A Pharmacokinetic Interaction Study Between Apatinib Mesylate and Transporter Pgp Substrate Digoxin in Advanced Solid Tumor Subjects

A Single Arm, Open and Fixed Sequence Study to Investigate the Pharmacokinetic Effects of Apatinib Mesylate on Transporter Pgp Substrate Digoxin in Advanced Solid Tumor Subjects

Apatinib, an oral inhibitor of vascular endothelial growth factor receptor 2#VEGFR-2#, Induces Transporter Pgp function in vitro. This study in patients with advanced cancer evaluated the effect of Apatinib on Transporter Pgp function by comparing the pharmacokinetics of Transporter Pgp-specific probe drugs in the presence and absence of Apatinib. The probes used Substrate Digoxin.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: Apatinib Mesylate; Drug: Digoxin tablet

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410013
      • Hunan Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of advanced solid tumors. 2. ECOG PS score: 0-1; 3. Expected survival ≥ 3 months; 4. Major organs must function normally, meeting the following criteria:

1. Hematology

   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. ALP≤2.5×ULN;
   4. Serum Cr ≤ 1.5 × ULN or endogenous CrCl ≥ 60 mL/min (Cockcroft-Gault formula);
   5. Albumin > 30 g/L;
   6. K+>3.0mmol/L; 5. Able to understand and sign an informed consent form (ICF).

Exclusion Criteria:

1. Primary liver cancer; gastric cancer;
2. Active brain metastasis (medically uncontrolled), carcinomatous meningitis, spinal cord compression;
3. Presence of clinically symptomatic third space fluid;
4. Uncontrolled hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg despite optimal pharmacological treatment);
5. Uncontrolled clinically significant heart disease, including but not limited to the following: (1) >2 NYHA 2 congestive heart failure; (2) left ventricular ejection fraction (LVEF) < 50% (3) heart rate <60 (4) Grade II or greater myocardial ischemia or myocardial infarction(5) QTc interval ≥ 450 ms in males and ≥ 470 ms in females;
6. Abnormal coagulation function;
7. Prior radiotherapy, systemic chemotherapy (< 6 weeks if chemotherapy including nitrosoureas or mitomycin), hormone therapy, surgery or target therapy within 4 weeks before the study drug administration, or any unresolved AEs > CTC-AE Grade 1;
8. History of psychotropic substance abuse, alcoholism or drug abuse;
9. Use of study drugs in other clinical trials within 4 weeks prior to the first dose；
10. Use of a potent CYP3A4 inhibitor or inducer within 2 weeks prior to the first dose;
11. Use of any prescription or over-the-counter medication, vitamin products or herbs within 2 weeks before taking the investigational drug;
12. Other factors that may lead to the termination of the participation in the study at the discretion of the investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treament; In phase A, subjects receiving a single 0.25 mg of digoxin orally and wash-out for 5 days, then apatinib once daily will be conducted on D5 through D16 ； In addition, a single dose of 0.25 mg digoxin (in combination with apatinib) will be orally administered in fasting conditions on D12；	Drug: Apatinib Mesylate; Apatinib at a dosage of will be administered daily from on D5 through D16; Drug: Digoxin tablet; Digoxin at a dosage of 0.25mg will be administered at day 1 and day 12

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2020
• Primary Completion (Actual): April 3, 2021
• Study Completion (Actual): May 3, 2021

Study Registration Dates

• First Submitted: March 17, 2020
• First Submitted That Met QC Criteria: March 24, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Cardiotonic Agents; Protein Kinase Inhibitors; Digoxin; Apatinib
• Other Study ID Numbers: HR-APTN-I-007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No