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

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 8 weeks 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):

   a. HB≥100 g/L; b. ANC≥1.5×109/L; c. PLT≥90×109/L; (2) Blood biochemistry: d. TBIL≤ 1.25×ULN; e. ALT and AST≤2.5×ULN; f. ALP≤2.5×ULN; g. Serum Cr ≤ 1.5 × ULN or endogenous CrCl \> 60 mL/min (Cockcroft-Gault formula); h. 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 ≥ ++ and 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;
17. Use of drugs affected gastric acid secretion or inhibitors of cytochrome enzyme CYP2C8、CYP2B6、CYP2D6、CYP3A or transporter OATP1B1, or traditional Chinese medicine within 2 weeks prior to the first dose; use of inducers of metabolic enzymes CYP2C8, CYP2B6, CYP2D6, or CYP3A within 4 weeks prior to the first dose;
18. Unable to hold drugs that may prolong QT interval during the study (such as antiarrhythmics);
19. Habitual alcohol consumption or smoking, tested positive for alcohol screening, and unable to abstain from smoking and alcohol during the trial;
20. Other factors affecting drug absorption, distribution, metabolism, excretion within 48 hours；
21. Active hepatitis B (positive HBsAg and 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);
22. Active infection requiring antimicrobial therapies (such as antibacterials, antivirals, or antifungals);
23. Immunodeficiency, including positive results of HIV test or other acquired or congenital immunodeficiencies, or a history of organ transplantation;
24. Allergic constitution, or known allergies to drug components used in this study;
25. Pregnant or lactating women;
26. Other factors that may affect the progress or the conclusion of the study, as determined by the investigator.