Clinical trial NCT01727128: Pharmacokinetic Study of BKM120 in Subjects With Hepatic Impairment
Official title: A Phase I, Multicenter, Open-label, Single-dose, Parallel Group Study to Assess the Pharmacokinetics of BKM120 in Subjects With Mild, Moderate and Severe Hepatic Impairmen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Impairment
Keywords: Hepatic impairment
Clinical pharmacology study
Volunteer study
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-11-15
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: To assess pharamcokinetics, safety and tolerability of a single oral dose of BKM120 in subjects with mild, moderate and severe hepatic impairment


Eligibility criteria: Inclusion Criteria:

* Subjects should be in good health (except for additional/ specific inclusion criteria related to hepatic impaired subjects) as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests of no significance at screening
* Subjects must weigh at least 45 kg to participate in this study, and must have a body mass index (BMI) from (18.5-35.0 kg/m2)
* Subjects must be able to communicate well with the investigator, to understand the requirements of the study and agree to use strict contraception for 16 weeks after the last BKM120 dose

  ---Additional inclusion criteria Group 1 - control healthy subjects
* Subjects should be matched to the hepatic impaired subjects of group 2 in gender, age (± 10 years), weight (± 20%), and BMI (±5%)

  ---Additional inclusion criteria Group 2 - hepatic impaired subjects
* Subjects with physical signs consistent with stable hepatic impairment
* Child-Pugh Clinical Assessment Score consistent with degree of hepatic impairment (mild , moderate or severe)
* Subjects must be free of significant medical disorders unrelated to the subject's hepatic disorder as judged by the investigator.
* Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
* Platelet count ≥ 50 x 109 /L
* serum creatinine ≤ 1.5 x ULN

Exclusion Criteria:

* Significant illness, including infections, or hospitalization within the 2 weeks prior to dosing, except for the hepatic impaired subjects who due to their liver disease may be affected by significant medical problems which require frequent hospitalizations. Invasive systemic fungal infections need to be fully resolved prior to study entry
* Use of tobacco products within 2 weeks prior to dosing or during the study.
* Consumption of alcohol within 2 days prior to dosing or during the study
* Subjects with known ongoing alcohol and or/drug abuse within 1 month prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and/or at baseline
* Subjects not willing to avoid certain study prohibited food, drink, over the counter medicines and supplements
* Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study.
* Medical history of cardiac disease and/or clinically significant ECG abnormalities.
* History of clinically significant hematologic, renal, endocrinologic, pulmonary cardiovascular, hepatic, or allergic disease medically documented
* Medical history of relevant psychiatric disorders
* Subjects with Diabetes Mellitus or subjects with glucose levels out of normal range as judge by the investigator
* History of immunodeficiency diseases, including Human Immunodeficiency Virus (HIV), as confirmed by (HIV-1, HIV-2) test

  * Additional exclusion criteria Group 1 (matched healthy control subjects) History or presence of liver disease or liver injury as indicated by an abnormal liver function profile A positive Hepatitis C test or a positive Hepatitis B surface antigen (HBsAg)
  * Additional exclusion criteria Group 2- hepatic impaired subjects
* Subjects with clinically significant abnormal findings, not consistent with clinical disease, upon physical examination, ECG or laboratory evaluation
* Any evidence of progressive liver disease (within the last 4 weeks prior to the screening visit) as indicated by liver transaminases, alkaline phosphatase and GGT or a ≥ 50% worsening of serum bilirubin or prothrombin time
* Total bilirubin \> 6mg/dl
* Subject has ascites requiring intervention

Primary outcomes:
measure: Plasma concentration of pharmacokinctis (PK) parameter Tmax
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
measure: Plasma concentration of PK parameter Cmax
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
measure: Plasma concentration of PK parameter AUC-t
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
measure: Plasma concentration of PK parameter AUC-last
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
measure: Plasma concentration of PK parameter AUC-inf
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
measure: Plasma concentration of PK parameter CL/F
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
measure: Plasma concentration of PK parameter Vz/F
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
measure: Plasma concentration of PK parameter terminal T 1/2
timeFrame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Secondary outcomes:
measure: Adverse events severity
timeFrame: From baseline day-1 to 30 days post dose
measure: Change from baseline in laboratory parameters
timeFrame: From baseline day-1 to 30 days post dose
measure: Change from baseline in ECG parameters
timeFrame: From baseline day-1 to 30 days post dose
measure: Change from baseline between PK parameters and total bilirubin, prothrombin time or INR and serum albumin
timeFrame: From baseline day-1 to 15 days post dose
measure: measurement of plasma binding
timeFrame: From baseline day-1 to 15 days post dose
measure: Adverse events frequency
timeFrame: From baseline day-1 to 30 days post dose
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: