Pharmacokinetics of Lanraplenib in Adults With Impaired Renal Function

A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics of GS-9876 in Subjects With Impaired Renal Function

The primary objective of this study is to evaluate the pharmacokinetics (PK) of lanraplenib in participants with impaired renal function relative to matched healthy controls. Participants in this study will be enrolled using an adaptive design that includes up to 3 enrolled cohorts. Based on safety and/or PK data in Cohort 1, participants will be enrolled in adaptive Cohorts 2 and/or 3.

Study Overview

• Status: Completed
• Conditions: Inflammatory Disease
• Intervention / Treatment: Drug: Lanraplenib.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Munich, Germany
    • Apex Gmbh
• New Zealand
  • Christchurch, New Zealand
    • Christchurch Clinical Studies Trust
  • Auckland
    • Grafton, Auckland, New Zealand
      • Auckland Clinical Studies
• United States
  • Florida
    • Miami, Florida, United States
      • Clinical Pharmacology of Miami, Inc. (CPMI)
    • Orlando, Florida, United States
      • Orlando Clinical Research Center
    • Orlando, Florida, United States
      • Omega Research Consultants, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

All Individuals

• Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
• Have a calculated body mass index (BMI) of ≥ 18 kg/m^2 and ≤ 36 kg/m^2 at screening
• Females of childbearing potential must have a negative pregnancy test at screening and clinic admission (Day -1).
• Individuals have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 30 days following the last dose of study drug.
• Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the sponsor
• Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs

For Individuals with Renal Impairment

• Must have diagnosis of chronic (> 6 months), stable renal impairment with no clinically significant change in renal function status within 90 days prior to study drug administration (Day 1).
• Have a creatinine clearance (CLcr) < 90 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening.

For Healthy Matched Controlled Individuals (Individuals with Normal Renal Function)

• Have a CLcr ≥ 90 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening
• Match in age (± 10 years), gender, and body mass index (± 20%, 18 kg/m^2 ≤ BMI ≤ 36 kg/m^2).

Key Exclusion Criteria:

• Be a lactating female
• Have received any investigational compound within 30 days prior to study dosing
• Have current alcohol or substance abuse judged by the investigator to potentially interfere with individual's compliance or individual's safety as judged by the investigator
• Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody
• Have poor venous access that limits phlebotomy

For Individuals with Renal Impairment

• Require or are anticipated to require dialysis within 90 days of study dosing
• Require during the study or have received moderate or strong inhibitors or inducers of cytochrome P450 (CYP) 3A within 2 weeks prior to study drug administration.

For Healthy Matched Controlled Individuals (Individuals with Normal Renal Function)

• Have taken any prescription medications or over-the-counter medications, including herbal products and antacids, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications and/or stable hormone replacement therapy in peri- /post-menopausal female

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderate Renal Impairment (Cohort 1); Participants with moderate renal impairment and matched healthy controls will receive a single dose of lanraplenib	Drug: Lanraplenib.; 20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1; Other Names: GS-9876
Experimental: Severe Renal Impairment (Adaptive Cohort 2); Participants with severe renal impairment and matched healthy controls will receive a single dose of lanraplenib	Drug: Lanraplenib.; 20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1; Other Names: GS-9876
Experimental: Mild Renal Impairment (Adaptive Cohort 3); Participants with mild renal impairment and matched healthy controls will receive a single dose of lanraplenib	Drug: Lanraplenib.; 20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1; Other Names: GS-9876

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr	AUClast is defined as the concentration of drug from time zero to the last observable concentration. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min	0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1
PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr	AUCinf is defined as the concentration of drug extrapolated to infinite time. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min	0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1
PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr	Cmax is defined as the maximum concentration of drug. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × ([140-age in years] × [body weight in kg])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min	0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events		Day 1 up to Day 31
Percentage of Participants Who Experienced Graded Laboratory Abnormalities	Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. The criteria used for grading was Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.	Day 1 up to Day 31

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Hsueh CH, Zheng H, Matzkies F, Mozaffarian A, Medzihradsky O, Tarnowski T, Curry N, and Mathias A. Pharmacokinetics and Short-Term Safety of GS-9876, an Oral Spleen Tyrosine Kinase Inhibitor in Subjects with Renal Impairment. American Society for Clinical Pharmacology and Therapeutics 2019; Washington D.C.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2016
• Primary Completion (Actual): October 5, 2018
• Study Completion (Actual): October 5, 2018

Study Registration Dates

• First Submitted: November 7, 2016
• First Submitted That Met QC Criteria: November 7, 2016
• First Posted (Estimate): November 8, 2016

Study Record Updates

• Last Update Posted (Actual): October 25, 2019
• Last Update Submitted That Met QC Criteria: October 3, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency
• Other Study ID Numbers: GS-US-379-1932; 2016-003823-47 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No