Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib
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ClinicalTrials.gov Identifier: NCT02621047 |
Recruitment Status :
Completed
First Posted : December 3, 2015
Results First Posted : August 24, 2018
Last Update Posted : August 24, 2018
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Hepatic Impairment | Drug: Alectinib | Phase 1 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 28 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
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 |
Actual Study Start Date : | December 4, 2015 |
Actual Primary Completion Date : | December 8, 2016 |
Actual Study Completion Date : | December 8, 2016 |

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.
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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. |
- Maximum Observed Plasma Concentration (Cmax) of Total 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) ]Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
- 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 [ 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) ]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 [ 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 = 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 [ 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) ]Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
- 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) ]
- Cmax of Total Metabolite of 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) ]Total M4 = unbound M4 plus M4 bound to plasma proteins
- 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) [ 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) ]Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
- 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 [ 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) ]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 [ 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 = 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 [ 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) ]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 [ 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 = 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 [ 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) ]Total M4 = unbound M4 plus M4 bound to plasma proteins
- 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 [ 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) ]Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
- 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 [ 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) ]Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
- Tmax for Total 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) ]Total M4 = unbound M4 plus M4 bound to plasma proteins
- Apparent Terminal Half-life (t1/2) of Total 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) ]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 [ 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) ]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 [ 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) ]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 [ 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) ]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 [ 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) ]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 [ 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) ]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 [ 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) ]Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. fu = ratio of unbound alectinib to total alectinib multiplied by 100.

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Ages Eligible for Study: | 18 Years to 70 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02621047
Czechia | |
Pharmaceutical Research Associates CZ, s.r.o. | |
Praha 7, Czechia, 170 00 | |
Slovakia | |
Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie | |
Bratislava, Slovakia, 831 01 |
Study Director: | Clinical Trials | Hoffmann-La Roche |
Responsible Party: | Hoffmann-La Roche |
ClinicalTrials.gov Identifier: | NCT02621047 |
Other Study ID Numbers: |
NP29783 2015-002976-25 ( EudraCT Number ) |
First Posted: | December 3, 2015 Key Record Dates |
Results First Posted: | August 24, 2018 |
Last Update Posted: | August 24, 2018 |
Last Verified: | November 2017 |
Healthy volunteer Alectinib Hepatic impairment |
Liver Diseases Digestive System Diseases |