Gleevec is a pill that is taken either once or twice daily, depending on the dose. Gleevec is different from traditional chemotherapy in that it is very selective. Traditional chemotherapy kills all cells that are dividing quickly. This is what causes so many of the side effects of traditional chemotherapy. In addition to the cancer cells, this type of chemotherapy also kills many of the bodies normal cells. Gleevec is much more selective and as a result has fewer side effects. It was designed to block the activity of a mutant type of enzyme (an enzyme is a specific type of protein) that causes Chronic Myeloid Leukemia (CML). It is used in GIST because it also blocks KIT and PDGFRA.
Gleevec is available in 100 mg and 400 mg tablets. Tablets are scored and may be broken in half.
The standard starting dose is 400 mg. This may be adjusted based on mutation type, side effects, low plasma levels (based on preliminary data) or upon progression. According to NCCN guidelines, “Patients with documented mutations in Exon 9 may benefit from dose escalation up to 800 mg daily (given as 00 mg twice daily, depending upon tolerance.”
Gleevec is taken once per day if the dose is 400 mg or 600 mg. For the 800mg dose, patients take 400 mg twice per day. In rare cases patients taking less than 800 mg may be directed to take Gleevec twice per day to decrease certain side effects.
It is important to take Gleevec with a large glass of water and with food to minimize nausea. Some patients will eat a little food first, take a pill, eat a little more food, take another pill, etc. This may help reduce nausea.
The following link goes to the full FDA patient prescribing information at the Novartis website: http://www.gleevec.com/patient/advanced-kit-gist.jsp?usertrack.filter_applied=true&NovaId=2935377102244456938
Dose and Dose Concentrations
Patients metabolize drugs at different rates. This means that 2 patients taking the same dose can have different concentrations of the drug in their body.
Documentation supplied to the FDA shows that drug concentrations can vary up to 40% between patients taking the same dose.
Other drugs can affect Gleevec drug concentrations. Gleevec is primarily metabolized by an enzyme in the liver known as P450 3A4, also known as CYP 3A4.
Drugs that INDUCE CYP 3A4 can LOWER Gleevec drug concentrations. In extreme cases, this could cause Gleevec to become ineffective. These drugs speed up the metabolism of Gleevec. Co-medications that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John’s Wort) may reduce exposure to Gleevec. No formal study of CYP3A4 inducers has been conducted, but a CML patient on chronic therapy with phenytoin (a CYP3A4 inducer) given 350 mg daily dose of Gleevec had about one fifth of the typical AUC of 20 µg.h/mL (one fifth of the typical drug concentration). This probably reflects the induction of CYP3A4 by phenytoin. This patient stopped responding to Gleevec until phenytoin was discontinued (although the dose of Gleevec was also increased to 500 mg at the same time).
Drugs that INHIBIT CYP 3A4 can INCREASE Gleevec drug concentrations. This can cause increased side effects from Gleevec. Some of these drugs include: ketoconazole, itraconazole, erythromycin, and clarithromycin.
Studies related to dosage:
Both the Sarcoma Task Force Report at the National Comprehensive Cancer Network (NCCN), and the GIST Consensus Conference of March 20-21, 2004 (ESMO), recommend starting doses of 400 mg day. The consensus conference noted, “Of note, however, both trials reported a superiority in terms of progression-free survival in the 800 mg arm, one reaching a significant statistical value (median progression-free survival 22 months versus not reached; P=0.02), the other being statistically non-significant (median progression-free survival 22 versus 27 months; P=0.13). Longer follow-up is therefore needed; this conclusion may evolve in the future.”
As follow-up data became available from the EORTC trial, researchers published the additional recommendations that their results suggest that imatinib should be dosed at 400 mg twice a day in patients with tumors bearing KIT exon 9 mutations.
The preliminary report from 2008 GI ASCO suggests that at least one-fourth of GIST patients may be underdosed. Gleevec blood level testing is available, and preliminary results suggest that trough levels should be above approximately 1,100 ng/ml for GIST patients.
An internal Life Raft Group Study found that when looking at the dose that patients actually took (versus the dose they started at), a select group of patients (those with initial shrinkage on Gleevec, and that had been on Gleevec for over one year) on more than 400 mg of Gleevec had significantly longer progression-free survival than patients on 400 mg or less. This study was not a controlled randomized trial (these type studies may have bias).
Determining dose seems to be somewhat of a balancing act between response and side effects. Given that there seems to be a weak correlation between dose and response and a strong correlation between dose and side effects, and that side effects seem to improve over time, the dose escalation approach seems to be a logical approach. Exon 9 patients may have a shorter time period for safe dose escalation.
It should be noted that the commonly prescribed doses, 400 mg, 600 mg, and 800 mg were determined by clinical trials. We are aware of a couple of patients that have responded at doses as low as 100 mg and some patients that require 800 mg (or more) to be effective. This also raises the question of doses in between. Might 500 mg or 700 mg be the optimum dose for some individuals? We should note that the only reason the patients that received 100 mg per day did so was because of severe toxicities at higher doses. In other words, the dose was varied by their doctors to achieve the optimum dose for these patients, taking into account both the patients response to the drug and the patients side effects. Doses below 300 mg should generally be avoided.
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Science: Biology – Genes and proteins
GIST: From Pathology Puzzle to Targeted Therapy
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