
==== Front
Clin Transl Sci
Clin Transl Sci
10.1111/(ISSN)1752-8062
CTS
Clinical and Translational Science
1752-8054
1752-8062
John Wiley and Sons Inc. Hoboken

10.1111/cts.70021
CTS70021
CTS-2024-0224-T
Article
Article
Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers
Effects of CYP3A4 on the PK of olverembatinib
Wang et al.
Wang Hengbang https://orcid.org/0000-0003-3740-9056
1
Yang Yun https://orcid.org/0009-0001-4999-6975
1
Chen Zi https://orcid.org/0009-0007-9586-2867
1
Fu Lei https://orcid.org/0009-0004-7586-8709
2
Yu Min https://orcid.org/0009-0006-7768-5249
1
Jiang Lixin https://orcid.org/0009-0006-8614-142X
2
Wang Cunlin https://orcid.org/0009-0002-4705-8827
2
Men Lichuang https://orcid.org/0009-0007-5530-7869
1
Minto Ilisse https://orcid.org/0009-0001-6148-7399
2
Yang Dajun https://orcid.org/0000-0002-6027-3604
1 2
Zhai Yifan https://orcid.org/0000-0003-1672-2262
1 2 yzhai@ascentage.com

1 Guangzhou Healthquest Pharma Co., Ltd. Guangzhou China
2 Ascentage Pharma Group Inc Rockville Maryland USA
* Correspondence
Yifan Zhai, Ascentage Pharma Group Inc., 700 King Farm Blvd., Suite 510, Rockville, MD 20850, USA.
Email: yzhai@ascentage.com

03 9 2024
9 2024
17 9 10.1111/cts.v17.9 e7002112 8 2024
25 4 2024
14 8 2024
© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Abstract

Olverembatinib (HQP1351) is a BCR‐ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug‐resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open‐label, 2‐part, fixed‐sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time‐concentration curve (AUC)0‐last, and AUC0‐inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

Guangzhou Healthquest Pharma Co., Ltd. source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:03.09.2024
Wang H , Yang Y , Chen Z , et al. Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers. Clin Transl Sci. 2024;17 :e70021. doi:10.1111/cts.70021
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pmc Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Olverembatinib (HQP1351) is a BCR‐ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia who harbor drug‐resistant mutations, such as T315I. WHAT QUESTION DID THIS STUDY ADDRESS?

In vitro studies suggested that the metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). In a 2‐phase study, we examined whether concomitant administration of itraconazole and of rifampin with olverembatinib altered the pharmacokinetic properties of the latter drug. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Coadministration of olverembatinib with itraconazole greatly increased both the maximum plasma concentration and duration of exposure of olverembatinib, whereas coadministration with rifampin greatly decreased the maximum plasma concentration and duration of exposure of olverembatinib. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These data can be used to recommend appropriate dose modifications when patients are treated with both olverembatinib and other strong CYP3A4 inhibitors or inducers.

INTRODUCTION

The acquired reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2)], which is cytogenetically visible as the Philadelphia chromosome (Ph), is a hallmark of chronic myelogenous leukemia (CML). 1 The t(9;22) translocation leads to fusion of sequences from the ABL1 gene on 9q34 downstream of the BCR gene on 22q11 and generates a constitutively active BCR‐ABL1 fusion oncogene. 1 , 2 Numerous downstream pathways are activated by BCR‐ABL1, culminating in abnormal cellular proliferation, 3 reduced apoptosis, abnormal adhesion and migration, and genomic instability. 4 BCR‐ABL1 is both necessary and sufficient for the development of CML. 5

Tyrosine kinase inhibitors (TKIs) are the standard of care for newly diagnosed patients with CML in all disease phases. 6 Imatinib is a first‐generation (1G) TKI; dasatinib, nilotinib, bosutinib, and radotinib are second‐generation (2G) TKIs; and ponatinib is a third‐generation (3G) TKI. 6 , 7 , 8 , 9 These TKIs differ in their potency and activity against BCR‐ABL1 mutants.

Olverembatinib is a novel, orally active adenosine 5′‐triphosphate (ATP) binding‐site inhibitor against wild‐type BCR‐ABL1 (BCR‐ABLWT) kinase and a broad spectrum of BCR‐ABL1 mutations, including the T315I mutation (BCR‐ABL T315I ), which confers resistance against all first‐ and second‐generation TKIs. It binds tightly to BCR‐ABLWT and BCR‐ABLT315I, with dissociation constant (Kd) values of 0.32 and 0.71 nmol/L, respectively, thereby strongly inhibiting mutant kinase functions with nanomolar IC50 values. 10

Olverembatinib has been developed as a new generation of TKIs, and it was approved in China for treatment of adult patients with chronic‐phase CML (CML‐CP) or accelerated‐phase CML (CML‐AP) harboring the T315I mutation that is resistant and/or intolerant to 1G and 2G TKI therapies. The recommended dosage of olverembatinib is 40 mg administered orally every other day (QOD) with food.

Clinical pharmacokinetic data have shown that olverembatinib is absorbed after oral administration in patients with CML, with a maximum plasma concentration (C max) observed at approximately 4–8 h after dosing. Exposure (C max and the area under the concentration‐time curve from dosing [time 0] to the time of the last measured concentration [AUC0‐last]) to olverembatinib increases in an approximately dose‐proportional manner from 1 to 60 mg. The mean terminal elimination half‐life (t 1/2) of olverembatinib is approximately 25 h, with minimal accumulation observed after repeated dosing.

In humans, olverembatinib undergoes metabolism in the liver via mono‐oxidation, demethylation, and glucuronidation pathways to form multiple metabolites. Unchanged olverembatinib, mono‐oxidation metabolites, demethylation metabolites, and glucuronidation metabolites represent the predominant circulating components in human plasma.

In in vitro studies, the metabolism of olverembatinib was shown to be primarily mediated by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2C9. 10 Therefore, concurrent administration of strong inducers or inhibitors of CYP3A4 may alter olverembatinib pharmacokinetics, resulting in increased or decreased olverembatinib exposure in vivo.

Thus, we performed a clinical drug–drug interaction (DDI) study of olverembatinib in combination with itraconazole (a strong CYP3A4 inhibitor) or rifampin (a strong CYP3A4 inducer) in healthy participants.

METHODS

Subjects

Thirty‐two healthy subjects, aged 18–55 years, were enrolled in this study. Before participation, male or postmenopausal or surgically sterile female participants underwent medical screening that included medical history, physical examination, vital signs, electrocardiogram (ECG) results, and routine laboratory tests (especially tests for renal and hepatic function). Subjects were required to have a body mass index of 18–30 kg/m2 and a body weight of >50 kg at screening.

Study exclusion criteria included: (1) clinically significant illness; (2) use of any P‐glycoprotein (P‐gp) and/or CYP450 hepatic microsomal enzyme‐inducing or inhibiting drugs within 30 days before first study drug administration or use of prescription and nonprescription drugs or herbal remedies (e.g., St. John's wort) within 2 weeks before administration of the initial dose of study drug; (3) a history of drug or alcohol use disorders; (4) consumption of excessive amounts of caffeine 1 month before study drug administration; (5) a history of hypersensitivity to itraconazole (or other azole antifungal agents) or any component of itraconazole (for subjects in Part 1) or a history of hypersensitivity to rifampin or any component of rifampin (for subjects in Part 2); (6) abnormalities in vital signs or laboratory values; or (7) clinically significant abnormalities determined from physical examination, medical history, or 12‐lead ECG (i.e., QTc interval > 450 ms).

Subjects were also asked to refrain from consuming foods known to influence CYP metabolism, including grapefruit or grapefruit‐containing products, blood oranges, apples, mulberry juice, and vegetables from the mustard green family, approximately 2 weeks before initial administration of study drug, throughout the study, and until the poststudy visit.

Study design

This was an open‐label, parallel‐group, fixed‐sequence study in healthy male and female subjects conducted in two parts. Part 1 investigated the effect of CYP3A4 inhibition by steady‐state itraconazole on the single‐dose pharmacokinetics of olverembatinib 20 mg. Part 2 investigated the effect of CYP3A induction by steady‐state rifampin on the single‐dose pharmacokinetics of olverembatinib 40 mg. The study planned to enroll approximately 32 subjects (16 in each part) to ensure that at least 24 subjects (12 in each part) would complete the study.

Treatments

In Part 1, participants received a single oral 20‐mg dose of olverembatinib in the fed state on Days 1 and 9. Oral itraconazole 200 mg (Alkem Laboratories, Ltd., Mumbai, India) was administered once daily, approximately 30 minutes after completing a meal on Days 5 through 12.

All doses of study medication (olverembatinib on Days 1 and 9 and itraconazole on Days 5–12) were administered with a low‐fat breakfast, consisting of 1 packet of instant flavored oatmeal (e.g., maple and brown sugar‐flavored), 237 mL of 1% milk, 1 hard‐boiled egg, and 1 medium‐sized banana. This meal contained approximately 400–500 cal, of which approximately 25% (11–14 g) was derived from fat. The meal was consumed within 30 min before dosing. On Day 9, olverembatinib and itraconazole were coadministered.

In Part 2, participants received a single oral 40‐mg dose of olverembatinib in the fed state on Days 1 and 12. Oral rifampin 600 mg (Lannett Company, Inc., Trevose, PA, USA) was administered once daily in the fasted state on Days 5–15. All doses of rifampin were administered 1 h before subjects consumed a low‐fat breakfast (same as described in Part 1). The meal was consumed ≥60 min after rifampin dosing. On Days 1 and 12, olverembatinib was administered with a low‐fat breakfast (same as described in Part 1), which was consumed within 30 min before dosing.

Sample collection

Serial blood samples were collected with olverembatinib alone and when combined with itraconazole or rifampin to measure olverembatinib plasma concentrations. Plasma samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 h after dosing on Days 1 and 9 in Part 1 and on Days 1 and 12 in Part 2.

Bioanalytical methodology

Plasma concentrations of olverembatinib were determined using validated high‐performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS/MS). Protein precipitation was used to extract the analyte and internal standard (deuterium‐labeled olverembatinib) from human plasma containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) as an anticoagulant. The analytical method utilized a reversed‐phase HPLC column (Agilent Zorbax Eclipse Plus C18, Santa Clara, CA, USA; 4.6 × 50 mm, 3.5 μm) with a gradient flow of 0.1% formic acid in water (mobile phase A) and 0.1% formic acid in acetonitrile (mobile phase B) at a rate of 0.8 mL/min. The analyte and internal standard were detected using an AB Sciex API‐6500/6500+ LC–MS/MS system (Framingham, MA, USA) equipped with a positive electrospray ionization detection. The calibration range of olverembatinib in the assay was 0.02–10 ng/mL using a 50‐μL aliquot of plasma, with a lower limit of quantitation of 0.02 ng/mL. The performance of calibration standards showed a good linearity from 0.02 to 10 ng/mL, with the coefficient of correlation (r 2) > 0.996. The results indicated the method to be sensitive, selective, accurate, and reproducible.

Pharmacokinetic analysis

Noncompartmental pharmacokinetic analysis was conducted using the Phoenix WinNonlin software (Version 8.1) (Certara Inc., Princeton, NJ, USA). Pharmacokinetic parameters were derived for olverembatinib alone and in combination with itraconazole or rifampin, including area under the plasma concentration‐time curve (AUC), C max, time to C max (T max), apparent terminal elimination half‐life (t 1/2), elimination rate constant (λ z [Kel]), apparent total oral clearance (CL/F), and apparent volume of distribution during the terminal elimination phase (Vz/F).

A mixed‐effect model under the sequential design was applied to the natural log‐transformed C max, AUC0‐last, and AUC0‐∞. The model included treatment as a fixed effect and subject as a random effect. For each of the parameters, the comparisons included: Part 1: olverembatinib coadministered with itraconazole versus without itraconazole.

Part 2: olverembatinib coadministered with rifampin versus without rifampin.

Estimates of geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) were derived for the comparisons of C max, AUC0‐last, and AUC0‐∞.

Safety analysis

The safety and tolerability of a single oral dose of olverembatinib alone and in combination with multiple doses of itraconazole or rifampin were assessed by evaluating treatment‐emergent adverse events (TEAEs), study discontinuation information, laboratory test results, vital signs, physical examination, and ECG findings.

Safety variables were tabulated and presented for all subjects in the safety population. Adverse events (AEs) were coded using Medical Dictionary of Regulatory Activities (MedDRA; Version 22.1) by preferred term and system organ class. All AEs were graded as mild, moderate, or severe except for special‐interest AEs (i.e., decreased platelet and leukocyte counts and other laboratory AEs), which were graded using National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE; Version 5.0) as mild (grade 1), moderate (grade 2), severe (grade 3), or life‐threatening (grade 4).

TEAEs were summarized by treatment, where “treatment‐emergent” was defined as any event with a start date on or after the date and time of the first dose date and time of study drug within a treatment period. All TEAEs were summarized by relationship to study drug and intensity. By‐subject listings of all safety data and concomitant medication were generated. Deaths, serious adverse events (SAEs), and AEs resulting in study discontinuation were tabulated and detailed in narratives.

Ethics approval

The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice and the Declaration of Helsinki guidelines. All participants provided written informed consent before study entry. The protocol was reviewed and approved by the Institutional Review Board at the study center.

RESULTS

Demographics

In Part 1, 16 subjects were enrolled, of whom 16 completed the study; while in Part 2, 16 subjects were enrolled, of whom 15 completed. All subjects in Parts 1 and 2 were included in the safety and pharmacokinetic analysis sets. Baseline demographics for participants in Parts 1 and 2 are shown in Table 1. The median participant age was 37.0 years in Part 1 and 39.5 years in Part 2. In both parts, 93.8% of subjects were male. In Parts 1 and 2, 62.5% and 68.8% were Black or African American, and 37.5% and 31.3% were White.

TABLE 1 Summary of participant demographics at screening.

Variable	Part 1 (N = 16)	Part 2 (N = 16)	
Age, years	
Mean (SD)	37.5 (9.1)	39.5 (8.5)	
Median	37.0	39.5	
Min, max	18, 55	27, 51	
Sex, n (%)	
Male	15 (93.8)	15 (93.8)	
Female	1 (6.3)	1 (6.3)	
Race, n (%)	
White	6 (37.5)	5 (31.3)	
Black or African American	10 (62.5)	11 (68.8)	
Ethnicity, n (%)	
Hispanic or Latino	6 (37.5)	6 (37.5)	
Non‐Hispanic or Latino	10 (62.5)	10 (62.5)	
Weight, kg	
Mean (SD)	78.46 (12.8)	80.47 (9.3)	
Median	79.50	82.78	
Min, max	59.1, 102.4	64.9, 95.2	
Height, cm	
Mean (SD)	175.9 (7.1)	172.7 (7.4)	
Median	176.10	172.85	
Min, max	161.3, 186.1	157.3, 187.2	
Body mass index, kg/m2	
Mean (SD)	25.2 (2.6)	26.9 (2.0)	
Median	25.4	27.5	
Min, max	21, 30	24, 30	
Note: Part 1, Days 1 and 9: single oral dose of olverembatinib 20 mg; Days 5–12: oral dose of itraconazole 200 mg once daily. Part 2, Days 1 and 12: single oral dose of olverembatinib 40 mg; Days 5–15: oral dose of rifampin 600 mg once daily.

Abbreviation: SD, standard deviation.

Pharmacokinetics

Part 1

The plasma concentration‐time profiles and pharmacokinetic parameters of olverembatinib in the absence and presence of itraconazole are shown in Figure 1 and Table 2, respectively. Plasma concentrations of olverembatinib were markedly higher after coadministration of olverembatinib 20 mg with itraconazole 200 mg than olverembatinib 20 mg alone. As shown in Table 2, the GMR (90% CI) for olverembatinib C max, AUC0‐last, and AUC0‐∞ were 175.63% (161.76%–190.69%), 247.06% (224.77%–271.55%), and 258.66% (235.38%–284.24%), respectively. The results demonstrated that coadministration of olverembatinib with itraconazole increased the C max of olverembatinib by 75.63%; AUC0‐last, by 147.06%; and AUC0‐∞, by 158.66%.

FIGURE 1 Arithmetic mean (+SD) olverembatinib plasma concentration profiles following an administration of 20 mg alone and combined with itraconazole 200 mg. Olverembatinib plasma concentrations on the Y‐axis are shown on log scale.

TABLE 2 Summary of pharmacokinetic parameters of olverembatinib following administration of olverembatinib 20 mg alone and combined with itraconazole 200 mg—Part 1.

Least square geometric means	
Variable a	n	Olverembatinib 20 mg	n	Olverembatinib 20 mg + itraconazole 200 mg	Geometric mean ratio b (%)	90% CI	
C max, ng/mL	16	5.019 (33.341)	16	8.815 (29.019)	175.63	(161.76–190.69)	
AUC0‐last, h*ng/mL	16	105 (42.64)	16	260 (34.1)	247.06	(224.77–271.55)	
AUC0‐inf, h*ng/mL	16	117 (42.33)	15	302 (29.65)	258.66	(235.38–284.24)	
CL/F, L/h	16	171.60 (42.29)	15	62.94 (29.68)	–	–	
T max, h c	16	8.00 (6.0, 12.0)	16	6.00 (4.0, 8.0)	–	–	
Vz/F, L	16	8221.4 (49.0)	15	3123.2 (30.0)	–	–	
t 1/2, h	16	33.24 (21.07)	15	34.40 (17.40)	–	–	
AUC, area under the plasma concentration‐time curve; CL/F, apparent total oral clearance; C max, maximum plasma concentration; t 1/2, terminal elimination half‐life; T max, time of the maximum observed plasma concentration; V z/F, apparent volume of distribution.

a Geometric mean data (% coefficient of variation) except where otherwise noted.

b Ratio of olverembatinib in combination with itraconazole versus olverembatinib alone.

c Median (min, max).

Part 2

The plasma concentration‐time profiles and pharmacokinetic parameters of olverembatinib in the absence and presence of rifampin are shown in Figure 2 and Table 3, respectively. Plasma concentrations of olverembatinib were markedly lower after coadministration of olverembatinib 40 mg with rifampin 600 mg than olverembatinib 40 mg alone. As shown in Table 3, the GMRs (90% CI) for olverembatinib C max, AUC0‐last, and AUC0‐∞ were 38.73% (32.85%–45.67%), 25.79% (23.01%–28.91%), and 24.81% (21.98%–28.00%), respectively. The results indicated that coadministration of olverembatinib with rifampin decreased the Cmax of olverembatinib by 61.27%; AUC0‐last, by 74.21%; and AUC0‐∞, by 75.19%.

FIGURE 2 Arithmetic mean (+SD) olverembatinib plasma concentration profiles following an administration of 40 mg alone and combined with rifampin 600 mg. Olverembatinib plasma concentrations on the Y‐axis are shown on log scale.

TABLE 3 Summary of pharmacokinetic parameters of olverembatinib following administration of olverembatinib 40 mg alone and in combination with rifampin 600 mg—Part 2.

Least square geometric means	
Variable a	n	Olverembatinib 40 mg	n	Olverembatinib 40 mg + rifampin 600 mg	Geometric mean ratio b (%)	90% CI	
C max, ng/mL	15	11.43 (40.075)	15	4.426 (23.932)	38.73	(32.85–45.67)	
AUC0‐last, h*ng/mL	15	246 (42.49)	15	63.55 (34.61)	25.79	(23.01–28.91)	
AUC0‐inf, h*ng/mL	14	271 (41.96)	14	67.20 (35.18)	24.81	(21.98–28.00)	
CL/F, L/h	15	142.83 (41.97)	14	579.23 (35.26)	–	–	
T max, h c	16	8.00 (6.0, 12.0)	15	6.00 (2.0, 8.0)	–	–	
Vz/F, L	15	5368 (45.8)	14	25,493 (42.6)	–	–	
t 1/2, h	15	26.05 (20.55)	14	30.52 (30.37)	–	–	
AUC, area under the plasma concentration‐time curve; CL/F, apparent total oral clearance; C max, maximum plasma concentration; t 1/2, terminal elimination half‐life; T max, time of the maximum observed plasma concentration; Vz/F, apparent volume of distribution.

a Geometric mean data (% coefficient of variation) except where otherwise noted.

b Ratio of olverembatinib in combination with rifampin versus olverembatinib alone.

c Median (min, max).

Safety

Single daily doses of olverembatinib 20 mg or 40 mg were generally safe and well tolerated in this population of healthy male and female subjects. Single daily doses of olverembatinib 20 mg coadministered with itraconazole 200 mg, as well as single daily doses of olverembatinib 40 mg coadministered with rifampin 600 mg, were also generally safe and well tolerated.

In Part 1, a total of 7 TEAEs were reported by 3 subjects (18.8%). In all cases, the TEAEs were considered to be related to itraconazole. None of the reported TEAEs were severe or serious, and none resulted in study discontinuation. No TEAEs required treatment, and all TEAEs resolved without sequelae.

In Part 2, a total of 15 TEAEs were reported by 7 subjects (43.8%). Four subjects (25.0%) experienced TEAEs that were considered to be treatment‐related. One subject experienced a mild headache (considered olverembatinib‐related); 1 experienced mild chromaturia (considered rifampin‐related); and 1 had mild headaches on 2 separate days (1 possibly related to olverembatinib, 1 olverembatinib‐ and rifampin‐related). One subject (6.3%) discontinued study treatment after rifampin administration on Day 11 because of AEs (moderate elevated creatine kinase, mild alanine aminotransferase increase, and mild aspartate aminotransferase increase), all of which were considered related to rifampin. None of these TEAEs were severe or serious. During the study, there were no deaths, SAEs, or AEs resulting in study discontinuation.

DISCUSSION

In this study, an itraconazole dose of 200 mg once daily was administered for 8 days in Part 1, and a rifampin dose of 600 mg once daily was administered for 11 days in Part 2. Olverembatinib was coadministered on the fifth day of itraconazole administration, and itraconazole dosing continued for an additional 3 days to maintain full CYP3A4 inhibition in Part 1. Olverembatinib was coadministered on the eighth day of rifampin administration, and rifampin dosing continued for an additional 3 days to maintain full CYP3A4 induction in Part 2. Previously published research has shown that 4–5 days of itraconazole at 200 mg once daily are sufficient to cause drug inhibitory effects on CYP3A substrates, and full induction of CYP3A4 enzymes is reached in about 1 week after starting rifampin treatment. 11 , 12 , 13 , 14 , 15 , 16

The recommended dosage of olverembatinib is 40 mg QOD. In Part 1, half the recommended dosage, 20 mg QOD, was used because strong 3A4 inhibitors can increase the exposure of olverembatinib and hence increase the frequency or severity of AEs. In Part 2, AEs were not a concern because olverembatinib was combined with a 3A4 inducer; therefore, the full recommended dosage of 40 mg QOD was used.

In the clinic, olverembatinib is administered orally with food. In this DDI study, olverembatinib was administered under fed conditions to retain the same conditions as those in the clinic. The food effect study indicated that food can improve the absorption of olverembatinib and reduce inter‐individual variation.

Results from this DDI study confirm that olverembatinib is primarily metabolized by CYP3A in humans and is a moderately sensitive CYP3A substrate. The results indicate that coadministration with itraconazole, a strong CYP3A4 inhibitor, increased the C max of olverembatinib by 75.63%; AUC0‐last, by 147.06%; and AUC0‐∞, by 158.66%. On the other hand, coadministration of olverembatinib with rifampin, a strong CYP3A4 inducer, decreased the C max of olverembatinib by 61.27%; AUC0‐last, by 74.21%; and AUC0‐∞, by 75.19%.

Drug–drug interactions with strong CYP3A inhibitors and inducers have also been reported with other BCR‐ABL1 inhibitors, including the 1G TKI imatinib (40% increase in AUC0‐∞ with ketoconazole and 74% reduction in AUC0‐∞ with rifampin), the 2G TKI nilotinib (3‐fold increase in AUC0‐∞ with ketoconazole and 80% reduction in AUC0‐∞ with rifampin), and the 3G TKI ponatinib (78% increase in AUC0‐∞ with ketoconazole and 63% reduction in AUC0‐∞ with rifampin). 17 , 18 , 19 , 20 , 21

No substantial difference was observed in the terminal elimination half‐life (t 1/2) of olverembatinib when administered alone or combined with itraconazole or rifampin, which may be attributed to a reduction or increase in first‐pass metabolism. Itraconazole and rifampin might largely affect the first‐pass metabolism of olverembatinib rather than the hepatic metabolism. Therefore, the terminal elimination half‐life appeared to be similar in the absence and presence of itraconazole or rifampin. The more plausible explanation for the increase or decrease in exposure (AUC) to olverembatinib is inhibition or induction of drug metabolism. This is supported by the decrease or increase in apparent clearance (CL/F) in the itraconazole and rifampin combination regimens. Moreover, olverembatinib is a substrate of P‐gp and likely a substrate of breast cancer resistance protein (BCRP) based on data from the in vitro transporter study. Consequently, strong inhibitors or inducers of P‐gp or BCRP may be expected to act as perpetrators to alter the pharmacokinetics of olverembatinib. Itraconazole, a potent inhibitor of CYP3A4, is also an inhibitor of P‐gp, which might increase olverembatinib plasma concentrations by enhancing the absorption of olverembatinib through inhibition of P‐gp in the intestinal wall. 22 Rifampin, a potent CYP3A4 inducer that is also known to induce P‐gp, might decrease olverembatinib plasma concentrations of olverembatinib by reducing its bioavailability and increasing its hepatic clearance. 23 In addition, the change in the apparent volume of distribution (Vz/F) may be due to the alteration of the oral bioavailability of olverembatinib associated with reduction or increase in the first‐pass metabolism caused by itraconazole or rifampin.

The results from this DDI study were used to refine the in silico physiologically based PK (PBPK) simulations assessing the impact of strong, moderate, and mild CYP3A4 inhibitors and inducers on the pharmacokinetics of olverembatinib. 24 The PBPK result demonstrated that strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib systemic exposure by approximately 2.39‐, 1.80‐ to 2.39‐, and 1.08‐fold, respectively; strong and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29‐ and 0.35‐ to 0.56‐fold, respectively. Findings from this clinical study and the PBPK simulations, in conjunction with safety and efficacy data from clinical studies, can be used to recommend appropriate dose modifications when patients are required to take olverembatinib concomitantly with moderate or strong inhibitors and inducers of CYP3A4. In this study, single doses of olverembatinib (40 or 20 mg) administered alone or combined with itraconazole 200 mg or rifampin 600 mg, respectively, were well tolerated in healthy subjects.

This DDI study confirms that olverembatinib is primarily metabolized by CYP3A4 in humans. There was a significant increase or decrease in exposure to olverembatinib in healthy volunteers when the BCR‐ABL1 TKI was coadministered with itraconazole or rifampin. Therefore, caution should be exercised when administering olverembatinib with inhibitors or inducers of the CYP3A4 family.

AUTHOR CONTRIBUTIONS

All authors wrote the manuscript. H.W. and Y.Y. designed the research. Y.Z., H.W., Z.C., M.Y., L.J., C.W., I.M., and D.Y. performed the research. L.F. and L.M. analyzed the data.

FUNDING INFORMATION

This study and its report were supported by Guangzhou Healthquest Pharma Co., Ltd.

CONFLICT OF INTEREST STATEMENT

All authors are stockholders of Ascentage Pharma Group International and employees of its affiliates Guangzhou Healthquest Pharma Co., Ltd. or Ascentage Pharma Group Inc. Y.Z. and D.Y. hold Leadership positions in Guangzhou Healthquest Pharma Co., Ltd. and Ascentage Pharma Group Inc. D.Y. holds fiduciary positions in Guangzhou Healthquest Pharma Co., Ltd., Ascentage Pharma Group Inc., and Ascentage Pharma Group International.

ACKNOWLEDGMENTS

We thank Jennifer Coe (an employee of Ascentage Pharma Group Inc.), who managed and coordinated the research activity planning and execution of this study. Ashutosh K. Pathak, MD, PhD, MBA, FRCP (Edin.), Stephen W. Gutkin, Ndiya Ogba, PhD, and Paul Fletcher, PhD, employed by Ascentage Pharma Group Inc., provided substantive input in manuscript research and preparation. Ascentage Pharma Group Inc. is an affiliate of Guangzhou Healthquest Pharma Co., Ltd., and Ascentage Pharma Group International is the ultimate parent of Ascentage Pharma Group Inc.
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