Imatinib toxicity

Drug-drug interactions Imatinib Peripheral neuropathy is uncommon in imatinib-treated patients and has previously been reported only during combination therapy with cytotoxic agents that affect microtubule function, such as vinca alkaloids and taxanes. A suspected adverse interaction with amlodipine has been reported, with a temporal association between amlodipine and symptoms of imatinib toxicity [21 ]. 

A 74-year-old man with chronic myeloid leukemia took imatinib mesylate 400 mg bd. His other medications were perindopril and ator-vastatin. After 2 months he developed angio-edema, probably related to perindopril, which was withdrawn and replaced by amlodipine 10 mg/day. After 2 weeks he developed typical symptoms of imatinib toxicity nausea, marked periorbital, and ankle edema. Diuretics improved the edema, but after 10 days he complained of numbness of the chin and bilateral pain and numbness in the soles of the feet. Light touch and vibration sense were reduced, but power and reflexes were intact. Imatinib was reduced to 400 mg/day and amlodipine was withdrawn. The edema, numbness and neuropathic pain resolved. Despite residual plantar numbness he was able to increase the dose of imatinib to 600 mg/day without worsening symptoms. About 1 month later he took two doses of amlodipine in error and developed nausea and palpitation, which resolved when the amlodipine was withdrawn. Nerve conduction testing 1 month later showed a mild sensorimotor axonal neuropathy. After 9 months the neuropathy had resolved despite continuing imatinib therapy. 

The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxic-ities in older patients. The adverse prognostic factor, the Philadelphia chromosome, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.17 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR-ABL tyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone,... 

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,... 

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]. 

Imatinib is administered orally and is well absorbed it is highly protein-bound in plasma. The drug is metabolized in the liver, and elimination of metabolites occurs mainly in feces via biliary excretion. This agent is approved for use as first-line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior interferon- therapy. Imatinib is effective also for treatment of gastrointestinal stromal tumors expressing the c-kit tyrosine kinase. Dosage and toxicities are listed in Table 55-6. 

The relationships between nilotinib plasma concentration and clinical efficacy (or toxicity) have not been studied yet. Irrespective of nilotinib PK-PD per se, Saglio et al. [72] showed that nilotinib at a dose of either 300 or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML. At 12 months, the rates of major molecular response for nilotinib were nearly twice that observed for imatinib. The rates of complete cytogenetic response by 12 months were also significantly higher for nilotinib than for imatinib [72], No data have been published for nilotinib concentration-toxicity relationships nor plasma target values to be achieved for optimal clinical response. 

In conclusion, most recent TKIs share with imatinib the same large interindividual pharmacokinetic variability with, at least for a few of them, some reports of concentration-efficacy and concentration-toxicity relationships, calling for further extensive evaluation of the TDM approach. The development of analytical methods allowing to confidently quantifying TKIs in biological fluids is a prerequisite prior to the implementation of any clinically useful TDM Service. 

FLECAINIDE ANTICANCER AND IMMUNOMODULATING DRUGS - IMATINIB Imatinib may cause an t in plasma concentrations of flecainide with a risk of toxic effects, e.g. visual disturbances, dyspnoea, liver dysfunction Imatinib is a potent inhibitor of CYP2D6 isoenzymes, which metabolize flecainide Monitor for clinical efficacy and toxicity of flecainide. Monitor liver function and BP, and do FBCs if toxicity is suspected... 

ANGIOTENSIN II RECEPTOR ANTAGONISTS IMATINIB t plasma concentrations of losartan, irbesartan and valsartan Imatinib is a potent inhibitor of CYP2C9 isoenzymes, which metabolize these angiotensin II receptor blockers Monitor for toxic effects of losartan, e.g. hypotension, hyperkalaemia, diarrhoea, cough, vertigo and liver toxicity... 

CALCIUM CHANNEL BLOCKERS IMATINIB t plasma concentrations of imatinib when is co-administered with dilti-azem, nifedipine or verapamil, t risk of toxicity (e.g. abdominal pain, constipation and dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesias and peripheral neuropathy) Due to inhibition of hepatic metabolism of imatinib by the CYP3A4 isoenzymes by diltiazem Monitor for clinical efficacy and for the signs of toxicity listed along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes and liver function, and for cardiotoxicity... 

TOPIRAMATE ANTICANCER AND IMMUNOMODULATING DRUGS-IMATINIB t topiramate levels Imatinib is a potent inhibitor of CYP2C9-mediated metabolism of topiramate Watch for the early features of toxicity. If necessary, consider using alternative drugs while the patient is being given imatinib... 

CLOZAPINE, HALOPERIDOL, PERPHENAZINE, RISPERIDONE IMATINIB Imatinib may cause t plasma concentrations of these drugs with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

IMATINIB ANALGESICS-OPIOIDS May cause t plasma concentrations, with a risk of toxic effects of codeine, dextromethorphan, hydroxycodone, methadone, morphine, oxycodone, pethidine and tramadol Inhibition of CYP2D6-mediated metabolism of these opioids Monitor for clinical efficacy and toxicity. Warn patients to report t drowsiness, malaise or anorexia. Measure amylase and lipase levels if toxicity is suspected. Tramadol causes less respiratory depression than other opiates, but need to monitor BP and blood counts, and advise patients to report wheezing, loss of appetite and fainting attacks. Need to consider 1 dose. Methadone may cause Q-T prolongation the CHM has recommended that patients with heart and liver disease who are on methadone should be carefully monitored for heart conduction abnormalities such as Q-T prolongation on ECG as they may lead to sudden death. Also need to monitor patients on more than 100 mg methadone daily and thus an t in plasma concentrations necessitates close monitoring of cardiac and respiratory function... 

IMATINIB 1. ANTIARRHYTHMICS -flecainide, mexiletine, propafenone 2. ANTIDEPRESSANTS - fluoxetine, paroxetine, TCAs, trazodone, venlafaxine 3. ANTIPSYCHOTICS -clozapine, haloperidol, perphenazine, risperidone, thioridazine 4. BETA-BLOCKERS - metoprolol, propanolol, timolol 5. DONEPEZIL 6. METHAMPHETAMINE Imatinib may cause t plasma concentrations of these drugs, with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

IMATINIB CICLOSPORIN t plasma concentrations of cidosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity and excessive immunosuppression, with risk of infection and post-transplant lymphoproliferative disease Inhibition of metabolism of cidosporin Monitor plasma cidosporin levels to prevent toxicity... 

IMATINIB IRINOTECAN t plasma concentrations of SN-38 (the active metabolite of irinotecan) and t toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease Inhibition of CYP3A4-mediated metabolism of SN-38 Peripheral blood counts should be checked before each course of treatment. Monitor lung function. The recommendation is to 1 dose of irinotecan by 25%... 

IMATINIB VINCA ALKALOIDS t adverse effects of vinblastine and vincristine Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine Monitor FBCs and watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, ileus). Consider selecting an alternative drug... 

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