Clinically relevant drug-drug interactions in oncology

Although anticancer agents are one of the most toxic classes of medication prescribed today, there is relatively little information available about clinically relevant drug-drug interactions. Pharmacokinetic drug interactions have been described, including alterations in absorption, catabolism, and excretion. For example, an increased bioavailability of 6-mercaptopurine has been observed when combined with either allopurinol or methotrexate, leading to increased toxicity in some patients. Induction of etoposide or teniposide clearance by anticonvulsants has also been described, resulting in a lower systemic exposure and risk for lower anticancer activity. Alterations in elimination of methotrexate has been observed with probenecid, presumably through competition for renal secretion. There are also several examples of pharmacodynamic interactions. The combination of 5-fluorouracil plus folinic acid results in more efficient inhibition of thymidylate synthase, a finding which is now utilized routinely in the treatment of colorectal cancer. Improvements in the in vitro and early clinical testing now allow a relatively high degree of prediction of potential clinical drug interactions, prior to observations of untoward drug effects. In conclusion, drug interactions among commonly used anticancer agents have been identified. Their clinical significance can have more impact than many other classes of medications due to the narrow therapeutic index of antineoplastic agents and the potential for lethal side-effects. It is only through prospective, preclinical and early clinical evaluation that the presence of clinically significant drug interactions can be identified and the information used to provide better therapy for this significant health problem.