Pharmacokinetics of Everolimus in Subjects With Hepatic Insufficiency

An Open-label, Single-dose Study to Assess the Pharmacokinetics of Oral Everolimus (Afinitor®) in Subjects With Impaired Hepatic Function

This clinical pharmacology research study will assess the safety and pharmacokinetics of the drug everolimus in patients with impaired hepatic function as compared to healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency
• Intervention / Treatment: Drug: Everolimus

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Frankfurt, Germany
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All subjects:

• In good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory test values (except for values related to hepatic insufficiency).

Hepatic impaired subjects:

• A Child-Pugh Classification score clinically determined as Class A, Class B, or Class C.
• Absolute neutrophil count (ANC) > 1000 cells/mm3
• Hemoglobin > 9 mg/mL
• Platelet count > 50,000/mm3 at screening and baseline
• Serum creatinine ≤ 2.0 x ULN
• Free of significant medical disorders unrelated to the subject's hepatic disorder

Exclusion Criteria:

All subjects:

• Significant illness, including infections, or hospitalization within 4 weeks prior to dosing (hospitalization is allowed for hepatic impaired subjects if related to liver disease). Invasive systemic fungal infections need to be fully resolved prior to study entry.
• History of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated).
• History of clinically significant drug allergy; history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug (everolimus) or drugs similar to the study drug (other mTOR inhibitors, e.g., rapamycin or temsirolimus).
• Active bleeding during the last 28 days prior to dosing, including variceal bleeding.
• Except for hepatic impairment, any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the subject in case of participation in the study.
• Use of tobacco within 7 days prior to dosing or during the study.
• Consumption of alcohol within 3 days prior to dosing or during the study.
• Consumption of grapefruits, grapefruit juice, Sevilla oranges, starfruit or related foods within 7 days prior to dosing or during the study period.
• Use of any drugs known to affect CYP3A4 or PgP, including both inhibitors and inducers, within 7 days prior to dosing or during the study.

Hepatic impaired subjects:

• Symptoms or history of Grade 3 or 4 hepatic encephalopathy within 4 weeks of study entry.

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RAD001	Drug: Everolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evaluate the pharmacokinetics of a single oral dose of everolimus in subjects with severely impaired hepatic function (Child-Pugh C) relative to healthy controls. Measure: AUC, Cmax, tmax, λz, Vd/F, CL/F and t1/2	First 8 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluate the pharmacokinetics of a single oral dose of everolimus in subjects with mild and moderate impaired hepatic function (Child-Pugh A and B, respectively) relative to healthy controls.	First 8 days
Assess the safety and tolerability of a single oral dose of everolimus in subjects with impaired hepatic function (Child-Pugh A, B, and C).	First 8 days plus day 15 and day 28 post-dose follow-ups for safety
Explore correlation between pharmacokinetics and hepatic function parameters	First 8 days

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Peveling-Oberhag J, Zeuzem S, Yong WP, Kunz T, Paquet T, Bouillaud E, Urva S, Anak O, Sellami D, Kobalava Z. Effects of hepatic impairment on the pharmacokinetics of everolimus: a single-dose, open-label, parallel-group study. Clin Ther. 2013 Mar;35(3):215-25. doi: 10.1016/j.clinthera.2013.02.007. Epub 2013 Mar 1.

Helpful Links

• Results for CRAD001X2102 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): November 1, 2010
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: August 27, 2009
• First Submitted That Met QC Criteria: August 28, 2009
• First Posted (Estimate): August 31, 2009

Study Record Updates

• Last Update Posted (Actual): December 21, 2020
• Last Update Submitted That Met QC Criteria: December 17, 2020
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: pharmacokinetics; cirrhosis; Hepatic insufficiency; liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CRAD001X2102; EudraCT 2009-012295-27

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No