A Study of The Effect of Hepatic Impairment on The Pharmacokinetics of Aleglitazar

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01197911
First received: September 8, 2010
Last updated: November 20, 2015
Last verified: November 2015
  Purpose
This open-label study will assess the effects of hepatic impairment on the pharmacokinetics of a single oral dose of aleglitazar in subjects with mild or moderate hepatic impairment (Child-Pugh class A or B) and in matched control subjects with normal hepatic function. Subjects will receive a single oral dose of aleglitazar, with assessment of the pharmacokinetics of aleglitazar on Days 1-5. Anticipated duration of study for each enrolled subject is approximately 6 weeks.

Condition Intervention Phase
Healthy Volunteer
Drug: aleglitazar
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: The Effect of Hepatic Impairment on the Pharmacokinetics of Aleglitazar: A Multiple-centre, Open-label Study Following a Single Oral Dose of Aleglitazar to Subjects With Mild or Moderate Hepatic Impairment and Healthy Subjects With Normal Hepatic Function.

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    AUCinf was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values.

  • Maximum Plasma Concentration (Cmax) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    Cmax was obtained directly from the concentration-time data.


Secondary Outcome Measures:
  • AUCinf of M1 (RO4408754) and M6 (RO4583746) [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    M1 and M6 are pharmacologically inactive metabolites of aleglitazar. AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. AUCinf was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values.

  • Cmax of M1 and M6 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    M1 and M6 are pharmacologically inactive metabolites of aleglitazar. Cmax was obtained directly from the concentration-time data.

  • Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Post-dose (AUC0-48) of Aleglitazar, M1, and M6 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    M1 and M6 are pharmacologically inactive metabolites of aleglitazar. AUC0-48 was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values.

  • Area Under the Plasma Concentration-time Curve From 0 to the Last Quantifiable Time-point Post-dose (AUClast) of Aleglitazar, M1, and M6 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    AUClast was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values.

  • Apparent Total Body Clearance (CL/F) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity.

  • Renal Clearance (CLR) of Aleglitazar, M1, and M6 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72, and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine ] [ Designated as safety issue: No ]
    CLR was calculated as Ae0-48/AUC0-48, where Ae0-48 as amount excreted in urine from time 0 to 48 hours post-dose and AUC0-48 represents area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose.

  • Apparent Non-renal Clearance (CLNR/F) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine ] [ Designated as safety issue: No ]
    Plasma and urine samples were collected for this PK parameter. CLNR/F was estimated as CL/F, based on the approximated formula of CLNR/F = (CL-CLR)/F with CLR of aleglitazar being equal to zero. CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. CLR was calculated as Ae0-48/AUC0-48, where Ae0-48 as amount excreted in urine from time zero to 48 hours post-dose and AUC0-48 represents area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose.

  • Time of Maximum Plasma Concentration (Tmax) of Aleglitazar, M1, and M6 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    M1 and M6 are pharmacologically inactive metabolites of aleglitazar. Tmax was measured as time to reach the maximum concentration in the plasma after post-dose.

  • Apparent Terminal Half-life (t½) of Aleglitazar, M1, and M6 [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    M1 and M6 are pharmacologically inactive metabolites of aleglitazar. T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%.

  • Elimination Rate Constant (Kel) of Aleglitazar [ Time Frame: 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose ] [ Designated as safety issue: No ]
    The kel is fraction of a substance that is removed per unit time measured at any particular instant. It was calculated using at least 3 concentration-time points and ideally covered more than 2 half-lives.

  • Apparent Volume of Distribution (Vz/F) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine ] [ Designated as safety issue: No ]
    Vz/F is the apparent volume of distribution during terminal phase after non-intravenous administration. It was calculated as CL/F/kel, where CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity and kel as constant elimination rate of aleglitazar.

  • Amount Excreted in Urine From Time 0 to 48 Hours Post-dose (Ae0-48) of Aleglitazar, M1, and M6 [ Time Frame: 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose ] [ Designated as safety issue: No ]
    The cumulative amount excreted in urine Ae0-48 over the entire collection interval of 48 hours was calculated by adding the Ae of the intervals 0-4, 4-8, 8-12, 12-24, and 24-48 hours, where Ae was calculated by multiplying the urine volume within the collection interval by the associated drug concentration.

  • Fraction of Drug Excreted in Urine From Time 0 to 48 Hours Post-dose (fe0-48) of Aleglitazar [ Time Frame: 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose ] [ Designated as safety issue: No ]
    fe0-48 was calculated as Ae0-48/dose. The cumulative amount excreted in urine Ae0-48 over the entire collection interval of 48 hours was calculated by adding the Ae of the intervals 0-4, 4-8, 8-12, 12-24, and 24-48 hours. Ae was calculated by multiplying the urine volume within the collection interval by the associated drug concentration.

  • Mean of Fraction of Unbound Aleglitazar (fu) [ Time Frame: 2 and 24 hours post-dose ] [ Designated as safety issue: No ]
    fu was calculated using the mean of the 2-hour (reflecting Cmax) and 24-hour (reflecting Ctrough) values for each participant or, if the result of only one time-point was available, fu was the result of the available time-point. Ctrough) is a measured concentration at the end of a dosing interval at steady state.

  • Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From Time 0 to Infinity (AUCu,Inf) [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. It was assessed using an analysis of variance model on the log-transformed values of AUCinf of aleglitazar with hepatic impairment group as factor.

  • Maximum Unbound Plasma Concentration (Cmax,u) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    Cmax was obtained directly from the concentration-time data.

  • Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From 0 to the Last Quantifiable Time-point Post-dose (AUCu,Last) [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    Plasma samples were collected for this PK parameter. AUClast represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero 0 to the last quantifiable time-point post-dose. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. AUClast was extrapolated to AUCinf by adding the ratio of Clast/kel to the AUClast, where Clast was the last observed concentration and kel was elimination rate constant.

  • Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From Time 0 to 48 Hours Post-dose (AUCu,0-48) [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose ] [ Designated as safety issue: No ]
    AUClast represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values.

  • Apparent Unbound Volume of Distribution (Vz/Fu) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine ] [ Designated as safety issue: No ]
    VzF/u is an apparent volume of Unbound distribution during terminal phase after non-intravenous administration. It was calculated as CL/F/kel, where CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity and kel as constant elimination rate of aleglitazar.

  • Apparent Unbound Total Body Clearance (CL/Fu) of Aleglitazar [ Time Frame: Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine ] [ Designated as safety issue: No ]
    CL/F is an apparent total clearance of the drug from plasma after oral administration. It was calculated as dose/AUCinf. AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity.

  • Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), Death, and Study Discontinuation [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect.

  • Number of Participants With Low and High Electrocardiograms (ECGs) Parameter Values [ Time Frame: Screening (Days -28 to -2), baseline (Day -1), Days 1 to 5, and follow-up visit (Day 10) ] [ Designated as safety issue: No ]
    The ECG evaluations were performed after participants were at rest and in supine position for at least 5 minutes before recording and remain resting and supine during the recordings. ECGs parameters included heart rate (HR), RR interval, PR interval, QRS duration, QT interval, QTcB, and QTcF intervals. The normal ranges of ECG parameter values were: HR as 40-100 beats per minute, RR as 600-1500 milliseconds (msec), PR as 120-200 msec, QRS as 80-120 msec, QT as 200-500 msec, QTcB as 350-450 msec, and QTcF as 350-450 msec. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range).

  • Number of Participants With Low and High Vital Signs Values [ Time Frame: Days -28 to -2, Day -1, Days 1 to 5, and Day 10 for blood pressure and pulse rate; and Days -28 to -2, Day -1, and Day 10 for oral body temperature ] [ Designated as safety issue: No ]
    Vital signs were assessed after participants had rested in a supine position for no less than 5 minutes. Vital signs included systolic blood pressure, diastolic blood pressure, pulse rate, and oral body temperature. The normal ranges of vital signs were: systolic blood pressure as 90-140 millimeter of Hg (mm Hg), diastolic blood pressure as 50-90 mm Hg, pulse rate as 45-100 beats per minute, and oral body temperature as 36.3-37.5 degree Celsius. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range).

  • Number of Participants With Marked Abnormalities in Clinical Laboratory Parameters [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    Laboratory parameters included hematology, coagulation, biochemistry, and urinalysis. A marked abnormality was defined as a test result which was outside of the marked abnormality range. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range).


Enrollment: 38
Study Start Date: September 2010
Study Completion Date: August 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Mild impairment Drug: aleglitazar
single oral dose
Experimental: Moderate impairment Drug: aleglitazar
single oral dose
Experimental: Normal HF Drug: aleglitazar
single oral dose

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male and female adults, 18-70 years of age inclusive
  • Normal hepatic function or mild to moderate impaired liver function (Child-Pugh class A or B)
  • Body mass index (BMI) 18 to 40 kg/m2 inclusive
  • Females must be either surgically sterile, postmenopausal, or willing to use two reliable methods of contraception for the duration of the study and started 3 months before study start

Exclusion Criteria:

  • For subjects with hepatic impairment: evidence of progressive liver disease within the last 4 weeks, or biliary liver cirrhosis or other causes of hepatic impairment not related to parenchymal disorder and/or disease
  • For healthy volunteers: positive test for hepatitis B or C, alcohol intake of more than 14 units per week, or history of clinically significant alcohol or drug abuse
  • Acute infection or current malignancy requiring treatment
  • History of clinically significant allergic disease or drug hypersensitivity
  • Positive test for HIV-1 or HIV-2 at screening
  • Participation in a clinical study with an investigational drug or new chemical entity within 2 months prior to screening
  • Females who are pregnant or lactating
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01197911

Locations
United States, Florida
Orlando, Florida, United States, 32809
United States, Tennessee
Knoxville, Tennessee, United States, 37920
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01197911     History of Changes
Other Study ID Numbers: BP25240 
Study First Received: September 8, 2010
Results First Received: November 20, 2015
Last Updated: November 20, 2015
Health Authority: United States: Food and Drug Administration

ClinicalTrials.gov processed this record on July 28, 2016