Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates.
OBJECTIVE
Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration.


METHODS
Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods.


RESULTS
Peak plasma imatinib concentrations ranged from 6.4 to 9.5 microM after i.v. dosing and 0.8 to 2.8 microM after p.o. dosing. The mean +/-SD area under the plasma concentration versus time curve was 2480 +/-1340 microM.min and 1191 +/-146 microM.min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 +/-167 min after i.v. dosing and 266 +/-88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 +/-2.8 liter/kg, and the total body clearance was 12 +/-5 ml/min/kg. The mean peak CSF concentration was 0.25 +/-0.07 microM after i.v. dosing and 0.07 +/-0.04 microM after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% +/-2%.


CONCLUSIONS
There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.
Neville
Kathleen
K
Texas Children's Cancer Center, Houston, 77030, USA.
Parise
Robert A
RA
Thompson
Patrick
P
Aleksic
Alexander
A
Egorin
Merrill J
MJ
Balis
Frank M
FM
McGuffey
Leticia
L
McCully
Cynthia
C
Berg
Stacey L
SL
Blaney
Susan M
SM
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000652:urine*; D001549:Benzamides; D002851:Chromatography, High Pressure Liquid; D000068877:Imatinib Mesylate; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D010879:Piperazines / Q000097:blood* / Q000134:cerebrospinal fluid*; D011485:Protein Binding; D011743:Pyrimidines / Q000097:blood* / Q000134:cerebrospinal fluid*; D013997:Time Factors; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate