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

Phase 1

Completed

• Conditions: Advanced Solid Tumor
• Interventions: Drug: Apatinib Mesylate; Drug: Digoxin tablet

• Registration Number: NCT04322552
• Lead Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2020-03
• Study Start: 2020-03-12
• Study First Submitted: 2020-03-17
• Study First Submitted QC: 2020-03-24
• Study First Posted: 2020-03-26
• Primary Completion: 2021-04-03
• Study Completion: 2021-05-03
• Last Update Submitted: 2022-11-04
• Last Update Posted: 2022-11-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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:

2. Hematology

   1. HB≥100 g/L;
   2. ANC≥1.5×109/L;
   3. PLT≥90×109/L;

3. 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treament	Digoxin tablet	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；
Treament	Apatinib Mesylate	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；

Primary Outcome Measures

Name	Time	Method
Pharmacokinetics parameter: Cmax of digoxin	through study completion, an average of 16 days	Peak Plasma Concentration (Cmax) of digoxin
Pharmacokinetics parameter: AUC of digoxin	through study completion, an average of 16 days	Area under the plasma concentration versus time curve (AUC) of digoxin

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Hunan Cancer Hospital; 🇨🇳 Changsha, Hunan, China