Imatinib dosing

An increase in imatinib dose may be required if patients have no hematologic response at 3 months or no complete cytogenetic response at 9 to 12 months. 

Faber E et al (2010) Imatinib dose escalation in two patients with chronic myeloid leukemia, with low trough imatinib plasma levels measured at various intervals from the beginning of therapy and with suboptimal treatment response, leads to the achievement of higher plasma levels and major molecular response. Int J Hematol 91 897-902... 

RIFAMPICIN IMATINIB 1 imatinib levels Due to induction of CYP3A4-mediated metabolism of imatinib Dose adjustments are necessaiy if concomitant administration is considered absolutely necessary best, however, to avoid concomitant use... 

No specific studies have been carried out with imatinib and other CYP3A4-inducing drugs, but the manufacturers suggest that carbamazepine, dexamethasone, phenobarbital, and phenytoin, may also reduce imatinib serum levels, and they have a possible case on file with phenytoin. The manufacturers therefore reasonably recommend caution, and suggest that concurrent use with these drugs should be avoided. However, if this is not possible it would be prudent to monitor the outcome of concurrent use, and increase the imatinib dose as necessary. 

Prior to the introduction of imatinib, the combination of interferon-alfa and low dose cytarabine was the nontransplant treatment of choice for patients in chronic phase CML. The precise mechanism of action of interferon-alfa remains unknown. The addition of cytarabine to interferon-alfa improves the response compared with interferon alone. This combination produces cytogenetic response rates of 30%, much lower than imatinib.13 One of the major drawbacks, in addition to the low response rates, is interferon s toxicity,... 

Patients are placed on imatinib at the time of diagnosis. Patients should be monitored for a dose-dependent myelo-suppression, Cl intolerance, edema, and rash. Drug interactions with CYP450 3A4 inducers are clinically important and should be monitored. 

ONO 12380 was tested in an in vivo model where nude mice were injected iv with the 32Dcl3 cells containing the T3151 Abl mutation. After one day, the animals were dosed with both ON012380 and imatinib at 100 mg/kg ip in a saline vehicle for 14 days. Blood samples were examined on days 7 and 14. The blood of the ON012380 treated animals had a reduced number of T315I cells compared to the blood of both the control and the imatinib treated animals. No toxicity was observed in the animals treated with ONO 12380. ONO 12380 is being further evaluated for use in CML by Onconova Therapeutics [62]. 

The effect of BMS-354825 on cells from patients resistant to imatinib by mechanisms other than the presence of point mutations was also examined [150]. Treatment of these cells with concentrations of 1 xM imatinib had no effect on the regulation of SFK activity, while a 0.5 xM dose of BMS-354825 completely inhibited activation of two SFKs, namely Hck and Lyn, as measured by autophosphorylation. Both imatinib and BMS-354825 inhibited Bcr-Abl activity in these cells, as measured by the inhibition of CrkL phosphorylation. Therefore since BMS-354285 inhibits SFKs in addition to Abl, it may overcome clinical resistance to imatinib in those cases where resistance is due to the loss of Bcr-Abl mediated regulation of SFKs. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Sunitinib (Sutent) [Kinase Inhibitor] Uses Advanced GI stromal tumor refractory/intolerant of imatinib advanced RCC Action Kinase inhibitor Dose Adults, 50 mg PO daily x 4 wk, followed by 2 wk holiday = 1 cycle X to... 

Reed SD, Anstrom KJ, Ludmer JA, Glendeiming GA, Schulman KA. Cost-effectiveness of imatinib versus interferon-alpha plus low-dose cytarabine for patients with newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2004 101 2574-83. 

The CCR was 35% with dasatinib and 16% with IM suggesting that dasatinib may be more effective in achieving MCR than high-dose imatinib (97). Dasatinib is also active in patients who have failed both IM and nilotinib where in a small trial of 23 patients who were mostly in accelerated or blastic phase achieved a CHR in 43% with some form of cytogenetic response in 32% (98). 

O Brien SG, Guilhot F, Larson RA et al. Imatinib eompared with interferon and low-dose cytarabine for newly diagnosed ehronie-phase ehronie myeloid leukemia. ABrag/JMed2003 348 994-1004. 

Kantarjian HM, Talpaz M, O Brien S et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003 101 473 75. 

Shah N, Pasquini R, Rousselot P et al. Dasatinib (SPRYCEL) vs. escalated dose of imatinib (IM) in patients (pts) with ehronie phase chronic myeloid leukemia (CP-CML) resistant to imatinib results of the CA180-017 START-R randomized study (Abstract 167). B/ooii2006 108 53a. 

Sunirinib (Sutent) [Kinase Inhibitor] Uses Advanced GI stromal tumor refractory/intolerant of imatinib advanced RCC Action Kinase inhibitor Dose Adults. 50 mg PO daily x 4 wk, followed by 2 wk holiday = 1 cycle 4- to 37.5 mg w/ CYP3A4 inhibitors (Table VI-8), to T 87.5 mg w/ CYP3A4 inducers Contra w/ atazanavir Caution [D, -] Multiple interactions require dose modification (eg, St. John s wort) Disp Caps SE -l WBC pit, bleeding, T BP, -l ejection fraction, T QT interval, pancreatitis, DVT, Sz, adrenal insuff, N/V/D, skin discoloration, oral ulcers, taste perversion, hypothyroidism Interactions Multiple interactions require dose modification (eg, St. John s wort) EMS Monitor ECG for T QT interval grapefruit juice may T adverse effects may affect potassium level (hypo-/hyperkalemia) monitor for S/Sxs of heart failure drug can 4- ejection fraction OD May cause abd pain, muscle weakness, and chills symptomatic and supportive... 

---