The Lancet Oncology. 2011;12(1):9-11.

Who is in charge of assessing therapeutic drug monitoring? The case of imatinib.

Buclin T, Widmer N, Biollaz J, Decosterd LA.          PMID: 21111679

Exctract

In April, 2010, the US Food and Drug Administration (FDA) sent a warning letter to Novartis for sponsoring disease-awareness websites relating to chronic myeloid leukaemia and gastrointestinal stromal tumour. The websites were accused of promoting imatinib for unapproved use while not mentioning important safety information, and of making unsubstantiated dosing claims that could put patients at risk of serious adverse events. [...]

Although further observational studies have confirmed that drug-concentration exposure modulates clinical response, the formal assessment of therapeutic drug monitoring, in particular regarding the long-term outcome of patients, is eagerly awaited. We developed blood measurement immediately after imatinib was approved, and years before obtaining a supportive grant from Novartis, to launch a prospective randomised controlled trial aiming to establish how best to use drug monitoring for imatinib (Imatinib Concentration Monitoring Evaluation, I-COME, ISRCTN 31181395, registered August, 2009). Whatever the outcome of the dispute between Novartis and the FDA, scientific evidence and the potential benefits for patients should prevail. [...]

Online article: http://dx.doi.org/10.1016/S1470-2045(10)70258-8

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Blood 2011;117(8). e75-e87.

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib.

Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA.         PMID: 20810928

Abstract

Several cancer treatments are shifting from traditional, time-limited, non-specific cytotoxic chemotherapy cycles to continuous oral treatment with specific protein targeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia (CML). It has opened the way to the development of additional anti-CML TKIs, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacological mechanisms of interactions between imatinib, dasatinib and nilotinib, and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory, and so is the prospective reporting of unexpected clinical observations.

Online article: http://dx.doi.org/10.1182/blood-2010-07-294330

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Leukemia Research 2010;34(6):698-9.

Tyrosine kinase inhibitors concentration monitoring in chronic myeloid leukemia.

Widmer N, Gotta V, Haouala A, Decosterd LA.         PMID: 20074797

Extract

[...] Among the candidate prognostic factors, imatinib trough plasma concentration in patients has been suggested to predict clinical response and adverse events. In fact, besides having an impressively specific pharmacodynamic profile, imatinib is also characterized by an important inter-individual pharmacokinetic variability. Thus, with the standard 400 mg once daily recommended dosage, imatinib plasma exposure may vary by as much as about 6-fold in-between patients, while the intra-individual variability in imatinib pharmacokinetics is limited to about 30%. Various factors have been proposed to explain the inter-individual pharmacokinetic variability, such as variable distribution throughout body compartments (influenced by drug transporters and plasma protein binding) and liver cytochrome activity (mainly cytochrome 3A4/5). Demographic factors (sex, age, body weight, etc.), co-medication and adherence to therapy are also implicated. Moreover, several studies have demonstrated that imatinib trough plasma concentrations above 1000 µg/L were predictive of higher rates of complete cytogenetic response and major molecular response. Similar results were also observed in GIST patients [...]

Online article: http://dx.doi.org/10.1016/j.leukres.2009.12.009