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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Apatinib Mesylate
* Drug: Repaglinide
* Drug: Bupropion


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment<br>In phase A, subjects receiving a single dose of Repaglinide 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 Repaglinide (in combination with apatinib) orally on day 12 , a single dose of Bupropion (in combination with apatinib) orally on day 13. | Drug: Apatinib Mesylate<br>* Apatinib will be administered daily from on D5 through D16<br>Drug: Repaglinide<br>* Repaglinide will be administered daily on D1 and D12<br>Drug: Bupropion<br>* Bupropion will be administered daily on D2 and D13<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameter: Cmax of digoxin | Peak Plasma Concentration (Cmax) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetics parameter: AUC of digoxin | Area under the plasma concentration versus time curve (AUC) of digoxin | through study completion, an average of 16 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameter: Tmax of digoxin | Time of maximum observed concentration (Tmax) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetics parameter: T1/2 of digoxin | Half time (T1/2) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetic parameters CL/F of digoxin | Total body clearance for extravascular administration (CL/F) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetics parameter: Vz/F of digoxin | Volume of distribution (Vz/F) of digoxin | through study completion, an average of 16 days | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | An adverse event is any untoward medical occurrence in a patient or clinical study participant criteria | through study completion, an average of 16 days |