Pharmacokinetic Study of BKM120 in Subjects With Hepatic Impairment
Study Details
Study Description
Brief Summary
To assess pharamcokinetics, safety and tolerability of a single oral dose of BKM120 in subjects with mild, moderate and severe hepatic impairment
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Mild Hepatic Impaired Group Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - mildly hepatically impaired |
Drug: BKM120
|
| Experimental: Moderate Hepatic Impaired group Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - moderately hepatically impaired |
Drug: BKM120
|
| Experimental: Severe Hepatic Impaired Group Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - Severely hepatically impaired |
Drug: BKM120
|
| Experimental: Control Group Matching healthy control subjects who do not have hepatic impairment and are matched to the hepatic impaired subjects by sex, age, gender and BMI |
Drug: BKM120
|
Outcome Measures
Primary Outcome Measures
- Plasma concentration of pharmacokinctis (PK) parameter Tmax [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter TMax (time to maximum concentration)
- Plasma concentration of PK parameter Cmax [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CMax (maximum concentration)
- Plasma concentration of PK parameter AUC-t [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-t (Area under the curve at specified timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response
- Plasma concentration of PK parameter AUC-last [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-last (Area under the curve at last timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response
- Plasma concentration of PK parameter AUC-inf [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-inf (Area under the curve to time infinity)
- Plasma concentration of PK parameter CL/F [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
infMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CL/F (clearance)
- Plasma concentration of PK parameter Vz/F [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
FMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter Vz/F (Volume distribution)
- Plasma concentration of PK parameter terminal T 1/2 [predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose]
Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter terminal T 1/2 (terminal half-life)
Secondary Outcome Measures
- Adverse events severity [From baseline day-1 to 30 days post dose]
Severtiy of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120
- Change from baseline in laboratory parameters [From baseline day-1 to 30 days post dose]
Change from baseline in hematological and biochemical laboratory parameters
- Change from baseline in ECG parameters [From baseline day-1 to 30 days post dose]
Change from baseline in ECG parameters
- Change from baseline between PK parameters and total bilirubin, prothrombin time or INR and serum albumin [From baseline day-1 to 15 days post dose]
Relationship between PK parameters and baseline hepatic function parameters
- measurement of plasma binding [From baseline day-1 to 15 days post dose]
Determination of the free fraction of BKM120 in plasmaexpressed weher relevant in terms of unbound drug concentration
- Adverse events frequency [From baseline day-1 to 30 days post dose]
Frequency of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Sofia | Bulgaria | 1618 | |
| 2 | Novartis Investigative Site | Berlin | Germany | 14050 | |
| 3 | Novartis Investigative Site | Moscow | Russian Federation | 117198 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- CBKM120C2104
- 2011-002311-28