EUTOS Path to cure

About the subproject Pharmacological Monitoring

Imatinib has dramatically improved treatment for BCR-ABL positive CML producing unprecedented response rates that are durable for years. Clinical experience with imatinib established that it is easy to administer, safe and well tolerated and now the standard of care in CML (Druker, NEJM 2006; Hughes, NEJM 2003; Kantarjian, NEJM 2002, O’Brien, NEJM 2003; Sawyers, Blood 2002; Talpaz, Blood 2002). However, there exists a large inter-subject variation of imatinib plasma concentration for patients due to a complex interplay of factors that include P450 3A4 metabolism (Goldman, NEJM 2001), cellular efflux via the MDR1 protein (Mahon, Blood 2003).
The pharmacokinetic parameters of imatinib have been determined in patients with Ph+ CML from the phase 1 dose-finding study (Druker et al., NEJM 2001; Gschwind et al., Drug Metab Dispos 2005; Peng et al., JCO 2004). Imatinib doses ranging from 25 mg to 1000 mg daily were tested, but the maximal tolerated dose was not identified. Residual or trough plasma imatinib concentration has been found to be correlated to both cytogenic response and molecular response, 1002 ng/ml being the minimum required for full molecular response (Picard, Blood 2007).
It is recommended that imatinib dosing should be considered where:

• there is suspicion that the patient may be nonadherent with imatinib
• there is suspicion that the patient may be experiencing a drug–drug interaction
• the patient is not responding to imatinib as well as he or she should be
• the patient is experiencing side effects that are unusually severe for the dose of imatinib he or she is taking

Imatinib dosing (trough plasma concentration determination) is currently performed at the Bordeaux teaching hospital. This laboratory has been designated by Novartis as the European dosing centre but up to now, this service and sample transportation is only freely available for patients treated in France. After ten weeks therapeutic monitoring of imatinib in France, 267 patients have been tested and trough plasma imatinib concentration was found to be below 1000 ng/ml in 156 patients of which 65 were below 500 ng/ml, underlining the importance of imatinib monitoring to ensure therapeutic response.

Created by: A. Hellenbrecht , generated 2007/12/19 , last changed: 2011/05/12