Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

Hepatic Impairment Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02621047
• Other study ID #: NP29783
• Secondary ID: 2015-002976-25
• Status: Completed
• Phase: Phase 1
• Start date: December 4, 2015
• Est. completion date: December 8, 2016

Study information

• Verified date: November 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: December 8, 2016
• Est. primary completion date: December 8, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Hepatic Impairment
• Liver Diseases

Intervention

Drug:
• Alectinib
Participants will receive alectinib as per the dosage schedule mentioned in arm description.

Locations

Country	Name	City	State
Czechia	Pharmaceutical Research Associates CZ, s.r.o.	Praha 7
Slovakia	Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie	Bratislava

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Czechia,  Slovakia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)