Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies.
OBJECTIVE
Ibrutinib is an oral Bruton's tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients.


METHODS
Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25-12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling.


RESULTS
A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively.


CONCLUSIONS
The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent.
Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
Eleonora
E
Marostica
Juthamas
J
Sukbuntherng
David
D
Loury
Jan
J
de Jong
Xavier Woot
XW
de Trixhe
An
A
Vermeulen
Giuseppe
G
De Nicolao
Susan
S
O'Brien
John C
JC
Byrd
Ranjana
R
Advani
Jesse
J
McGreivy
Italo
I
Poggesi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D015331:Cohort Studies; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D018565:Food-Drug Interactions; D006207:Half-Life; D007408:Intestinal Absorption; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D008954:Models, Biological; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents; C551803:ibrutinib; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011743:Pyrimidines