 8 | 417.0 | 16 | 85.66 (54.70–134.15) | 47.65 | 98.96 |
| C max (ng/mL) | 123.0 | 8 | 108.4 | 16 | 113.52 (82.50–156.21) | 40.45 | 53.26 |
| Moderate HI | |||||||
| AUC0–24 (ng*h/mL) | 507.5 | 8 | 415.3 | 16 | 122.20 (64.51–231.48) | 47.51 | 98.51 |
| AUC0–inf (ng*h/mL) | 510.8 | 8 | 417.0 | 16 | 122.49 (64.50–232.63) | 47.65 | 98.96 |
| C max (ng/mL) | 127.8 | 8 | 108.4 | 16 | 117.90 (82.04–169.44) | 40.45 | 53.26 |
| Severe HI | |||||||
| AUC0–24 (ng*h/mL) | 488.5 | 6 | 415.3 | 16 | 117.62 (67.44–205.13) | 66.87 | 98.51 |
| AUC0–inf (ng*h/mL) | 494.4 | 6 | 417.0 | 16 | 118.57 (67.46–208.38) | 68.57 | 98.96 |
| C max (ng/mL) | 127.6 | 6 | 108.4 | 16 | 117.78 (87.42–158.68) | 29.89 | 53.26 |
Note: GMR = 100 × (test/reference).
Abbreviations: AUC0–24, area under the plasma concentration‐time curve from time 0 to 24 h after dosing; AUC0–inf, area under the plasma concentration‐time curve from time 0 to infinity; CI, confidence interval; C max, maximum plasma concentration; CV, coefficient of variation; GMR, geometric mean ratio; HI, hepatic impairment; LSM, least squares mean; PK, pharmacokinetics.
Healthy control subjects matched to a participant in one HI group could also be matched to a participant fitting the same demographic criteria (age, body mass index, and sex) in another HI group. Three control subjects were matched to a participant in each of the mild and moderate HI groups, and three control subjects were matched to a participant in each of the mild and severe HI groups.
Visual inspection of scatter/regression plots of Child‐Pugh scores, bilirubin, albumin, INR, and AST versus plasma futibatinib PK parameters suggested no conclusive trends between hepatic function measures and futibatinib PK. Representative plots for PK parameters (AUC0–inf, Cmax, and CL/F) versus Child‐Pugh scores are shown in Figure 3, with corresponding figures for liver function tests provided in Figures S3–S6. The slope (p value) of each regression was greater than 0.05, suggesting no significant relationship for any correlation.
FIGURE 3.
Scatter/regression plots of Child‐Pugh scores versus individual plasma futibatinib (a) AUC0–inf, (b) C max, and (c) CL/F following a single oral dose of 20 mg futibatinib in participants with mild, moderate, and severe HI. AUC0–inf, area under the plasma concentration–time curve from time 0 to infinity; CI, confidence interval; CL/F, apparent total clearance after extravascular administration; C max, maximum plasma concentration; HI, hepatic impairment.
Safety
Futibatinib was well‐tolerated in all groups. In total, four TEAEs were reported, including two grade 1 TEAEs of dyspepsia and headache in two (12.5%) participants in the healthy control cohort and two grade 1 TEAEs of toothache and headache in two (25.0%) participants with mild hepatic impairment. No participants in the moderate or severe hepatic impairment cohorts reported TEAEs. All TEAEs were reported as related to the study drug, and all resolved by study completion. There were no study discontinuations due to TEAEs.
No unexpected findings or remarkable trends were noted in the laboratory results, and there were no notable results for vital signs, electrocardiograms, or physical or ophthalmologic examinations.
DISCUSSION
The primary objective of this study was to determine the PKs of futibatinib in individuals with varying degrees of hepatic impairment compared with matched healthy control participants. Liver impairment can result in decreased hepatic blood flow and reduced activity of drug‐metabolizing enzymes, potentially causing alterations in drug PKs by decreasing hepatic clearance. 19 Assessing the effect of hepatic impairment on drug exposures is recommended if hepatic impairment is expected to significantly alter the PKs of the parent drug or active metabolite (i.e., if hepatic metabolism and/or excretion accounts for >20% of elimination) and is particularly important if the drug is intended to be used in patients with hepatic impairment. 19 As hepatic metabolism represents a major clearance pathway for futibatinib, a study evaluating the effect of hepatic impairment on futibatinib PKs was warranted. Additionally, risk factors for intrahepatic CCA include older age and chronic liver disease, 20 and impaired hepatic function may result from the tumor mass itself. 21 Therefore, the intended patient population for futibatinib is likely to include individuals with hepatic impairment, providing additional rationale for evaluating the effect of hepatic impairment on futibatinib PKs.
In this open‐label, nonrandomized, single‐dose study, the concentration–time profiles of futibatinib were generally well‐characterized (mean percentage of AUC0–inf extrapolated, <2%). Compared with matched controls, AUC0–inf increased by 21%, 20%, and 18% and C max by 43%, 15%, and 10% in participants with mild, moderate, and severe hepatic impairment, respectively. However, the magnitude of exposure changes in participants with hepatic impairment was not considered to be clinically relevant, as GMRs were within the range of 80%–125%, 22 except for C max (143%) in participants with mild hepatic impairment. The latter may be due to random variability, because increasing severity to moderate or severe hepatic impairment was not found to be associated with any further increase in futibatinib exposure; however, the reason has not been confirmed.
Visual inspection of the comparisons of measurements of hepatic impairment and plasma futibatinib PKs suggested no conclusive trends between plasma futibatinib PK parameters versus Child‐Pugh scores, bilirubin, albumin, INR, and AST. Moreover, the slope (p value) of each regression was greater than 0.05, suggesting no significant relationship for any correlation. Unlike other approved FGFR inhibitors, which have no established dose recommendations for patients with severe HI, 23 , 24 these data support the same starting dose of futibatinib 20 mg once daily for all patients, irrespective of the degree of hepatic impairment, including severe hepatic impairment.
The PK parameters in the control group of this study were largely comparable with those observed under fasted conditions among healthy subjects in the phase I food effect study and in subjects who received futibatinib alone in a phase I study that evaluated the effect of concomitant proton pump inhibitors (lansoprazole). 15 Although C max and AUC in the control group of the current study were numerically lower than observed in the food effect and lansoprazole studies (C max: 108.4 vs. 154.6 and 216.1; AUC0–t: 411.5 vs. 617.8 and 934.0; AUC0–inf: 417.0 vs. 625.7 and 941), this likely reflects the inherent variability of futibatinib PKs along with potential differences between the study populations, because a similar magnitude of difference in these parameters was observed between the reference groups in the other phase I studies. 15
Of note, based on the results of the food effect study, the US label recommends that futibatinib may be taken with or without food. 11 Considering that the degree of food effect on oral futibatinib bioavailability was not considered to be clinically meaningful in healthy subjects, 15 administering futibatinib with food is not expected to have a clinically meaningful impact on exposure compared with administration under fasted conditions in patients with hepatic impairment.
In terms of safety, futibatinib administered as a single oral 20 mg dose was well‐tolerated regardless of hepatic function, with only four TEAEs (all grade 1) observed across the mild hepatic impairment and healthy control cohorts.
In addition to total plasma concentrations, unbound futibatinib plasma concentrations were measured at one predose and two postdose timepoints. However, calculation of unbound futibatinib was restricted because ~22% of samples at the 12‐h timepoint were below the limit of quantification. Consequently, no interpretation of unbound futibatinib PK parameters was made, and the results were excluded from this analysis. Further analysis of the clinical impact of unbound futibatinib would therefore be of interest. An additional limitation was the high level of interindividual variability observed for AUC and C max, particularly within the matched healthy control cohorts. Interindividual variability was also observed for t 1/2 and CL/F, such that these parameters were summarized as geometric means to minimize the impact of outliers. Despite the observed variability, the study design minimized possible imbalances between cohorts as far as possible by matching each of the hepatic impairment groups to a control group with normal hepatic function. Furthermore, no protocol deviations occurred that were determined to have affected the results or conclusions; therefore, all participants were included in the PK and safety analyses.
In conclusion, the results of this study address the question of whether hepatic impairment has a clinically relevant impact on futibatinib exposure. Following administration of a single oral dose of 20 mg futibatinib, there was no clinically relevant association between the degree of hepatic impairment and futibatinib exposure, based on Child‐Pugh scores and liver function tests. The results demonstrate that no dose adjustment is required for mild, moderate, or severe hepatic impairment in patients receiving futibatinib. These findings are particularly relevant for patients with intrahepatic CCA or other tumors with liver involvement who have severe HI and are being considered for treatment with an FGFR inhibitor.
AUTHOR CONTRIBUTIONS
L.G., I.Y., M.P., N.H., and V.W. designed the research. L.G., I.Y., M.P., J.C.R., and T.M. performed the research. L.G., I.Y., M.P., J.R., T.M., G.T., L.M., N.H., and V.W. participated in the interpretation/analysis of the data and writing or reviewing and editing of the manuscript, agreed to be accountable for all aspects of the work, and approved the final manuscript for submission.
FUNDING INFORMATION
The trial was sponsored by Taiho Oncology, Inc. The sponsors were involved in the design and conduct of the trial and the data collection and analysis, in the writing of the manuscript, and in the decision to submit for publication.
CONFLICT OF INTEREST STATEMENT
L.G., M.P., G.T., L.M., N.H., and V.W. are employees of Taiho Oncology, Inc. I.Y. is an employee of Taiho Pharmaceutical Co., Ltd., a stockholder of Otsuka Holdings, and a former employee of Taiho Oncology, Inc. J.C.R. has no conflicts of interest to declare. T.M. is an employee and equity owner of the Orlando Clinical Research Center.
Supporting information
Appendix S1
ACKNOWLEDGMENTS
The authors thank and acknowledge all the participants, their families, and study personnel for participating in the study. Medical writing assistance was provided by Fiona Scott, PhD, on behalf of Envision Pharma Group, funded by Taiho Oncology, Inc.
Gao L, Yamamiya I, Pinti M, et al. A phase I, open‐label, single‐dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib. Clin Transl Sci. 2023;16:1713‐1724. doi: 10.1111/cts.13585
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Supplementary Materials
Appendix S1