Pharmacokinetics of LCZ696 in Subjects With Mild and Moderate Renal Impairment Compared to Healthy Subjects With Normal Renal Function

Phase 1

Completed

• Conditions: Mild and Moderate Renal Impairment
• Interventions: Drug: LCZ696

• Registration Number: NCT01569815
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

The purpose of this study is to determine the multiple dose pharmacokinetics of LCZ696 and its metabolites in subjects with mild to moderate renal impairment and to evaluate the safety of LCZ696 in this population.

Detailed Description

Not available

Study Timeline

• Study Start: 2009-02
• Study First Submitted: 2012-03-30
• Study First Submitted QC: 2012-03-30
• Study First Posted: 2012-04-03
• Primary Completion: 2014-08
• Study Completion: 2014-08
• Results First Submitted: 2015-07-30
• Results First Submitted QC: 2015-07-30
• Results First Posted: 2015-08-27
• Status Verified: 2015-09
• Last Update Submitted: 2015-09-25
• Last Update Posted: 2015-10-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

1. Male, and female subjects of non-child bearing potential,
2. Subjects were to weigh at least 50 kg to participate in the study,
3. and body mass index < 40 kg/m2
4. Subjects were able to communicate well with the investigator, to understand and comply with the requirements of the study;
5. Subjects were able to understand and sign the written informed consent;

For renal insufficient subjects:

1. stable renal disease without evidence of renal progressive

   • mild renal function: calculated CrCl of 50-≤80 mL/min
   • moderate renal function: calculated CrCl of 30-<50 mL/min

2. Vital signs:

   • oral body temperature between 35.0-37.8 °C
   • systolic blood pressure, 95-180 mm Hg
   • diastolic blood pressure, 60-110 mm Hg
   • pulse rate, 54-95 bpm

For healthy subjects only

1. A serum creatinine with a calculated CrCl of >80 mL/min

2. Vital signs:

   • oral body temperature between 35.0-37.2 °C
   • systolic blood pressure, 95-140 mm Hg
   • diastolic blood pressure, 60-100 mm Hg
   • pulse rate, 45-90 bpm

Exclusion Criteria

1. Current use of ACE inhibitors, valsartan, and drugs that were known as CYP2C9 substrates, potassium-sparing diuretics;
2. Smokers;
3. History of renal transplant at any time in the past and on immunosuppressant therapy;
4. Dialysis patients;
5. Medical history of clinically significant ECG abnormalities or a family history of a prolonged QT-interval syndrome;
6. Any surgical or medical condition which may significantly alter the absorption, distribution, metabolism or excretion of any drug substance; Other protocol defined inclusion/exclusion criteria may apply

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LCZ696 400 mg	LCZ696	LCZ696 400 mg once daily for 5 days

Primary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve (AUC0-24) From Time Zero to 24- Hour Post-dose (Day 1), and After Multiple Dose Administration (Day 5)	Day 1 and day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Elimination Half-life (t1/2) After Multiple Dose (Day 5) Administration	Day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Systemic Clearance From Plasma Following Extravascular Administration (CL/F) After Multiple Dose Administration (Day 5)	Day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Accumulation Ratio (Racc) After Multiple Dose Administration (Day 5)	Day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Renal Clearance From Plasma (CLr) After Multiple Dose Administration (Day 5)	Day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Amount of Drug Excreted Into the Urine From Time Zero to 24-hours Post-dose (Ae0-24) After Single Dose (Day 1), and After Multiple Dose Administration (Day 5)	Day 1 and Day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Maximum Peak Plasma Concentration (Cmax) Observed After Single Dose (Day 1), and After Multiple Dose Administration (Day 5)	Day 1, day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Time to Reach Maximum Peak Plasma Concentration (Tmax) After Single Dose (Day 1), and After Multiple Dose Administration (Day 5)	Day 1 and day 5	Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)

Secondary Outcome Measures

Name	Time	Method
Change in Mean 24-hours Sodium Clearance From Baseline to Day 7	From baseline to Day 7	Sodium clearance will be measured in urine from baseline until Day 7

Trial Locations

Locations (1)

Novartis Investigative Site; 🇷🇸 Belgrade, Serbia