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Completed

NCT Number: NCT02621047

Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

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.

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Key information

Conditions

Hepatic Impairment

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Pharmaceutical Research Associates CZ, s.r.o., Prague, Czechia

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Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Alectinib

Drug

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

Primary outcomes

  1. 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

  2. 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)

  3. 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.

  4. 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.

  5. 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

  6. 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 outcomes

  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

  2. 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)

  3. 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

  4. 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)

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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)

  11. 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

  12. 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)

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

Sponsors and collaborators

Lead sponsor

Hoffmann-La Roche

Industry

Registry information

Official study 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

Important dates

Study start
2015
Primary completion
2016
Study completion
2016
First posted
Dec 3, 2015
Registry last updated
Aug 24, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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