Drug Interactions of Vebreltinib, a Novel Type I c‐Met Inhibitor, Coadministration With Rifampin or Itraconazole in Healthy Participants

ABSTRACT

Vebreltinib is a novel, highly selective type I c‐Met inhibitor developed for treating non–small cell lung cancer (NSCLC) and glioma. As in vitro studies indicate that vebreltinib is primarily metabolized via cytochrome P450 (CYP) 3A4, this study aimed to characterize the drug–drug interaction (DDI) potential of vebreltinib with strong CYP3A4 modulators. Following a preliminary single ascending dose (SAD) study to establish baseline safety and pharmacokinetics (PK) in healthy participants, a DDI study was designed to evaluate the impact of the strong CYP3A4 inducer rifampin and the strong CYP3A4 inhibitor itraconazole on vebreltinib exposure. In the CYP3A4 induction part of the DDI study, participants (n = 14) received 200 mg vebreltinib on Days 1 and 15, with rifampin (600 mg once daily) administered on Days 8–21. In the inhibition part, participants (n = 14) received 200 mg vebreltinib on Days 1 and 11. Itraconazole was administered as a loading dose (200 mg BID on Day 8) followed by maintenance dosing (200 mg QD from Days 9 to 19). PK blood samples were collected at predetermined time points. Vebreltinib plasma concentrations were assessed using a validated liquid chromatography–tandem mass spectrometry (LC–MS) method. Co‐administration with rifampin reduced the AUC_0‐t and AUC_0‐∞of vebreltinib by ~65% and ~66%, respectively, whereas the C_max did not change significantly. In contrast, coadministration with itraconazole led to an increase in the AUC and C_max of vebreltinib by about 56% and 46%, respectively. Vebreltinib, both alone and in combination with rifampin or itraconazole, was well tolerated in healthy participants.

Study Highlights

• What is the current knowledge on the topic?

  • ○
    Vebreltinib, a novel type I c‐Met inhibitor, achieved ideal responses in non–small cell lung cancer and glioblastoma patients with MET alterations. It has recently been approved by the National Medical Products Administration (NMPA) of China. Preclinical analysis showed that vebreltinib was metabolized by CYP3A4. The clinical drug–drug interaction (DDI) studies were performed to evaluate the potential object DDIs of vebreltinib.
• What question did this study address?

  • ○
    A preliminary single ascending dose (SAD) study explored the safety and pharmacokinetics (PK) characteristics of vebreltinib in healthy participants. Then the drug–drug interaction study evaluated the clinical drug interaction of vebreltinib with rifampin (a strong inducer of CYP3A4) and itraconazole (a strong inhibitor of CYP3A4).
• What does this study add to our knowledge?

  • ○
    For CYP3A4 induction, rifampin could induce the metabolism of vebreltinib and reduce the exposure of vebreltinib, which may affect its antitumor efficacy. In contrast, for CYP3A4 inhibition, itraconazole increased the exposure of vebreltinib.
• How might this change clinical pharmacology or translational science?

  • ○
    Vebreltinib showed a notable interaction with CYP3A4 inhibitors. The result of this DDI study will provide a reference for guiding vebreltinib clinical use and DDI risk management.

Pharmacokinetic and drug–drug interaction evaluation of vebreltinib in healthy participants, showing decreased exposure with rifampin and increased exposure with itraconazole.

1. Introduction

C‐Met, a receptor tyrosine kinase, binds to hepatocyte growth factor (HGF) to activate c‐Met, as well as interacts with other receptor tyrosine kinases (RTKs) to induce downstream signaling cascade activation [1]. It is crucial for cell growth and survival, and its abnormal triggering has been found in various cancers, leading to a poor prognosis [2].

As a promising treatment option, c‐Met inhibitors enhance patient survival, as well as prolong patients' lifespan [3]. A recent study showed that a c‐Met inhibitor could enhance the efficacy of chemo‐immunotherapy in small cell lung cancer [4, 5]. To date, various tyrosine‐kinase inhibitors (TKIs) targeting MET have received approval for use in treating tumors characterized by abnormal MET amplification [6]. As a novel type I c‐Met inhibitor with high selectivity and efficiency, vebreltinib has recently been approved by the National Medical Products Administration (NMPA) of China for treating non–small cell lung cancer (NSCLC) and glioma. A phase 2 clinical trial verified that vebreltinib presented an ideal objective response rate (ORR) of 75.0% and sustained duration of response (median, 15.9 months) among MET exon 14 skipping (METex14) mutant NSCLC patients, regardless of previous treatment [7]. Vebreltinib also achieved partial responses in patients with MET‐altered chemoresistant secondary glioblastoma. In addition, vebreltinib has the potential to treat the central nervous system (CNS) metastases because of its superior blood–brain barrier permeability [8, 9]. In previous studies, the safety of vebreltinib was acceptable and generally manageable [7, 9, 10]. By blocking the c‐Met signaling pathway, vebreltinib has also demonstrated effectiveness in treating gastric cancer, breast cancer, and intrahepatic cholangiocarcinoma [11, 12, 13]. The findings suggest that vebreltinib could be beneficial in treating various types of cancers with MET alterations.

Preclinical analysis of CYP phenotyping in human liver microsomes (HLMs) using selective chemical inhibitors and recombinant enzyme kinetics suggests that CYP3A4 plays a relatively predominant role in the metabolism of vebreltinib, while CYP2C9 may contribute to a lesser extent, and other CYP isoforms are not involved in the process. According to the human mass balance study, the principal metabolic pathways of vebreltinib in humans are N‐demethylation, N‐decyclopropanation, oxidation (hydroxylation), and glucuronidation. The study also shows that fecal excretion is the predominant route of radioactivity recovery, with 79.5% of the administered dose recovered in feces and 13.5% recovered in urine. Unchanged vebreltinib is the major radioactive component in feces, accounting for 70.8% of the administered dose. Aligned with recommendations of ICH M12, clinical DDI studies should be conducted for any new molecular entity (NME) confirmed preclinically to be metabolized by CYP3A [14]. CYP3A‐mediated DDIs may alter drug exposure and consequently impact the clinical efficacy and safety of the affected medications. Therefore, we explored the drug–drug interaction of vebreltinib with rifampin (CYP3A4 inducer) and itraconazole (CYP3A4 inhibitor) to inform its clinical administration.

2. Methods

2.1. Overall Study Information

First, an open‐label, single‐center, single ascending dose (SAD) study was performed to explore the pharmacokinetics (PK) and safety of vebreltinib in healthy Chinese participants. Then a single‐center, open‐label, fixed‐sequence drug–drug interaction (DDI) study was performed. The trial was prospectively registered with the Chinese Clinical Trial Registry under identifier CTR20212186. The Ethics Committee of the Institute of Beijing Friendship Hospital, Capital Medical University, approved both studies (The Ethics Approval Date/Number: 2021.06.29/2021‐P1‐055‐02). Both studies were conducted in compliance with applicable guidelines and regulations, including but not limited to the Declaration of Helsinki and the Guideline for Good Clinical Practice. Prior to participating in any study procedures, all participants provided their informed consent by signing the necessary forms.

2.2. Participants

Healthy participants between the ages of 18 and 45, with a body mass index (BMI) ranging from 19.0 to 26.0 kg/m² and a minimum body weight of 50 kg for males or 45 kg for females, were enrolled. During the screening phase, evaluations included checking vital signs, conducting a physical examination, reviewing medical history, performing electrocardiogram (ECG) tests, and carrying out clinical laboratory tests. Participants with significant medical conditions or those who had taken prescription medications or drugs influencing liver drug metabolism within 14 days prior to joining were not eligible. The use of any medication during the study was prohibited unless it was necessary due to adverse events. Pregnant or breastfeeding individuals were also excluded.

2.3. Study Design

This study was conducted approximately one year after the initiation of vebreltinib's phase II trial in patients with NSCLC. In previous phase I dose‐escalation and expansion studies, no dose‐limiting toxicities (DLTs) or maximum tolerated dose (MTD) were observed across the explored dose range (50 mg BID to 275 mg BID and 300 mg QD). Treatment‐related adverse events (AEs) were predominantly CTCAE grade 1–2, reflecting a favorable and manageable safety profile [15]. In addition, PK analysis demonstrated that vebreltinib exhibited dose‐proportional pharmacokinetic characteristics, with the recommended phase II dose (RP2D) set at 200 mg BID [15].

Considering that the previous trials were conducted in patients with tumors [7, 15, 16], a single ascending dose study was conducted to preliminarily explore the safety and pharmacokinetic properties of vebreltinib in healthy individuals. In the SAD study, there were two dose cohorts (50 mg and 100 mg cohorts). Four participants were enrolled in each cohort, and participants received a single oral dose of vebreltinib capsules on D1 after an overnight fast of at least 10 h.

The DDI study was divided into two parts: The enzyme induction part and the enzyme inhibition part. Fourteen participants were enrolled in each part, and the oral dose of vebreltinib capsules was 200 mg. The 200 mg dose was chosen for the DDI study because it represents the clinically recommended dose. First, to assess CYP3A4 induction, the effect of rifampin on the pharmacokinetics of vebreltinib was studied. A sentinel cohort of 4 subjects was enrolled first to assess the safety of a single 200 mg vebreltinib among healthy participants. Participants took a single 200 mg oral dose of vebreltinib capsules on the first day after an overnight fast of at least 10 h, followed by a 7‐day washout. From days 8 to 21, rifampin capsules were administered at 600 mg once daily under fasted conditions. On day 15, 200 mg vebreltinib capsules were taken together with rifampin capsules. For CYP3A4 inhibition, the influence of itraconazole on vebreltinib's pharmacokinetics was investigated. Participants received 200 mg of vebreltinib capsules on day 1 under fasted conditions, followed by a 7‐day washout. Itraconazole capsules were given from days 8 to 19, with a dosage of 200 mg twice daily on day 8 and 200 mg once daily from days 9 to 19. Itraconazole capsules were administered BID orally immediately after a meal on day 8 and QD immediately after breakfast on days 9 to 10, days 12–19. On day 11, vebreltinib capsules (200 mg) were co‐administered with itraconazole capsules after an overnight fast of at least 10 h. The overall study design is shown in Figure 1.

FIGURE 1.

Overall study design.

2.4. Pharmacokinetics

In the SAD study, PK blood samples (4 mL each) were collected at the following time points: 0 h (predose), 0.25, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 28, 32, 36, 48, 60, 72, 96, and 120 h after dosing. In the enzyme induction part, PK blood samples (4 mL each) were collected before vebreltinib dosing and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 28, 32, 36, 48, 60, 72, 96, 120, and 144 h after vebreltinib administration both in periods 1 (vebreltinib alone) and 2 (co‐administration with rifampin). In the enzyme inhibition part, blood samples (4 mL each) were collected before vebreltinib dosing and at 1, 2, 3, 4, 5, 6, 8, 9, 10, 12, 14, 16, 24, 28, 32, 36, 48, 60, 72, 96, 120, and 144 h after vebreltinib administration in period 1. Given the inhibitory effect of itraconazole, two more blood samples at 168 and 196 h were collected after vebreltinib co‐administration with itraconazole in period 2.

Immediately after whole blood collection, samples were placed in an ice‐water bath and centrifuged within 1 h of collection. All blood samples were centrifuged at 1,700 rpm (4°C) for 10 min. Following centrifugation, the top layer of plasma was stored at approximately −80°C until bioanalysis. The concentrations of vebreltinib were quantified using a validated liquid chromatography–tandem mass spectrometry (LC–MS) method.

2.5. Safety Assessment

Safety was monitored by assessing vital signs, physical examination, 12‐lead electrocardiogram, laboratory assessments including hematology, blood chemistry, coagulation, urinalysis, pregnancy assessment for women, and other evaluations as clinically indicated. Throughout the study, adverse events (AEs) were recorded and followed, with evaluations focusing on their duration, severity, treatment interventions, outcomes, and their relationship to the study medications.

2.6. Statistical Analysis

The PK analysis set included all individuals who received at least one dose of vebreltinib and had a PK profile that could be evaluated. Safety data were reviewed for all participants who received at least one dose of vebreltinib and had safety evaluation data available post‐dosing. PK parameters were determined using non‐compartmental analysis with Phoenix WinNonlin version 8.3. All statistical analyses were conducted using SAS software (version 9.4). A linear mixed‐effects model was used to analyze log‐transformed PK parameters (C_max, AUC_0‐t, and AUC_0‐∞) to assess the effects of rifampin and itraconazole on vebreltinib. The model considered treatment as a fixed effect and subject as a random effect. To assess the pharmacokinetic effects of rifampin or itraconazole on vebreltinib, the geometric mean ratios (vebreltinib+rifampin or vebreltinib+itraconazole/vebreltinib alone) were determined, along with 90% confidence intervals. Descriptive statistics, including mean, CV%, median, geometric mean, and geometric CV%, were used to present PK parameters. Only median values and ranges were reported for T_max.

3. Results

3.1. Demographics

A total of 108 candidates were screened, and 36 participants (8 participants in the SAD study and 28 participants in the DDI study) were enrolled. All enrolled participants completed the trial and were included in the PK and safety analysis sets. The age of the participants ranged from 22 to 44 years, and their body mass index (BMI) ranged from 19.23 to 25.88 kg/m². Detailed baseline demographic characteristics are presented in Table S1.

3.2. Pharmacokinetic Analysis

3.2.1. PK Evaluation of the Single Oral Dose of Vebreltinib

Within the dose range 50–200 mg, the exposure of vebreltinib increased in a dose‐proportional manner following a single oral dose, as evidenced by the parameters C_max, AUC_0‐t, and AUC_0‐∞. The elimination half‐life (t_1/2) showed no significant difference across these dose levels. The complete PK results (based on single oral 50 mg and 100 mg vebreltinib in the SAD study and single oral 200 mg vebreltinib in the rifampin group of the DDI study) of the single oral dose of vebreltinib are shown in Table S2 and Figure S1.

3.2.2. Effect of Rifampin on the PK of Vebreltinib

The mean plasma concentration‐time profiles for vebreltinib, administered alone or in combination with rifampin, are shown in Figure 2, a corresponding summary of the pharmacokinetic parameters is provided in Table 1 and Figure 4a–c. Co‐administration with rifampin did not significantly change the mean C_max (1063.36 vs. 1062.07 ng/mL), but reduced the mean AUC_0‐t and AUC_0‐∞ (49.52 vs. 16.89 ug·h/mL and 50.87 vs. 19.94 ug·h/mL). The mean t_1/2 was shortened from 21.84 h to 10.56 h, and the median T_max decreased from 16 h to 4 h. As anticipated, the apparent clearance CL/F increased when vebreltinib was co‐administered with rifampin (Table 1). The geometric mean ratios (GMRs) and their 90% confidence intervals for vebreltinib plus rifampin vs. vebreltinib alone were 1.06 (0.78–1.42) for C_max, 0.35 (0.29–0.43) for AUC_0‐t, and 0.34 (0.28–0.42) for AUC_0‐∞ (Table 2, Figure 4d). These results indicate that rifampin coadministration had no significant effect on C_max but reduced the systemic exposure of vebreltinib by approximately 65% to 66%, consistent with the induction of vebreltinib metabolism by rifampin.

FIGURE 2.

Mean plasma concentration‐time profiles (mean ± SD) of vebreltinib after a single dose of vebreltinib alone and in combination with rifampin. Left: Linear scale; Right: Semi‐logarithmic scale.

TABLE 1.

Vebreltinib PK parameters when administered alone or with rifampin or itraconazole.

PK parameter	Mean ± SD (CV%)
	Induction Part (N = 14)		Inhibition Part (N = 14)
	Vebreltinib alone	Vebreltinib + Rifampin	Vebreltinib alone	Vebreltinib + Itraconzole
Tmax*(h)	16.00 (4.00,48.00)	4.00 (2.00,16.00)	9.00 (3.00,36.00)	8.00 (2.00,36.00)
Cmax(ng/mL)	1063.36 ± 550.50 (51.77)	1162.07 ± 558.04 (48.02)	1282.71 ± 761.86 (59.39)	1787.79 ± 912.87 (51.06)
AUC0‐t(hμg/ml)*	49.52 ± 16.59 (33.50)	16.89 ± 4.06 (24.02)	48.46 ± 19.08 (39.37)	67.21 ± 20.54 (30.57)
AUC0‐∞(hμg/ml)*	50.87 ± 18.15 (35.69)	16.94 ± 4.05 (23.89)	48.83 ± 19.22 (39.35)	67.51 ± 20.63 (30.55)
t1/2(h)	21.84 ± 4.98 (22.80)	10.56 ± 3.32 (31.48)	16.88 ± 3.44 (20.37)	22.25 ± 4.98 (22.35)
Vd/F(L)	135.13 ± 47.54 (35.18)	186.78 ± 68.46 (36.65)	126.99 ± 90.16 (71.00)	105.65 ± 46.97 (44.46)
CL/F(L/h)	4.49 ± 1.86 (41.50)	12.45 ± 3.05 (24.49)	5.39 ± 4.45 (82.57)	3.24 ± 1.00 (31.01)

^*T_max, Median (Min, Max).

FIGURE 4.

(a) C_max, (b) AUC_0‐t, (c) AUC_0‐∞ and (d) Geometric mean ratios (GMR) and 90% confidence interval of vebreltinib under vebreltinib plus rifampin vs. vebreltinib alone; (e) C_max, (f) AUC_0‐t, (g) AUC_0‐∞ and (h) Geometric mean ratios (GMR) with 90% confidence interval of vebreltinib for vebreltinib plus itraconazole vs. vebreltinib alone.

TABLE 2.

Summary of Statistical Analysis of PK Parameters of vebreltinib alone or with rifampin or itraconazole.

PK Parameter	Geometric mean [90% CI]		Geometric mean ratio [90% CI]
Induction part	Vebreltinib alone	Vebreltinib+Rifampin	Vebreltinib+Rifampin/Vebreltinib alone
Cmax, ng/mL	976.93 [813.23 ~ 1173.59]	1040.45 [820.25 ~ 1319.77]	1.06 [0.80 ~ 1.42]
AUC0‐t, ug·h/mL	46.78 [39.41 ~ 55.53]	16.44 [14.68 ~ 18.42]	0.35 [0.29 ~ 0.43]
AUC0‐∞, ug·h/mL	47.77 [39.95 ~ 57.13]	16.50 [14.73 ~ 18.48]	0.34 [0.28 ~ 0.42]

Inhibition part	Vebreltinib alone	Vebreltinib+Itraconazole	Vebreltinib+Itraconazole/Vebreltinib alone
Cmax, ng/mL	1086.28 [813.07 ~ 1451.30]	1587.72 [1249.66 ~ 2017.25]	1.46 [1.02 ~ 2.10]
AUC0‐t, ug·h/mL	43.74 [34.04 ~ 56.21]	64.28 [55.45 ~ 74.51]	1.56 [1.11 ~ 1.95]
AUC0‐∞, ug·h/mL	44.06 [34.27 ~ 56.66]	64.56 [55.70 ~ 74.84]	1.55 [1.11 ~ 1.94]

3.2.3. Effect of Itraconazole on the PK of Vebreltinib

The mean plasma concentration‐time profiles of vebreltinib following a single oral dose administered alone and in combination with itraconazole are presented in Figure 3, with corresponding pharmacokinetic parameters summarized in Table 1 and Figure 4e–g. The median T_max of vebreltinib did not differ substantially between treatments (9 h vs. 8 h for administration alone vs. co‐administration). However, co‐administration with itraconazole resulted in increased plasma exposure of vebreltinib. The mean C_max rose from 1282.71 ng/mL to 1787.79 ng/mL, the mean AUC_0‐t and AUC_0‐∞ also increased from 48.46 to 67.21 μg·h/mL and from 48.83 to 67.51 μg·h/mL, respectively, and the mean t_1/2 was prolonged from 16.88 h to 22.25 h (Table 1). The geometric mean ratios (vebreltinib+itraconazole/vebreltinib alone) were 1.46 (1.02–2.10) for Cₘₐₓ, 1.56 (1.11–1.95) for AUC_0–t, and 1.55 (1.11–1.94) for AUC_0–∞ (Table 2, Figure 4h). These results confirm that concomitant use of the CYP3A4 inhibitor itraconazole increased the exposure of vebreltinib.

FIGURE 3.

Mean plasma concentration‐time profiles (mean ± SD) of vebreltinib after a single dose of vebreltinib alone and in combination with itraconazole. Left: Linear scale; Right: Semi‐logarithmic scale.

3.3. Safety

Vebreltinib was well‐tolerated alone and in combination with rifampin or itraconazole in all 36 enrolled healthy participants. No adverse events (AEs) were reported in the SAD study. In the DDI study, treatment‐emergent adverse events (TEAEs) were reported in 13 participants (36.1%): 3 in the induction phase (vebreltinib + rifampin) and 10 in the inhibition phase (vebreltinib + itraconazole), the latter including oral ulcers and laboratory abnormalities. In the induction part, three AEs occurred in three participants (21.43%), including elevated blood uric acid, hypertriglyceridemia, and elevated blood glucose. All of them occurred during the monotherapy phase with 200 mg vebreltinib. In the inhibition part, 10 AEs occurred in seven participants (50%). During the monotherapy phase with 200 mg vebreltinib, 3 AEs occurred in 2 participants, including hypertriglyceridemia and alanine aminotransferase increase. During the monotherapy phase with itraconazole, three AEs occurred in three participants, including oral ulcers, increased lymphocyte percentage, and hypertriglyceridemia. Four AEs occurred in two participants within the combination phase, including elevated bilirubin, creatine phosphokinase increase, and hypertriglyceridemia. Hypertriglyceridemia was the most common event (Table S3). All TEAEs were Grade 1, resolved without intervention, and did not lead to treatment discontinuation or death. A detailed summary is provided in Table 3.

TABLE 3.

TEAE subsystem analysis.

System Organ Class (SOC) Preferred Terminology (PT)	Vebreltinib+Rifampin N = 14 n (%)	Vebreltinib+Itraconazole N = 14 n (%)	Total N = 36 n (%)
At least one TEAE occurred	3 (21.43)	10 (71.43)	13 (36.11)
Various inspections	3 (21.43)	9 (64.28)	12 (33.33)
Alanine aminotransferase increased	0	1 (7.14)	1 (2.78)
Creatine phosphokinase increased	0	1 (7.14)	1 (2.78)
Blood Uric Acid Increased	1 (7.14)	0	1 (2.78)
Blood Bilirubin Increased	0	1 (7.14)	1 (2.78)
Unbound Bilirubin Increased	0	1 (7.14)	1 (2.78)
Lymphocyte percentage increased	0	1 (7.14)	1 (2.78)
Hypertriglyceridaemia	1 (7.14)	4 (28.57)	5 (13.89)
Blood glucose elevated	1 (7.14)	0	1 (2.78)
Gastrointestinal system diseases	0	1 (7.14)	1 (2.78)
Oral ulcers	0	1 (7.14)	1 (2.78)

4. Discussion

With vebreltinib being a substrate of CYP3A4, it was essential to perform a drug–drug interaction study to evaluate the influence of a strong CYP3A4 inducer and inhibitor on the metabolism of vebreltinib as guided [14]. These results could offer a reference for the concomitant use of CYP3A inhibitors with vebreltinib. In a phase 1 study conducted in NSCLC patients, vebreltinib demonstrated dose‐proportional exposure across a dosage range from 50 mg BID to 300 mg QD, and the recommended Phase 2 dose was 200 mg BID [15]. Vebreltinib was deemed safe and generally well tolerated in NSCLC patients within the dosage range [15]. In another previously conducted phase I clinical trial evaluating the PK and tolerability of vebreltinib (50 mg BID–300 mg BID) in recurrent high‐grade glioma patients, it was determined that vebreltinib was safe and well tolerated within this dosage range [17]. None of the enrolled patients experienced dose‐limiting toxicity or any serious adverse events related to the medication [17]. Similar to the previous results, the safety analysis of the single oral dose study showed that vebreltinib was well‐tolerated among healthy participants. PK analysis verified that the exposure of vebreltinib was dose‐proportional within the dose range 50 mg to 100 mg in healthy participants.

Based on the positive single oral dose results in healthy participants, we performed the following DDI study. Given the above observations, considering that vebreltinib exhibited good linear PK characteristics, good tolerability, and the recommended dose of vebreltinib for Phase 2/3 trials was 200 mg BID, a 200 mg dose of vebreltinib was selected for the DDI study. The administration regimens of rifampin or itraconazole were based on previous studies to maximize the interaction between perpetrators and vebreltinib [18, 19]. A limitation of this study is that nitrosamine impurity content in the rifampin formulation was not specifically verified, although the product met applicable regulatory quality standards at the time of study conduct.

When co‐administered with the CYP3A4 inducer rifampin, the exposure of vebreltinib decreased as anticipated. Following the concomitant administration of vebreltinib with rifampin, the AUC_0‐t and AUC_0‐∞ decreased by ~65% and ~66%, respectively, compared to those of vebreltinib alone (Figure 2, Table 2). C_max showed no significant difference between vebreltinib administered alone and vebreltinib co‐administered with rifampin. The average T_max and t_1/2 of vebreltinib were both shorter after co‐administration with rifampin (Table 1). The median T_max decreased from approximately 16 h to 4 h, and the mean t_1/2 decreased from 21.84 h to 10.56 h when vebreltinib was administered together with rifampin. The shortening of t_1/2 is consistent with the known pharmacological effect of rifampin as a strong inducer of CYP3A enzymes.

The shortened T_max observed after rifampin co‐administration should be interpreted with caution. Based on the plasma concentration–time profiles, rifampin shifted the peak concentration of vebreltinib to an earlier time point, which may partly reflect an increase in the absorption rate. In addition, rifampin is a strong inducer of CYP3A and may affect drug transporters; the observed earlier T_max may reflect changes in the apparent absorption phase and/or presystemic disposition rather than a single mechanism. In the human mass balance study, vebreltinib was administered orally. The high recovery of radioactivity in feces may represent unabsorbed dose or enterohepatic recirculation or both. Permeability studies using a Caco‐2 cell model showed that vebreltinib has good membrane permeability and an efflux ratio close to unity, suggesting passive diffusion and indicating that vebreltinib is unlikely to be a substrate of P‐glycoprotein (P‐gp). However, no in vitro data are currently available regarding whether vebreltinib is a substrate of BCRP or OATP2B1. Thus, while a P‐gp‐mediated effect is unlikely, the potential contribution of BCRP or OATP2B1 to the observed change in T_max cannot be excluded. Further mechanistic studies would be needed to clarify the underlying mechanism of the earlier T_max observed with rifampin.

The available in vitro metabolism data and clinical pharmacokinetic findings support the interpretation that the observed decrease in vebreltinib exposure is mainly attributable to induction of CYP3A‐mediated metabolism. These reductions of vebreltinib exposures may affect the antitumor efficacy. As a result, patients are advised that co‐administration of vebreltinib with strong CYP3A inducers should be avoided, whereas moderate CYP3A inducers may also decrease vebreltinib exposure and should be used with caution.

Itraconazole is a strong CYP3A4 inhibitor. Co‐administration with itraconazole is expected to increase the exposure of drugs primarily metabolized by CYP3A4. As expected, the concurrent administration of itraconazole led to an increased exposure of vebreltinib. Following a single oral dose of 200 mg vebreltinib capsules in healthy participants, co‐administration with itraconazole increased the C_max of vebreltinib by ~46%, AUC_0‐t by ~56%, and AUC_0‐∞ by ~56% compared with that of vebreltinib monotherapy(Table 2). T_max did not differ significantly between treatments, and t_1/2 was prolonged from 16.88 h to 22.25 h when compared with vebreltinib alone (Table 1). Due to the potential for increased frequency and intensity of adverse reactions, we recommend that strong CYP3A inhibitors require caution and close monitoring when used with vebreltinib. Moderate CYP3A inhibitors may also increase vebreltinib exposure and warrant clinical monitoring if coadministration is necessary.

Comparison of the effects on AUC and elimination half‐life provides additional insight into the mechanisms of these interactions. In the rifampin arm, both AUC and t_1/2 decreased markedly, suggesting enhanced metabolic clearance due to enzyme induction. In contrast, co‐administration with itraconazole increased AUC and prolonged t_1/2, which is consistent with inhibition of metabolic elimination. Because vebreltinib was administered orally, the potential contribution of first‐pass metabolism cannot be completely excluded; however, the observed changes in half‐life support a predominant effect on systemic metabolic clearance.

Regarding safety, vebreltinib was well‐tolerated among healthy participants. All AEs were Grade 1 in severity and resolved completely. The types of adverse events in this study were similar to those in previous vebreltinib clinical studies, while the incidence rate and severity were lower in our study [7, 15, 17]. This study was conducted in healthy participants with better baseline health status than patients in previous studies, and participants received a maximum total dose of 400 mg vebreltinib, which was much lower than the clinical treatment doses used in previous trials [7, 9, 15]. The above factors may account for a lower incidence of adverse events in this study.

5. Conclusion

Administering single doses of vebreltinib, either on its own or alongside rifampin or itraconazole, was found to be safe and well‐tolerated among healthy individuals. Vebreltinib showed a notable interaction with CYP3A4 inhibitors. Co‐administration with the strong CYP3A inhibitor itraconazole resulted in a moderate increase in vebreltinib exposure, whereas co‐administration with the strong CYP3A inducer rifampin markedly reduced systemic exposure. These findings indicate that CYP3A‐mediated metabolism contributes to the disposition of vebreltinib, although it does not appear to be the sole elimination pathway.

Co‐administration of the CYP3A4 inhibitor (itraconazole) increased the total exposure of vebreltinib. Close monitoring is advised when vebreltinib is co‐administered with itraconazole or other strong CYP3A4 inhibitors. Moderate CYP3A inhibitors may also alter vebreltinib exposure and should be used with caution, whereas weak CYP3A inhibitors are expected to have a limited effect. Co‐administration with the CYP3A4 inducer (rifampin) significantly reduced the exposure of vebreltinib. Co‐administration of vebreltinib with rifampin or other strong CYP3A4 inducers should be avoided. Moderate CYP3A inducers may also decrease vebreltinib exposure and should be used with caution if coadministration is necessary. However, moderate and weak CYP3A modulators were not directly evaluated in this study. These data will provide a reference for guiding vebreltinib clinical use and DDI risk management.

Author Contributions

J.C. and L.L. wrote the manuscript. R.D., W.X., J.C., J.W., and Y.S. designed the research. J.C., J.W., Y.S., L.L., Y.K., X.W., J.L., H.Y., M.H., B.Y.W., Q.G., R.L., L.W., and R.D. performed the research and analyzed the data.

Funding

The study was sponsored by Beijing Pearl Biotechnology Co, Ltd (Beijing, China). This study was also supported by the National Key Research and Development Program of China (2024YFF1207000), Beijing Health Science and Technology Achievements and Appropriate Technology Promotion Project (BHTPP2024093).

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1: Concentration‐time profiles for single oral administration of vebreltinib.

Table S1: Demographic data*.

Table S2: PK parameters of a single ascending dose (SAD) administration of vebreltinib.

Table S3: Complete listing of adverse events.