A Study To Test The Effect Of Apatinib On P450 Enzymes

Study Overview
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Brief Summary
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Apatinib, an oral inhibitor of vascular endothelial growth factor receptor 2（VEGFR-2）, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of Apatinib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of Apatinib. The probes used included Nifedipine (CYP3A specific), warfarin (CYP2C9 specific).

Detailed Description
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This open-label study consists of a drug interaction phase that (part A) and a drug-continuation phase (part B). Patients will receive CYP450-probe drugs, and PK assessments will be performed before apatinib-administration and aſter once-daily administration of apatinib for 5 days (the predicted time point when steady-state plasma apatinib concentrations will have been achieved).

Official Title
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A Single-center, Open-Label, Drug Interaction Study to Determine the Effects of Apatinib on the Metabolism of CYP3A4/5 and CYP2C9 Probe Drugs in Patients With Solid Tumors

Conditions
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Cytochrome P450 Interaction

Intervention / Treatment
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* Drug: Apatinib
* Drug: Nifedipine GTIS
* Drug: Warfarin Potassium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of advanced solid tumors. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate bone marrow, renal, lung, and liver function. A female subject must not be pregnant and will agree not to become pregnant during the trial Exclusion Criteria: Primary carcinoma of liver Any major surgery, chemotherapy, hormone therapy, investigational drugs, or radiotherapy within the last 28 days. Poorly controlled hypertension. A prior history of cardiovascular disease, arrhythmias, or significant ECG abnormalities, and corrected QT (QTc) prolongation defined as a QTc interval greater than or equal to 450 msec(male) or 470 msec(female). Arterial or venous thrombi (including cerebrovascular accident). Current use of therapeutic anticoagulation (low molecular weight heparin, oral anticoagulant agents). Active brain metastases. A history of bleeding problems.

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: Treament<br>In phase A, subjects receiving a single 30 mg oral dose of Nifedipine controlled-release tablets and wash-out for 2 days,a single 3 mg oral dose of warfarin tablets and wash-out for 12 days, then apatinib 750 mg once daily with a single 30 mg oral dose of Nifedipine controlled-release tablets co-administered on day 6 ,a a single 3 mg oral dose of warfarin tablets co-administered on day 9. | Drug: Apatinib<br>* Apatinib at a dosage of 750mg will be administered daily from day 9 of phase A<br>Drug: Nifedipine GTIS<br>* Nifedipine at a dosage of 30mg will be administered at day 1 and day 14 of phase A<br>* Other names: Nifedipine;Drug: Warfarin Potassium<br>* Nifedipine at a dosage of 3mg will be administered at day 3 and day 16 of phase A<br>* Other names: warfarin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) of warfarin or nifedipine | AUC0 t of warfarin and nifedipine in the absence or in presence of apatinib will be defined | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | to assess safety and tolerability of apatinib combined with warfarin or nifedipine in patients with advanced solid tumors. The vital signs, ECG, laboratory values and adverse events (AE and SAE) were judged according to NCI-CTCAE V4.0 criteria | Day 1 to 21 ( Phase A） |