DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

18
16
14
<2%
2–10%
>10%
1733
% of patients
12
10
8
6
4
2
0
M237
M244
L248
G250
Q252
Y253
E255
D276
V289
V304
F311
F311
T315
F317
G321
M343
M351
E352
Y353
E355
F539
V371
E373
V379
F382
L387
T389
H396
S417
E459
F486
I V V A R F V G I G I L N L E T T G H D A A G I L M A
E E H K
I
G C
H
V
This finding may explain the clinical response of some resistant
patients to dose escalation of imatinib.
Molecular studies of circulating tumor cells have detected
resistance-mediating kinase mutations prior to initiation of therapy,
particularly in patients with Ph + acute lymphoblastic leukemia
(ALL) (Roche-Lestienne et al., 2003) or CML in blastic crisis. This
finding strongly supports the hypothesis that drug-resistant cells arise
through spontaneous mutation and expand under the selective pressure
of drug exposure. Mutations may become detectable in the
peripheral blood of patients receiving imatinib in the accelerated
phase and in the late (>4 years from diagnosis) chronic phase of
CML (Branford et al., 2003), heralding the onset of drug resistance.
Mechanisms other than BCR-ABL kinase mutation play a
minor role in resistance to imatinib. Amplification of the wild-type
kinase gene, leading to overexpression of the enzyme, has been identified
in tumor samples from patients resistant to treatment (Morel
et al., 2003). The multidrug resistant (MDR) gene, which codes for
a drug efflux protein, confers resistance experimentally but has not
been implicated in clinical resistance.
Finally, Philadelphia chromosome-negative clones lacking
the BCR-ABL translocation and displaying the karyotype of
myelodysplastic cells may emerge in patients receiving imatinib for
CML and may progress to myelodysplasia (MDS) and to acute myelocytic
leukemia (AML). Their origin is unclear.
Amino acid (ABL-B)
P Y K S
R
Figure 62–1. The relative frequency of BCR-ABL kinase domain mutations detected at 31 different positions in clinical specimens from
245 patients in whom mutations were detected (219 with chronic myelocytic leukemia and 26 with Ph + acute lymphoblastic leukemia).
(Reproduced with permission from Hughes et al., 2006. Copyright © 2006 American Society of Hematology. Copyright restrictions
may apply.)
Pharmacokinetics
Imatinib. Imatinib is well absorbed after oral administration and
reaches maximal plasma concentrations within 2-4 hours. The elimination
t 1/2
of imatinib and its major active metabolite, the N-desmethyl
derivative, are ~18 and 40 hours, respectively. Mean imatinib area under
the curve (AUC) increases proportionally with increasing dose in the
range 25-1000 mg (Peng et al., 2004). Food does not change the pharmacokinetic
profile of imatinib. Doses >300 mg/day achieve trough
levels of 1 μM, which correspond to in vitro levels required to kill BCR-
ABL–expressing cells. Inhibition of the BCR-ABL tyrosine kinase in
white blood cells from patients with CML reaches a maximum in the
dose range of 250-750 mg/day. Nonrandomized studies suggest that
response may be restored in a minority of resistant patients with doses
of 600 or 800 mg/day, as opposed to the standard 400 mg/day
(Kantarjian et al., 2004). In the treatment of GI stromal cell tumors
(GIST), higher doses (600 mg/day) may improve response rates.
CYP3A4 is the major enzyme responsible for metabolism of
imatinib. CYPs 1A2, 2D6, 2C9, and 2C19 play minor roles in its
metabolism. Clinicians must be cautious in introducing drugs that
might interact with imatinib and CYP3A4. A single dose of ketoconazole,
an inhibitor of CYP3A4, increases the maximal imatinib
concentration in plasma and its plasma AUC by 26% and 40%,
respectively. Co-administration of imatinib and rifampin, an inducer
of CYP3A4, lowers the plasma imatinib AUC by 70%. Likewise,
CHAPTER 62
TARGETED THERAPIES: TYROSINE KINASE INHIBITORS, MONOCLONAL ANTIBODIES, AND CYTOKINES