Pharmacokinetic Study of Buparlisib in Subjects With Renal Impairment.

Phase 1

Completed

• Conditions: Renal Impairment
• Interventions: Drug: Buparlisib

• Registration Number: NCT02048787
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

To characterize the pharmacokinetics and safety of buparlisib following a single 50 mg oral dose in subjects with moderate and severe renal impairment.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-01-20
• Study First Submitted QC: 2014-01-28
• Study First Posted: 2014-01-29
• Study Start: 2014-03
• Primary Completion: 2015-03
• Study Completion: 2015-03
• Status Verified: 2015-12
• Last Update Submitted: 2020-12-06
• Last Update Posted: 2020-12-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

• Other than renal impairment, subjects should be in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, (except for additional inclusion criteria for renal impaired patients).

• Subjects must have a BMI between 18 kg/m2 and 34 kg/m2 and weight at least 50 kg and no more than 120 kg.

  • Additional criteria for renal impaired subjects: - Subjects must have stable renal disease without evidence of renal progressive disease defined as moderate renal impairment (eGFR 30-59 mL/min/1.73m2) or severe renal impairment (eGFR 15-29 mL/min/1.73m2).
  • Additional criteria for matched healthy control subjects: - Matched to at least one renal impaired subject by gender, race, age (± 10 years), and weight (± 20%).

• An estimated GFR as determined by MDRD equation within normal range as determined by eGFR ≥ 90 mL/min/1.73m2

Exclusion Criteria

• Significant illness, including infections, or hospitalization within the 2 weeks prior to dosing, except for the renal impaired subjects who due to their renal disease may be affected by significant medical problems which require frequent hospitalizations.
• Any surgical or medical condition that may significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study
• Subject has a medical history of cardiac disease and/or clinically significant ECG abnormalities within 6 months prior to screening.
• Subject has an active or a history within 6 months prior to screening of clinically significant hematologic, endocrinologic, pulmonary, cardiovascular, hepatic, or allergic disease, medically documented (other than clinical conditions associated with renal impairment for the renal impaired subjects only).
• • Additional exclusion criteria for renal impaired subjects: - Severe albuminuria > 300 mg/day.
• Subjects undergoing any method of dialysis.
• Subjects with renal impairment due to hepatic disease (hepatorenal syndrome).
• Subjects with clinically significant abnormal findings, not consistent with clinical disease, upon physical examination, ECG or laboratory evaluation.
• Use of any prescription or non-prescription medication that has the potential to interact with buparlisib within two weeks prior to dosing or during the study.
• • Additional criteria for matched healthy control subjects: - Use of any prescription or non-prescription medication or vitamins during 14 days prior to dosing.

Other protocol-defined inclusion/exclusion criteria may apply.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Matching healthy control group	Buparlisib	Subjects with normal renal function defined as eGFR ≥ 90 mL/min/1.73m2 at screening and matching to the renal impaired subject based on gender, race, age, and weight can be enrolled in this group.
Moderate renal impairment group	Buparlisib	Subjects with moderate renal impairment defined as eGFR of 30-59 mL/min/1.73m2 at screening can be enrolled in this group
Severe renal impairment group	Buparlisib	Subjects with severe renal impairment defined as eGFR of 15-29 mL/min/1.73m2 at screening can be enrolled in this group

Primary Outcome Measures

Name	Time	Method
Plasma pharmacokinetic (PK) parameter Cmax	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the maximum plasma concentration (PK parameter Cmax). Cmax directly determined from the plasma concentration-time profiles.
Plasma PK parameter AUC0-t	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter AU0-t (area under the plasma-concentration time curve from timepoint 0 to time t). AUC determined from the plasma concentration-time profile using non-compartmental analysis.
Plasma PK parameter CL/F	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter CL/F (clearance).
Plasma PK parameter AUCinf	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter AUCinf (area under the plasma concentration-time curve from time 0 to infinity). AUC determined from the plasma concentration-time profile using non-compartmental analysis.
Urine PK parameter CLR	predose, 0-4 h, 4-8 h, 8-12 h, 12-24 h, 24-48 h, 48-72 h, 72-96 h, 96-120 h, 120-144 h	Measurement of effect of renal impairment on PK of buparlisib by assessment of the urine clearance CLR.

Secondary Outcome Measures

Name	Time	Method
Change from baseline in laboratory parameters	From baseline Day 1 to 30 days post-dose	Assessment of safety and tolerability of a single dose buparlisib in renal impaired subjects compared with healthy control subjects by assessing the change from baseline in hematological and biochemical laboratory parameters.
Plasma PK parameter T1/2	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter T1/2 (terminal half-life).
Adverse Events severity and frequency	Baseline Day 1 to 30 days post-dose	Assessment of safety and tolerability of a single dose buparlisib in renal impaired subjects compared with healthy control subjects by assessing the frequency and severity of Adverse Events based on the CTCAE criteria.
Unbound plasma PK parameter Vu/F	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter Vu/F (the apparent unbound drug volume of distribution following extravascular administration).
Relationship between PK parameters Cmax, AUCinf, AUC0-t, CL/F, urine CLR and renal function.	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Determination of the relationship between the primary PK parameters (Cmax, AUCinf, AUC0-t, CL/F and urine PK parameter CLR) and renal function parameters eGFR (estimated glomerular filtration rate using the equation from the Modification of Diet in Renal Disease (MDRD) study).
Plasma PK parameter Tmax	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter Tmax (time to reach maximum plasma concentration), directly determined from the plasma concentration-time profile.
Plasma PK parameter Vz/F	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter Vz/F (the apparent volume of distribution following extravascular administration).
Plasma Protein Binding	predose, 1 hour post-dose	Measurement of effect of renal impairment on plasma protein binding. Fraction of buparlisib unbound will be determined (Fu).
Unbound plasma PK parameter Cmax,u	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter Cmax,u (Cmax,u is the observed maximum unbound plasma concentration following administration).
Unbound plasma PK parameter AUCinf,u	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameters AUCinf,u (AUCinf,u is the area under the unbound plasma concentration-time curve extrapolated to infinity).
Unbound plasma PK parameter CLu/F	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameter CLu/F (the unbound systemic clearance from plasma).
Urine PK parameter Ae0-t	predose, 0-4 h, 4-8 h, 8-12 h, 12-24 h, 24-48 h, 48-72 h, 72-96 h, 96-120 h, 120-144 h	Measurement of effect of renal impairment on PK of buparlisib by assessment of the urine PK parameter Ae0-t (the amount of unchanged buparlisib excreted into the urine from time 0 to a defined point in time).
Change from baseline in ECG parameters	From baseline Day 1 to 30 days post-dose	Assessment of safety and tolerability of a single dose buparlisib in renal impaired subjects compared with healthy control subjects by assessing the change from baseline in ECG parameters.
Unbound plasma PK parameter AUC0-t,u	predose, 10, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240 hours post-dose	Measurement of effect of renal impairment on PK of buparlisib by assessment of the PK parameters AUC0-t,u (AUC0-t,u is the area under the unbound plasma concentration-time curve from time zero to time t).

Trial Locations

Locations (1)

Novartis Investigative Site; 🇷🇴 Bucuresti, Romania