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.

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 single 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.

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.

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On Day 6 of each period, after overnight fasting for at least 10.00 hours the subjects were dosed either with the Treatment (A) [LANOXIN® (digoxin) USP 250 mcg (substrate drug)] or Treatment (B) [LANOXIN® (digoxin) USP 250 mcg (substrate drug) + Spironolactone Oral Suspension 100 mg (Perpetrator; Carospir® Oral Suspension 20 mL of 25 mg / 5 mL)] as per the randomization scheme.

9 days for period 18 Days for 2 periods

Spironolactone Oral Suspension