NCT02621047 - Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib | Crick | Crick

Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

Phase 1CompletedNCT02621047

Hoffmann-La Roche28 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

28

Conditions

Hepatic Impairment

Interventions

Participants will receive alectinib as per the dosage schedule mentioned in arm description.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (2)

Pharmaceutical Research Associates CZ, s.r.o.

Prague, Czechia

Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie

Bratislava, Slovakia

Outcomes

Primary Outcomes

Maximum Observed Plasma Concentration (Cmax) of Total Alectinib

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)

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)

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.

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)

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.

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)

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

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)

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)

Data from ClinicalTrials.gov

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Secondary Outcomes

Cmax of Total Metabolite of Alectinib (M4)

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)

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)

Cmax of Total Combined Alectinib and M4 (Alectinib + M4)

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)

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)

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.

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)

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.

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)

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.

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)

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.

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)

AUC 0-last of Total M4

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)

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)

AUC 0-last of Total Alectinib + M4

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)

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)

Time to Reach Maximum Observed Plasma Concentration (Tmax) for Total Alectinib

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)

Tmax for Total M4

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)

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.

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)

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.

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)

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.

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)

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.

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)

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.

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)

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.

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)

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.

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)