Back to resultsEffect of Hepatic Impairment on the Pharmacokinetics of Alectinib
Primary Purpose
Hepatic Impairment
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Alectinib
Sponsored by
About this trial
This is an interventional treatment trial for Hepatic Impairment focused on measuring Healthy volunteer, Alectinib, Hepatic impairment
Eligibility Criteria
Inclusion Criteria:
All Participants
- Body mass index between 18 to 35 kilograms per square meter (kg/m^2) inclusive and weight greater than (>) 50 kilograms (kg)
- Female participants must be surgically sterile or post-menopausal
- Male participants and their partners of child-bearing potential must be willing to use 2 effective methods of contraception, one of which must be a barrier method
Participants with Hepatic Impairment
- Documented chronic stable liver disease (Child-Pugh Class A, B or C)
Exclusion Criteria:
All Participants
- Pregnant or lactating women, males with female partners who are pregnant or lactating, or women of child bearing potential
- Positive test for drugs of abuse or alcohol
- Participation in an investigational drug or device study within 45 days or 5 half-lives (whichever time period is longer) or 6 months for biologic therapies prior to study drug administration
- History of hypersensitivity to any of the additives in the alectinib formulation
- Participants under judicial supervision, guardianship, or curatorship
- History of severe drug-related allergic reactions or drug-induced hepatotoxicity
Healthy Participants
- Use of any medications (prescription or over-the-counter), within 2 weeks or 5 half-lives (whichever longer) prior to study drug administration
- Use of any herbal supplements or any metabolic inducers within 4 weeks, or 5 half-lives (whichever is longer) prior to study drug administration
Participants with Hepatic Impairment
- Positive screening test for human immunodeficiency virus (HIV)
- History of liver transplantation
- Hepatocellular carcinoma or acute liver disease
- Severe ascites at screening or admission to the clinic
- Recent history (past 2 years) or current severe hepatic encephalopathy (Grade 3 or higher)
- Any evidence of progressive liver disease within the last 4 weeks
- Presence of surgically created or transjugular intrahepatic portal systemic shunts
Sites / Locations
- Pharmaceutical Research Associates CZ, s.r.o.
- Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Alectinib: Moderate Hepatic Impairment
Alectinib: Severe Hepatic Impairment
Alectinib: Normal Hepatic Function
Arm Description
Participants with moderate hepatic impairment (based on Child-Pugh score) will receive alectinib at a single oral dose of 300 milligrams (mg) on Day 1.
Participants with severe hepatic impairment (based on Child-Pugh score) will receive alectinib at a single oral dose of 300 mg on Day 1.
Participants with normal hepatic function will receive alectinib at a single oral dose of 300 mg on Day 1.
Outcomes
Primary Outcome Measures
Maximum Observed Plasma Concentration (Cmax) of Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
Cmax of Unbound Alectinib
Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) for Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. AUC 0-inf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
AUC 0-inf for Unbound Alectinib
AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measureable Concentration (AUC 0-last) for Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
AUC 0-last for Unbound Alectinib
Secondary Outcome Measures
Cmax of Total Metabolite of Alectinib (M4)
Total M4 = unbound M4 plus M4 bound to plasma proteins
Cmax of Unbound M4
Cmax of Total Combined Alectinib and M4 (Alectinib + M4)
Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
Cmax of Unbound Alectinib + M4
AUC 0-inf of Total M4
Total M4 = unbound M4 plus M4 bound to plasma proteins. AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
AUC 0-inf of Unbound M4
AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
AUC 0-inf of Total Alectinib + M4
Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins. AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
AUC 0-inf of Unbound Alectinib + M4
AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
AUC 0-last of Total M4
Total M4 = unbound M4 plus M4 bound to plasma proteins
AUC 0-last of Unbound M4
AUC 0-last of Total Alectinib + M4
Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
AUC 0-last of Unbound Alectinib + M4
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
Tmax for Total M4
Total M4 = unbound M4 plus M4 bound to plasma proteins
Apparent Terminal Half-life (t1/2) of Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. t1/2 = the time measured for the plasma concentration to decrease by one half.
t1/2 of Total M4
Total M4 = unbound M4 plus M4 bound to plasma proteins. t1/2 = the time measured for the plasma concentration to decrease by one half.
Apparent Oral Clearance (CL/F) of Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability.
CL/F of Unbound Alectinib
Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability.
Apparent Volume of Distribution (Vz/F) for Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. Volume of distribution is defined as the theoretical volume which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.
Vz/F for Unbound Alectinib
Volume of distribution is defined as the theoretical volume which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.
Fraction of Drug Unbound (fu) of Total Alectinib
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. fu = ratio of unbound alectinib to total alectinib multiplied by 100.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02621047
Brief Title
Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib
Official Title
The Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib: A Multiple-Center, Open-Label Study Following Single Oral Dosing of Alectinib to Subjects With Hepatic Impairment and Matched Healthy Subjects With Normal Hepatic Function
Study Type
Interventional
2. Study Status
Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
December 4, 2015 (Actual)
Primary Completion Date
December 8, 2016 (Actual)
Study Completion Date
December 8, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. Study Description
Brief Summary
This is a multicenter, non-randomized, single-dose, open-label study conducted in male and surgically sterile or post-menopausal female participants with stable chronic hepatic impairment and in healthy participants matched by age, gender, and body weight to assess the effect of hepatic impairment on the pharmacokinetics of alectinib.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Impairment
Keywords
Healthy volunteer, Alectinib, Hepatic impairment
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Alectinib: Moderate Hepatic Impairment
Arm Type
Experimental
Arm Description
Participants with moderate hepatic impairment (based on Child-Pugh score) will receive alectinib at a single oral dose of 300 milligrams (mg) on Day 1.
Arm Title
Alectinib: Severe Hepatic Impairment
Arm Type
Experimental
Arm Description
Participants with severe hepatic impairment (based on Child-Pugh score) will receive alectinib at a single oral dose of 300 mg on Day 1.
Arm Title
Alectinib: Normal Hepatic Function
Arm Type
Experimental
Arm Description
Participants with normal hepatic function will receive alectinib at a single oral dose of 300 mg on Day 1.
Intervention Type
Drug
Intervention Name(s)
Alectinib
Intervention Description
Participants will receive alectinib as per the dosage schedule mentioned in arm description.
Primary Outcome Measure Information:
Title
Maximum Observed Plasma Concentration (Cmax) of Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Cmax of Unbound Alectinib
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) for Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. AUC 0-inf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-inf for Unbound Alectinib
Description
AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measureable Concentration (AUC 0-last) for Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-last for Unbound Alectinib
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Secondary Outcome Measure Information:
Title
Cmax of Total Metabolite of Alectinib (M4)
Description
Total M4 = unbound M4 plus M4 bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Cmax of Unbound M4
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Cmax of Total Combined Alectinib and M4 (Alectinib + M4)
Description
Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Cmax of Unbound Alectinib + M4
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-inf of Total M4
Description
Total M4 = unbound M4 plus M4 bound to plasma proteins. AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-inf of Unbound M4
Description
AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-inf of Total Alectinib + M4
Description
Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins. AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-inf of Unbound Alectinib + M4
Description
AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-last of Total M4
Description
Total M4 = unbound M4 plus M4 bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-last of Unbound M4
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-last of Total Alectinib + M4
Description
Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
AUC 0-last of Unbound Alectinib + M4
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Tmax for Total M4
Description
Total M4 = unbound M4 plus M4 bound to plasma proteins
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Apparent Terminal Half-life (t1/2) of Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. t1/2 = the time measured for the plasma concentration to decrease by one half.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
t1/2 of Total M4
Description
Total M4 = unbound M4 plus M4 bound to plasma proteins. t1/2 = the time measured for the plasma concentration to decrease by one half.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Apparent Oral Clearance (CL/F) of Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
CL/F of Unbound Alectinib
Description
Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Apparent Volume of Distribution (Vz/F) for Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. Volume of distribution is defined as the theoretical volume which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Vz/F for Unbound Alectinib
Description
Volume of distribution is defined as the theoretical volume which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
Title
Fraction of Drug Unbound (fu) of Total Alectinib
Description
Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. fu = ratio of unbound alectinib to total alectinib multiplied by 100.
Time Frame
Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
All Participants
Body mass index between 18 to 35 kilograms per square meter (kg/m^2) inclusive and weight greater than (>) 50 kilograms (kg)
Female participants must be surgically sterile or post-menopausal
Male participants and their partners of child-bearing potential must be willing to use 2 effective methods of contraception, one of which must be a barrier method
Participants with Hepatic Impairment
- Documented chronic stable liver disease (Child-Pugh Class A, B or C)
Exclusion Criteria:
All Participants
Pregnant or lactating women, males with female partners who are pregnant or lactating, or women of child bearing potential
Positive test for drugs of abuse or alcohol
Participation in an investigational drug or device study within 45 days or 5 half-lives (whichever time period is longer) or 6 months for biologic therapies prior to study drug administration
History of hypersensitivity to any of the additives in the alectinib formulation
Participants under judicial supervision, guardianship, or curatorship
History of severe drug-related allergic reactions or drug-induced hepatotoxicity
Healthy Participants
Use of any medications (prescription or over-the-counter), within 2 weeks or 5 half-lives (whichever longer) prior to study drug administration
Use of any herbal supplements or any metabolic inducers within 4 weeks, or 5 half-lives (whichever is longer) prior to study drug administration
Participants with Hepatic Impairment
Positive screening test for human immunodeficiency virus (HIV)
History of liver transplantation
Hepatocellular carcinoma or acute liver disease
Severe ascites at screening or admission to the clinic
Recent history (past 2 years) or current severe hepatic encephalopathy (Grade 3 or higher)
Any evidence of progressive liver disease within the last 4 weeks
Presence of surgically created or transjugular intrahepatic portal systemic shunts
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
Pharmaceutical Research Associates CZ, s.r.o.
City
Praha 7
ZIP/Postal Code
170 00
Country
Czechia
Facility Name
Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie
City
Bratislava
ZIP/Postal Code
831 01
Country
Slovakia
12. IPD Sharing Statement
Citations:
PubMed Identifier
30052269
Citation
Morcos PN, Cleary Y, Sturm-Pellanda C, Guerini E, Abt M, Donzelli M, Vazvaei F, Balas B, Parrott N, Yu L. Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib. J Clin Pharmacol. 2018 Dec;58(12):1618-1628. doi: 10.1002/jcph.1286. Epub 2018 Jul 27.
Results Reference
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Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib
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