Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: Alectinib

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Praha 7, Czechia, 170 00
    • Pharmaceutical Research Associates CZ, s.r.o.
• Slovakia
  • Bratislava, Slovakia, 831 01
    • Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Alectinib: Moderate Hepatic Impairment; 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.	Drug: Alectinib; Participants will receive alectinib as per the dosage schedule mentioned in arm description.
EXPERIMENTAL: Alectinib: Severe Hepatic Impairment; Participants with severe hepatic impairment (based on Child-Pugh score) will receive alectinib at a single oral dose of 300 mg on Day 1.	Drug: Alectinib; Participants will receive alectinib as per the dosage schedule mentioned in arm description.
EXPERIMENTAL: Alectinib: Normal Hepatic Function; Participants with normal hepatic function will receive alectinib at a single oral dose of 300 mg on Day 1.	Drug: Alectinib; Participants will receive alectinib as per the dosage schedule mentioned in arm description.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Total Alectinib	Total alectinib = unbound alectinib plus alectinib bound to plasma proteins	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)
Cmax of Unbound Alectinib		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)
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.	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)
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.	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)
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	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)
AUC 0-last for Unbound Alectinib		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 Measures

Outcome Measure	Measure Description	Time Frame
Cmax of Total Metabolite of Alectinib (M4)	Total M4 = unbound M4 plus M4 bound to plasma proteins	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)
Cmax of Unbound M4		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)
Cmax of Total Combined Alectinib and M4 (Alectinib + M4)	Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins	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)
Cmax of Unbound Alectinib + M4		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)
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.	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)
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.	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)
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.	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)
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.	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)
AUC 0-last of Total M4	Total M4 = unbound M4 plus M4 bound to plasma proteins	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)
AUC 0-last of Unbound M4		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)
AUC 0-last of Total Alectinib + M4	Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins	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)
AUC 0-last of Unbound Alectinib + M4		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)
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Total Alectinib	Total alectinib = unbound alectinib plus alectinib bound to plasma proteins	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)
Tmax for Total M4	Total M4 = unbound M4 plus M4 bound to plasma proteins	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)
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.	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)
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.	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)
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.	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)
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.	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)
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.	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)
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.	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)
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.	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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 4, 2015
• Primary Completion (ACTUAL): December 8, 2016
• Study Completion (ACTUAL): December 8, 2016

Study Registration Dates

• First Submitted: December 1, 2015
• First Submitted That Met QC Criteria: December 1, 2015
• First Posted (ESTIMATE): December 3, 2015

Study Record Updates

• Last Update Posted (ACTUAL): August 24, 2018
• Last Update Submitted That Met QC Criteria: November 7, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Hepatic impairment; Healthy volunteer; Alectinib
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: NP29783; 2015-002976-25 (EUDRACT_NUMBER)