Drug Drug Interaction
Conditions
Brief summary
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.
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 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.
Interventions
DRUGDigoxin 250 MCG Oral Tablet
The intervention is for study of drug drug interaction of digoxin when administered with spironolactone oral suspension
DRUGSpironolactone 25 mg/ 5 mL S/F Suspension
The intervention is for study of drug drug interaction of digoxin when administered with spironolactone oral suspension
Sponsors
CMP Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Masking description
Spironolactone Oral Suspension
Intervention model description
An open label, balanced, randomized, single-dose, two-treatment, two-sequence, two-period, crossover, drug-drug interaction study in healthy adult human subjects under fasting condition for spironolactone oral suspension (Carospir®)
Eligibility
Sex/Gender
ALL
Age
20 Years to 35 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dogoxin Plasma Data for Cmax | 4 days | Primary Pharmacokinetic parameter The following pharmacokinetic parameters for Digoxin were obtained using non-compartmental method Cmax, AUC0-96, and tmax using plasma data, Renal clearance (CLR) /Percent Recovered, Unchanged drug excreted in urine (fe)/Amount Recovered using urine data. |
| Digoxin Plasma Data for AUC0-96 | 4 days | Area under the plasma concentration versus time curve from time 0 to the 96 hour time point concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Digoxin Plasma Data for Tmax | 4 days | If the maximum value occurs at more than one time point, Tmax is defined as the first time point with this value. |
| ECG Measurement Will be Performed to Evaluate Any Changes in the QT Interval | 4 days | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Renal Clearance (CLR)/Percent Recovered | 04 Days | Summary Statistics for Untransformed Urine PK Parameters of digoxin Per Treatment-Renal clearance (CLR)/Percent Recovered |
| Unchanged Drug Excreted in Urine (fe)/ Amount Recovered | 04 Days | Summary of Urine Pharmacokinetic parameters for digoxin -unchanged drug excreted in urine (fe)/ Amount Recovered |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Drug-Drug Interaction Study In both periods (Period-I and II), from Day 1 to Day 5 and Day 7 to Day 9, the subjects who were randomized to treatment B, were administered Spironolactone Oral Suspension 100 mg (Perpetrator; Carospir® Oral Suspension 20 mL of 25 mg / 5 mL), and the subject who were randomized to treatment A were not dosed.
On all these days the standard breakfast was served 0.50 hr (30 min) post dose.
On Day 6, 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. | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | Drug-Drug Interaction Study | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 28 Participants | — |
| Age, Continuous | 29 Years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment India | 28 participants | — |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 28 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 0 / 28 | 0 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
Digoxin Plasma Data for AUC0-96
Area under the plasma concentration versus time curve from time 0 to the 96 hour time point concentration.
Time frame: 4 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug-Drug Interaction Study | Digoxin Plasma Data for AUC0-96 | Treatment A | 13715.974 pg.hr/mL | Standard Deviation 2669.003 |
| Drug-Drug Interaction Study | Digoxin Plasma Data for AUC0-96 | Treatment B | 16551.500 pg.hr/mL | Standard Deviation 4108.5 |
Primary
Dogoxin Plasma Data for Cmax
Primary Pharmacokinetic parameter The following pharmacokinetic parameters for Digoxin were obtained using non-compartmental method Cmax, AUC0-96, and tmax using plasma data, Renal clearance (CLR) /Percent Recovered, Unchanged drug excreted in urine (fe)/Amount Recovered using urine data.
Time frame: 4 days
Population: The following pharmacokinetic parameters for Digoxin were obtained using non-compartmental method (WinNonlin, version 8.1, Pharsight Corporation, USA):~Cmax, AUC0-96, and tmax using plasma data, Renal clearance (CLR) /Percent Recovered, Unchanged drug excreted in urine (fe)/Amount Recovered using urine data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug-Drug Interaction Study | Dogoxin Plasma Data for Cmax | Treatment A | 1530.188 pg/mL | Standard Deviation 502.81 |
| Drug-Drug Interaction Study | Dogoxin Plasma Data for Cmax | Treatment B | 2432.908 pg/mL | Standard Deviation 870.562 |
Secondary
Digoxin Plasma Data for Tmax
If the maximum value occurs at more than one time point, Tmax is defined as the first time point with this value.
Time frame: 4 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug-Drug Interaction Study | Digoxin Plasma Data for Tmax | Treatment A | 0.744 hr | Standard Deviation 0.195 |
| Drug-Drug Interaction Study | Digoxin Plasma Data for Tmax | Treatment B | 0.901 hr | Standard Deviation 0.569 |
Secondary
ECG Measurement Will be Performed to Evaluate Any Changes in the QT Interval
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
Time frame: 4 days
Other Pre-specified
Renal Clearance (CLR)/Percent Recovered
Summary Statistics for Untransformed Urine PK Parameters of digoxin Per Treatment-Renal clearance (CLR)/Percent Recovered
Time frame: 04 Days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug-Drug Interaction Study | Renal Clearance (CLR)/Percent Recovered | Treatment A | 54.687 % recovered | Standard Deviation 29.158 |
| Drug-Drug Interaction Study | Renal Clearance (CLR)/Percent Recovered | Treatment B | 53.378 % recovered | Standard Deviation 21.256 |
Other Pre-specified
Unchanged Drug Excreted in Urine (fe)/ Amount Recovered
Summary of Urine Pharmacokinetic parameters for digoxin -unchanged drug excreted in urine (fe)/ Amount Recovered
Time frame: 04 Days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug-Drug Interaction Study | Unchanged Drug Excreted in Urine (fe)/ Amount Recovered | Treatment A | 136717.72 nanograms | Standard Deviation 72895.492 |
| Drug-Drug Interaction Study | Unchanged Drug Excreted in Urine (fe)/ Amount Recovered | Treatment B | 133446.07 nanograms | Standard Deviation 53141.044 |