Drug-drug Interaction (DDI) Study of Spironolactone (Perpetrator) and Digoxin (Substrate Drug)

Overview

An open label, balanced, randomized, single-dose, two-treatment, two-sequence, two-period, crossover oral drug-drug interaction study of spironolactone (perpetrator) and Digoxin (substrate drug) in healthy adult human subjects under fasting condition.

Full Title of Study: “Two Way Crossover Oral Drug-drug Interaction Study of Spironolactone (Perpetrator) and Digoxin (Substrate Drug) in Healthy Adult Human Subjects Under Fasting Condition”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 19, 2019

Detailed Description

Drug interaction studies between spironolactone and digoxin, particularly studies in which digoxin was administered intravenously (Waldorf, S 1978; Fenster, P.E. 1984), indicate that spironolactone may decrease the renal clearance of digoxin by 18-25%, and increase the (area under curve) AUC of digoxin by 35-44%. Although the radioimmunoassay used in the study may be confounded, these results suggest that inhibition of P-gp in the renal proximal tubules may be possible. To account for possible renal P-gp inhibition, subjects in the test group will be pretreated with spironolactone for about 5 days to allow accumulation of some of the metabolites which have a long half-life (e.g., canrenone ~33 hours) and continue to be treated with spironolactone while digoxin is renally eliminated from the body. Based on this assessment, the FDA suggested study design is Treatment A: Single dose of digoxin alone. Treatment B: Digoxin + Spironolactone; Day 1- 9: Spironolactone quarter die (QD) dose; Day 6: Digoxin single oral dose. Also, digoxin has a long half-life of 1.5-2 days, and the Pharmacokinetic (PK) sampling scheme of up to 72 hours may not be enough to characterize the elimination kinetics of digoxin. Hence, the plasma concentrations of digoxin up to 96 hours (4 days) postdose is considered This will allow you to detect possible differences in the clearance of digoxin mediated by an interaction with P-gp in the renal proximal tubules. The study also involves collecting urine samples and measuring renal clearance (CLR) and unchanged drug excreted in urine (fe) for digoxin.

Interventions

  • Drug: Digoxin 250 MCG Oral Tablet
    • The intervention is for study of drug drug interaction of digoxin when administered with spironolactone oral suspension
  • Drug: Spironolactone 25 mg/ 5 mL S/F Suspension
    • The intervention is for study of drug drug interaction of digoxin when administered with spironolactone oral suspension

Arms, Groups and Cohorts

  • Experimental: Digoxin 250 micrograms (MCG) Oral Tablet
    • Administration of 20 mL of 25 mg / 5 mL singe dose Day 1 to Day 9 randomized to digoxin and Spironolactone treatment. On day 6, after overnight fasting of at least 10.00 hours, either digoxin or spironolactone will be administered orally for drug drug interaction evaluation
  • Experimental: Spironolactone 25 mg/ 5 mL S/F Suspension
    • Crossover administration of 20 mL of 25 mg / 5 mL Day 1 to Day 9 randomized to Spironolactone or digoxin treatment. On day 6, after overnight fasting of at least 10.00 hours, either spironolactone or digoxin will be administered orally for drug drug interaction evaluation

Clinical Trial Outcome Measures

Primary Measures

  • Maximum observed plasma concentration (Cmax) of digoxin
    • Time Frame: 9 days
    • Primary Pharmacokinetic parameter Maximum measured plasma concentration. Area under the plasma concentration versus time curve from time 0 to the 96 hour time point concentration, calculated by linear trapezoidal method. subjects under fasting condition.
  • Area under the plasma concentration-time curve from time 0 to the 96 hr measurement (AUC0-96) of digoxin
    • Time Frame: 9 days
    • calculated by linear trapezoidal method.

Secondary Measures

  • Time to achieve maximum plasma concentration (Tmax)
    • Time Frame: 9 days
    • If the maximum value occurs at more than one time point, Tmax is defined as the first time point with this value.
  • Renal clearance (CLR) Ae0-240h/AUC0-240 h of digoxin in urine
    • Time Frame: 9 days
    • Renal clearance on digoxin in urine in concomitant administration with spironolactone oral suspension
  • Unchanged drug digoxin (fe) excreted in urine
    • Time Frame: 9 days
    • measurement of unchanged drug in urine in concomitant administration with spironolactone oral suspension
  • ECG measurement will be performed to evaluate any changes in the QT interval
    • Time Frame: 12
    • ECG will be performed at 1.00 and 3.00 hours post dose in each period on Day 6 and at check-out of each period of the study

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy human subjects aged between 20 and 35 years (including both). – Subjects with a BMI between 18.5 – 24.9 Kg/m2 (including both) but body weight not less than 60 Kgs. – Subjects who were screened at least 48 hours prior to check-in – Subjects with normal health as determined by personal medical history, clinical examination, and laboratory examinations including serological tests during the screening – Subjects with normal 2D echo – Subjects having normal 12-lead electrocardiogram (ECG) or ECG with no clinical significant abnormalities as determined by Investigator. – Subjects having normal chest X-Ray (P/A view) or chest X-ray with no clinically significant abnormalities as determined by investigator. – Subjects able to communicate effectively. – Subjects willing to give written informed consent and adhere to all the requirements of this protocol. – Additional inclusion criteria for female subjects, Female of childbearing potential practicing an acceptable method of birth control for the duration of the study as judged by the investigator(s), such as condoms, foams, jellies, diaphragm, intrauterine device (IUD), or abstinence: or Postmenopausal for at least 1 year, or Surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy has been performed on the subject). Exclusion Criteria:

  • Subjects having contraindications or hypersensitivity to study drug or related group of drugs. – History or presence of any medical condition or disease according to the opinion of the physician. – History or presence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder. – Subject having QT/ corrected QT interval (QTc) >450 milliseconds – History or presence of significant alcoholism or drug abuse in the past one year. – History or presence of significant smoking (more than 10 cigarettes /day or consumption of tobacco products). – Subjects who fail to abstain from consuming any alcoholic products from 48.00 hours prior to check-in to till check-out / last sample of the study. – Subjects who fail to abstain from any xanthine-containing food and/or beverages (like chocolate, tea, coffee, cola drinks), cigarettes and tobacco containing products and grapefruit and/or it's juice from 48.00 hours prior to check-in to till check-out / last sample of the study. – Subjects who fail to refrain from pan or pan masala, gutkha, masala (containing beetle nut and tobacco) for 48.00 hours prior to check-in to till check-out/last sample of the study. – Difficulty with donating blood. – Systolic blood pressure less than 110 mm Hg or more than 140 mm Hg. – Diastolic blood pressure less than 70 mm Hg or more than 90 mm Hg. – Pulse rate less than 60 beats/minute or more than 100 beats/minute. – Use of any prescribed medication during last two weeks or over-the- counter (OTC) medicinal products/ herbal products during the last one week prior to check-in. – Major illness during 90 days before check-in. – Participation in a drug research study within past 90 days of check-in. – Donation of blood (i.e. one unit or 350 mL) in the past 90 days before check-in. – History of unusual diet consumption in the past 3 weeks before check-in. – Additional exclusion criteria for female subjects, Volunteer demonstrating a positive pregnancy test. Volunteers who are pregnant, currently breast-feeding or who are likely to become pregnant during the study. Volunteers who have used implanted or injected hormonal contraceptives anytime during the 6 months prior to study or used hormonal contraceptives within 14 days before dosing. -

Gender Eligibility: All

Minimum Age: 20 Years

Maximum Age: 35 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • CMP Development, LLC
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Roopali K Somani, MD, Principal Investigator, Employee

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