Clinical significance of pharmacokinetic drug interactions between interferon-alpha and antineoplastic drugs

The major problems in chemotherapy are occasional low response rates in patients despite favourable in vitro action, the development of drug resistance and long or short term adverse effects. Therefore, in the past decade efforts have been made to circumvent these problems by combining antineoplastic drugs with biomodulating or cytoprotective agents. Most of the clinically useful drug regimens consist of a cocktail of drugs with different mechanisms of action, and hence different toxicity profiles. Dose-limiting factors in regard to toxicity and therapeutic efficacy predominate, and it is therefore clinically essential to know whether or not a pharmacokinetic drug interaction occurs. The introduction of interferon-alpha (IFNalpha) in chemotherapy is an alternative investigational approach to amplify the cytotoxicity of an antineoplastic drug in order to increase tumour response. Most of the clinical studies reported with IFNalpha provide useful information and identify major pharmacodynamic interactions, but only a few focus on and report potential pharmacokinetic interactions between antineoplastic drugs and IFNalpha in patients. The broad spectrum of antineoplastic drugs whose activity can be enhanced by IFNalpha argues for multiple levels of drug-drug interactions: protein binding (cisplatin), alteration in cellular uptake, modulation of drug target enzymes (dihydropyrimidine hydrogenase) and changes in biotransformation (tretinoin) or excretion. Pharmacokinetic and/or pharmacodynamic interactions may be beneficial (fluorouracil) or sometimes detrimental and coincidental (doxorubicin). This article focuses on observed pharmacokinetic drug interactions between IFNalpha and antineoplastic drugs and discusses possible mechanisms of action.