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

Inclusion criteria

• Age: 18-70 years old (Include both values).
• Patients with histopathologically or cytologically confirmed advanced solid tumor (not necessary to have measurable lesions).
• Refractory or intolerant to standard treatment regimens, or no effective standard treatment regimens available, or the patients refused to use standard treatment plan.
• ECOG PS score: 0-1.
• Expected survival ≥ 3 months.
• 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.
• 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.

• Sign the ICF voluntarily, have good compliance, corporate with follow-up visits, and follow the study requirements.

Exclusion criteria

• Gastric cancer; tumors with risk of bleeding which researchers evaluated.
• Active brain metastasis (medically uncontrolled);
• Symptomatic third space fluid that cannot be controlled by drainage or other methods;
• Dysphagia, chronic diarrhea, or other factors affecting drug intake and absorption;
• Uncontrolled hypertension;
• 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);
• Contraindications to Repaglinide and Bupropion;
• NYHA Class III-IV cardiac insufficiency or left ventricular ejection fraction (LVEF) < 50% by echocardiography;
• 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;
• Arterial/venous thrombosis within 6 months prior to the first dose;
• Hemorrhage and thrombophilia;
• Major surgery or with severe traumatic injury, fracture, or ulcer within 4 weeks prior to the first dose;
• Abdominal fistula, gastrointestinal perforation or abdominal abscess within 6 months prior to the first dose;
• Urine protein ≥ ++ and 24 h urine protein ≥ 1.0 g as indicated by urinalysis;
• Treatment with steroids for more than 50 days, or requires chronic steroid use;
• Use of study drugs in other clinical trials within 4 weeks prior to the first dose;
• 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;
• Unable to hold drugs that may prolong QT interval during the study (such as antiarrhythmics);
• Habitual alcohol consumption or smoking, tested positive for alcohol screening, and unable to abstain from smoking and alcohol during the trial;
• Other factors affecting drug absorption, distribution, metabolism, excretion within 48 hours；
• 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);
• Active infection requiring antimicrobial therapies (such as antibacterials, antivirals, or antifungals);
• Immunodeficiency, including positive results of HIV test or other acquired or congenital immunodeficiencies, or a history of organ transplantation;
• Allergic constitution, or known allergies to drug components used in this study;
• Pregnant or lactating women;
• Other factors that may affect the progress or the conclusion of the study, as determined by the investigator.