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A Pharmacokinetic Interaction Study Between Apatinib Mesylate and Repaglinide or Bupropion in Advanced Solid Tumor Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04457180
Recruitment Status : Recruiting
First Posted : July 7, 2020
Last Update Posted : July 7, 2020
Sponsor:
Information provided by (Responsible Party):
Jiangsu HengRui Medicine Co., Ltd.

Brief Summary:

The primary objective of the study was to assess investigate the pharmacokinetic effects of Apatinib Mesylate on CYP2C8 Substrate Repaglinide or CYP2B6 Substrate Bupropion and metabolite Hydroxy bupropion in Advanced solid tumor subjects.

The secondary objective of the study was to assess the safety of Apatinib or/and Repaglinide and Bupropion.


Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Drug: Apatinib Mesylate Drug: Repaglinide Drug: Bupropion Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm, Open and Fixed Sequence Study to Investigate the Pharmacokinetic Effects of Apatinib Mesylate on CYP2C8 Substrate Repaglinide or CYP2B6 Substrate in Advanced Solid Tumor Subjects
Estimated Study Start Date : June 25, 2020
Estimated Primary Completion Date : June 25, 2021
Estimated Study Completion Date : October 25, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treament

In phase A, subjects receiving a single dose of Repaglinid orally on day 1 , a single dose of Bupropion orally on day 2 and wash-out for 10 days, then apatinib once daily will be conducted on D5 through D16

# In addition, In phase B, subjects receiving a single dose of Repaglinid (in combination with apatinib) orally on day 12 , a single dose of Bupropion (in combination with apatinib) orally on day 13.

Drug: Apatinib Mesylate
Apatinib will be administered daily from on D5 through D16

Drug: Repaglinide
Repaglinide will be administered daily on D1 and D12

Drug: Bupropion
Bupropion will be administered daily on D2 and D13




Primary Outcome Measures :
  1. Pharmacokinetics parameter: Cmax of digoxin [ Time Frame: through study completion, an average of 16 days ]
    Peak Plasma Concentration (Cmax) of digoxin

  2. Pharmacokinetics parameter: AUC of digoxin [ Time Frame: through study completion, an average of 16 days ]
    Area under the plasma concentration versus time curve (AUC) of digoxin


Secondary Outcome Measures :
  1. Pharmacokinetics parameter: Tmax of digoxin [ Time Frame: through study completion, an average of 16 days ]
    Time of maximum observed concentration (Tmax) of digoxin

  2. Pharmacokinetics parameter: T1/2 of digoxin [ Time Frame: through study completion, an average of 16 days ]
    Half time (T1/2) of digoxin

  3. Pharmacokinetic parameters CL/F of digoxin [ Time Frame: through study completion, an average of 16 days ]
    Total body clearance for extravascular administration (CL/F) of digoxin

  4. Pharmacokinetics parameter: Vz/F of digoxin [ Time Frame: through study completion, an average of 16 days ]
    Volume of distribution (Vz/F) of digoxin

  5. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: through study completion, an average of 16 days ]
    An adverse event is any untoward medical occurrence in a patient or clinical study participant criteria



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Age: 18-70 years old (Include both values); 2. Patients with histopathologically or cytologically confirmed advanced solid tumor (not necessary to have measurable lesions); 3. Refractory or intolerant to standard treatment regimens, or no effective standard treatment regimens available, or the patients refused to use standard treatment plan 4. ECOG PS score: 0-1; 5. Expected survival ≥ 3 months; 6. Subjects have recovered from other treatments, at least 6 weeks since the last use of nitrosourea or mitomycin; at least 4 weeks since the last use of small molecule targeted therapy; at least 5 half-lives since the last use of biological macromolecular therapy; at least 4 weeks since radiotherapy or surgery; at least 4 weeks since the last use of other cytotoxic or cytostatic drugs; 7. Major organs must function normally, meeting the following criteria:

  1. Hematology (no blood transfusion or blood products within the last 14 days, not corrected with G-CSF or other hematopoietic colony-stimulating factors):

    1. HB≥100 g/L;
    2. ANC≥1.5×109/L;
    3. PLT≥90×109/L;
  2. Blood biochemistry:

    1. TBIL≤ 1.25×ULN;
    2. ALT and AST≤2.5×ULN;
    3. AKPALP≤2.5×ULN;
    4. Serum Cr ≤ 1.5 × ULN or endogenous CrCl ≥ 60 mL/min (Cockcroft-Gault formula);
    5. Albumin > 30 g/L; 8. Sign the ICF voluntarily, have good compliance, corporate with follow-up visits, and follow the study requirements.

      Exclusion Criteria:

      1. Gastric cancer; tumors with risk of bleeding which researchers evaluated. 2. Active brain metastasis (medically uncontrolled); 3. Symptomatic third space fluid that cannot be controlled by drainage or other methods; 4. Dysphagia, chronic diarrhea, or other factors affecting drug intake and absorption; 5. Uncontrolled hypertension; 6. Heart rate < 60, Grade II or greater myocardial ischemia or myocardial infarction, uncontrolled arrhythmias (QTc interval ≥ 450 ms in males and ≥ 470 ms in females); 7. Contraindications to Repaglinide and Bupropion; 8. NYHA Class III-IV cardiac insufficiency or left ventricular ejection fraction (LVEF) < 50% by echocardiography; 9.Abnormal coagulation function (INR > 1.5 or prothrombin time (PT) > ULN + 4 s or APTT > 1.5 ULN), bleeding tendency or who are currently receiving thrombolytics; 10. Arterial/venous thrombosis within 6 months prior to the first dose; 11.Hemorrhage and thrombophilia; 12. Major surgery or with severe traumatic injury, fracture, or ulcer within 4 weeks prior to the first dose; 13. Abdominal fistula, gastrointestinal perforation or abdominal abscess within 6 months prior to the first dose; 14. Urine protein ≥ ++ or 24 h urine protein ≥ 1.0 g as indicated by urinalysis; 15. Treatment with steroids for more than 50 days, or requires chronic steroid use; 16. Use of study drugs in other clinical trials within 4 weeks prior to the first dose; 27. Use of drugs affected gastric acid secretion or cytochrome enzyme CYP2C8、CYP2B6、CYP2D6、CYP3A and transporter OATP1B1 within 4 weeks prior to the first dose; 18. Use of Chinese medicine, traditional Chinese medicine preparation or health products within 2 weeks prior to the first dose; 19. Unable to hold drugs that may prolong QT interval during the study (such as antiarrhythmics); 20.Drug abuse within 12 months before the first dose or positive drug screening; 21. Drinking or smoking addiction ; 22.Other factors affecting drug absorption, distribution, metabolism, excretion Within 48 hours; 23.Active hepatitis B (HBV-DNA≥104 or 2000IU/ml) or C (Hepatitis C antibodies are positive and HCV-RNA is above the detection limit of the analytical method); 24. Active infection requiring antimicrobial therapies (such as antibacterials, antivirals, or antifungals); 25. Immunodeficiency, including positive results of HIV test or other acquired or congenital immunodeficiencies, or a history of organ transplantation; 26. Allergic constitution, or known allergies to drug components used in this study; 27. Pregnant or lactating women; 28. Other factors that may affect the progress or the conclusion of the study, as determined by the investigator.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04457180


Contacts
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Contact: Wang Yuya, Ph.D. 13918749176 ext 86 wangyuya@hrglobe.cn

Locations
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China, Anhui
The First Affiliated Hospital of University of Science and Technology of China Recruiting
Hefei, Anhui, China, 201203
Contact: pan yueyin    13805695536 ext 86    yueyinpan1965@126.com   
Sponsors and Collaborators
Jiangsu HengRui Medicine Co., Ltd.
Investigators
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Principal Investigator: pan yueyin, Ph.D. the First Affiliated Hospital of University of Science and Technology of China
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Responsible Party: Jiangsu HengRui Medicine Co., Ltd.
ClinicalTrials.gov Identifier: NCT04457180    
Other Study ID Numbers: HR-APTN-I-008
First Posted: July 7, 2020    Key Record Dates
Last Update Posted: July 7, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Repaglinide
Apatinib
Bupropion
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Hypoglycemic Agents