Fruquintinib DDI Study With P-gp and BCRP Substrates

Study Overview
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Brief Summary
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Fruquintinib DDI Study with P-gp and BCRP Substrates

Detailed Description
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A phase 1, open-label, 2-part, 2-period fixed-sequence study to evaluate the effect of Fruquintinib on the pharmacokinetics of Dabigatran Etexilate (A P-GP substrate) and Rosuvastatin (A BCRP substrate) in healthy subjects

Official Title
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A Phase 1, Open-label, 2-part, 2-period Fixed-sequence Study to Evaluate the Effect of Fruquintinib on the Pharmacokinetics of Dabigatran Etexilate (A P-GP Substrate) and Rosuvastatin (A BCRP Substrate) in Healthy Subjects

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Fruquintinib
* Drug: Dabigatran Etexilate
* Drug: Rosuvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is male or female between the ages of 18 and 55 years old (inclusive) at the time of informed consent. The subject has a body mass index (BMI) >18 and ≤29 kg/m2 at screening. Female subjects must be of non-childbearing potential (eg, postmenopausal [defined as cessation of all menstrual periods for at least 1 year without an alternative medical cause, and confirmed by follicle-stimulating hormone (FSH) test ≥40 IU/L] or surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation). Male subjects with partners of childbearing potential must always use a condom and must agree in addition to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: Oral hormonal contraception (combined estrogen/progestogen, or progestogen-only) associated with inhibition of ovulation Intrauterine device (IUD) Intrauterine hormone-releasing system (IUS) Bilateral tubal ligation Vasectomy True sexual abstinence in line with the preferred and usual lifestyle of the subject. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with a spermicide). The subject must provide written informed consent prior to any study-specific screening procedures. The subject is willing and able to comply with all aspects of the protocol, as determined by the Investigator. Exclusion Criteria: Clinical laboratory test results from the coagulation panel (international normalized ratio [INR], prothrombin time, and activated partial thromboplastin time) must be within the normal laboratory reference ranges or deemed not clinically significant by the Investigator and Sponsor. The subject has clinically significant renal laboratory findings, including estimated glomerular filtration rate <80 mL/min as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The subject has a known history of any gastrointestinal surgery or any condition possibly affecting drug absorption (eg, cholecystectomy, gastrectomy, achlorhydria, peptic ulcer disease, history of stomach or intestinal surgery or resection). Appendectomy and hernia repair are allowed. The subject had a clinically significant illness within 8 weeks or a clinically significant infection within 4 weeks prior to the first dose. The subject has evidence of a clinically significant deviation from normal in the physical examination, vital signs, or clinical laboratory determinations at screening or at Day -1 check-in (baseline). The subject has systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. The subject has a clinically significant ECG abnormality, including a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTcF interval >480 msec), or had a family history of prolonged QTc syndrome or sudden death. The subject has a history of smoking or use of nicotine-containing substances within the previous 2 months, as determined by medical history or subject's verbal report and confirmed by cotinine test at check in for each treatment period. The subject has a history of drug or alcohol misuse within 6 months prior to screening or a positive urine drug test at screening or at check in for each treatment period. The subject has been diagnosed with acquired immune deficiency syndrome (AIDS) or has performed tests that are positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). The subject has participated in a clinical trial of other drug before screening, and the time since the last use of other study drug is less than 5 times the half-life or 4 weeks, whichever is longer, or the subject is currently enrolled in another clinical trial. The subject has consumed grapefruit, starfruit, Seville oranges, or their products within 7 days prior to the first dose. The subject has consumed herbal preparations/medications, including, but not limited to, kava, ephedra (ma huang), Ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng, within 7 days prior to the first dose. The subject has experienced a weight loss or gain of >10% within 4 weeks prior to the first dose as noted by medical history and weight at screening and check-in. The subject has received blood or blood products within 4 weeks, or donated blood or blood products within 8 weeks prior to the first dose or donated double red cell within 16 weeks prior to first dose. Clinical Study Protocol 2021-013-00US3 Fruquintinib Original Protocol HUTCHMED Limited Page 32 CONFIDENTIAL The subject has used any over-the-counter (OTC) medications or prescription drugs that can affect gastric acid (proton pump inhibitors [PPIs], H2 blockers or locally acting antacids) or that inhibit CYP3A, P-gp, or BCRP in particular, within 2 weeks prior to the first dose. Subject has used CYP3A inducers (including St John's wort) within 30 days before the first dose. The subject is allergic to any of the study drugs (or its excipients) to be given in this study. Female participant is pregnant, lactating, or breastfeeding. Male subject who plans to donate sperm or father a child within 3 months after receiving the study drug. The subject has any condition that would make him or her, in the opinion of the Investigator or Sponsor, unsuitable for the study, or who, in the opinion of the Investigator, is not likely to complete the study for any reason. One repeat of laboratory assessments may be performed at screening and check in at the discretion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>On Day 1, a single oral dose of dabigatran etexilate 150 mg will be given under fasted conditions and serial PK samples will be collected as indicated on the schedule of events. On Day 5, subjects will receive a single oral dose of fruquintinib 5 mg at approximately 1 hour prior to administration of a single oral dose of dabigatran etexilate 150 mg under fasted conditions and serial PK samples will be collected | Drug: Fruquintinib<br>* Fruquintinib will be administered as a single oral 5mg dose on the morning of day 5<br>* Other names: HMPL-013;Drug: Dabigatran Etexilate<br>* Dabigatran Etexilate will be administered as a single oral dose 150mg on the morning of day 1 and morning of day 5<br>|
| Experimental: Part B<br>On Day 1, a single oral dose of rosuvastatin 10 mg will be given under fasted conditions and serial PK samples will be collected as indicated on the schedule of events. On Day 5, subjects will receive a single oral dose of rosuvastatin 10 mg with fruquintinib 5 mg under fasted conditions and serial PK samples will be collected | Drug: Fruquintinib<br>* Fruquintinib will be administered as a single oral 5mg dose on the morning of day 5<br>* Other names: HMPL-013;Drug: Rosuvastatin<br>* Rosuvastatin will be administered as a single oral dose 10mg on the morning of day 1 and the morning of day 5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameter for dabigatran and rosuvastatin: AUC0-t: | area under the plasma concentration-time curve from time 0 to time of the last measurable concentration | Day 1 to Day 13 | 
| PK parameter for dabigatran and rosuvastatin: AUC0-inf: | area under the plasma concentration-time curve from time 0 to infinity (if data permit) | Day 1 to Day 13 | 
| PK parameter for dabigatran and rosuvastatin: Cmax: | maximum observed plasma concentration | Day 1 to Day 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AEs/SAEs | Any untoward medical occurrence associated with the use of study drug | Day 1 to Day 13 | 
| PK parameter of fruquintinib and metabolite M11: AUC0-t: | area under the plasma concentration-time curve from time 0 to time of the last measurable concentration | Day 1 Day 13 | 
| PK parameters of fruquintinib and metabolite M11: AUC0-inf: | area under the plasma concentration-time curve from time 0 to infinity (if data permit) | Day 1 to Day 13 | 
| PK parameters of fruquintinib and metabolite M11: Cmax: | maximum observed plasma concentration | Day 1 to Day 13 |