Clinically relevant drug interactions with multikinase inhibitors: a review

Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have rapidly become an established factor in daily (hemato)-oncology practice. Although the oral route of administration offers improved flexibility and convenience for the patient, challenges arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for (severe) drug–drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors) as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning drug (uptake and efflux) transporters may be of significant clinical relevance during MKI therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes (CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy and need to be monitored closely in clinical practice. Based on the current knowledge and available literature, practical recommendations for management of these DDIs in clinical practice are presented in this review

Cost considerations in the treatment of colorectal cancer

Colorectal cancer is among the most common malignancies in developed countries. Screening can reduce mortality significantly, although the most appropriate method is still under debate. Observational studies have revealed that lifestyle measures may also be beneficial for prevention of colorectal cancer. Surgery is still the most effective treatment modality for colorectal cancer. The survival benefits of chemotherapy are only modest. For nearly 5 decades, 5-fluorouracil (5-FU) has been the main cytotoxic agent for treatment of colorectal cancer. In the last decade, the new cytotoxic agents raltitrexed, irinotecan and oxaliplatin have been introduced, next to the oral 5-FU analogues capecitabine and tegafur in combination with uracil (UFT). Moreover, the immunotherapeutics bevacizumab and cetuximab have become approved for treatment of metastatic colorectal cancer. The economic implications of colorectal cancer treatment are substantial. The costs of treatment are mainly attributable to the early and terminal stage of the disease (i.e. surgery, hospitalisation, chemo- and immunotherapy and supportive care). The introduction of new chemo- and immunotherapeutics has caused a continuing increase of treatment expenditures. Therefore, comparative costs and cost effectiveness are important for assessing the value of new treatment regimens. The available study results suggest that addition of irinotecan or oxaliplatin to 5-FU/folinic acid dosage regimens is cost effective. Also, capecitabine is calculated to be cost effective when compared with 5-FU/folinic acid. For UFT, no comparative studies of cost effectiveness were found. Since raltitrexed and 5-FU/ folinic acid have shown equal efficacy in terms of survival, cost-effectiveness analysis is considered not to be applicable and cost-minimisation analysis may be sufficient. At present, pharmacoeconomic analyses of combination treatment with the immunotherapeutics bevacizumab or cetuximab are not available, except for recent cost-effectiveness considerations by the UK National Institute for Health and Clinical Excellence with negative recommendations for both agents in the treatment of metastatic colorectal cancer. Given the high treatment costs, substantial toxicity and relatively limited efficacy of the fast changing chemo- and immunotherapeutic combinations for colorectal cancer, examination of cost-effectiveness studies should be conducted on a routine basis along with determination of clinical benefits

Ziekenhuisapotheker adviseert bij intoxicatie. Lithiumtabletten met gereguleerde afgifte.

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