Evaluation of Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension

Mild to Moderate Hypertension Clinical Trial

Official title:

An Open Label, Three-period, Single Sequence Study to Evaluate the Pharmacokinetic Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01601470
• Other study ID #: CLCZ696B2225
• Secondary ID: 2012-001632-64
• Status: Completed
• Phase: Phase 2
• First received: May 16, 2012
• Last updated: October 6, 2015
• Start date: September 2012
• Est. completion date: January 2013

Study information

• Verified date: October 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medicinal Products
• Study type: Interventional

Clinical Trial Summary

This study was conducted to investigate the potential for a pharmacokinetic drug-drug interaction in support of the co-administration of LCZ696 and sildenafil.

Description:

This study was conducted to investigate the potential for a pharmacokinetic drug-drug interaction in patients with mild-to-moderate hypertension in support of the co-administration of LCZ696 and sildenafil.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male subjects with mild to moderate hypertension, either treated or not currently on treatment, between age 18 and 65 years of age, and otherwise in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.

• At screening: systolic blood pressure 120-140 mmHg on therapy, or 140-160 mmHg if untreated

• At screening: diastolic blood pressure, 70-95 mmHg on therapy, or 90-100 mmHg if untreated

• Baseline: BP =140/90;

Exclusion Criteria:

• Use of non-antihypertensive prescription drugs, herbal supplements, and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (2) weeks prior to initial dosing

Other protocol-defined inclusion/exclusion criteria may apply.

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Hypertension
• Mild to Moderate Hypertension

Intervention

Drug:
• LCZ696
LCZ696 400mg QD was administered alone for 4 days and in combination with sildenafil for 1 day
• Sildenafil
Sildenafil 50 mg single dose was administered alone for 1 days and in combination with LCZ696 400mg QD for 1 day

Locations

Country	Name	City	State
Germany	Novartis Investigative Site	Berlin

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of LCZ696 Analytes	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmax is a mathematically-derived value from all measurements. Cmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Minimum Plasma Concentration Following Drug Administration at Steady State (Cmin,ss) of LCZ696 Analytes (AHU377, LBQ696 and Valsartan)	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmin is a mathematically-derived value from all measurements. Cmin is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Time to Reach the Maximum Concentration After Drug Administration (Tmax) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Tmax is a mathematically-derived value from all measurements. Tmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sildenafil and N-desmethyl-sildenafil Analytes	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Sildenafil and N-desmethyl-sildenafil Analytes	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Terminal Elimination Half-life (T1/2) of Sildenafil and N-desmethyl-sildenafil Analytes	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. T1/2 is a mathematically-derived value from all measurements. T1/2 is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Maximum Plasma Concentration Following Drug Administration (Cmax) of Sildenafil and N-desmethyl-sildenafil Analytes	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Primary	Time to Reach the Maximum Concentration After Drug Administration (Tmax) of Sildenafil and N-desmethyl-sildenafil Analytes	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed. 8pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.	From pre-dose on day 1 until 12 hours post dose on day 8	No
Secondary	Adverse Events, Serious Adverse Events and Deaths Were Monitored From Screening to End of Study	Number of patients with adverse events, serious adverse events and death	From the screening visit until 30 days past the final study assessment	Yes