Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase.
OBJECTIVE
We investigated the population pharmacokinetics and exposure-response relationship of nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase.


METHODS
Nilotinib was given at 300 mg or 400 mg twice daily. Serum concentration data (sparse and full pharmacokinetic profiles) were obtained from 542 patients over 12 months. A population pharmacokinetic analysis was performed using nonlinear mixed-effect modeling. Exposure-response relationships were explored graphically or using logistic regression models.


RESULTS
Nilotinib concentrations were stable over 12 months. Patients in the 400 mg twice-daily arm had an 11.5% higher exposure than did those in the 300 mg twice-daily arm, and the relative bioavailability of nilotinib 400 mg twice daily was 0.84 times that of 300 mg twice daily. Patient demographics did not significantly affect nilotinib pharmacokinetics. The occurrence of all-grade total bilirubin elevation was significantly higher in patients with higher nilotinib exposure, and a positive correlation was also observed between nilotinib exposure and QTcF change on electrocardiograms from baseline. There was no significant relationship between nilotinib exposure and major molecular response at 12 months.


CONCLUSIONS
There is a less than proportional dose-exposure relationship between nilotinib 300 mg and 400 mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib.
University of Chicago, Chicago, IL, USA.
Richard A
RA
Larson
Ophelia Q P
OQ
Yin
Andreas
A
Hochhaus
Giuseppe
G
Saglio
Richard E
RE
Clark
Hirohisa
H
Nakamae
Neil J
NJ
Gallagher
Eren
E
Demirhan
Timothy P
TP
Hughes
Hagop M
HM
Kantarjian
Philipp D
PD
le Coutre
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D015466:Leukemia, Myeloid, Chronic-Phase / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib