Oral topoisomerase 1 inhibitors in adult patients: Present and future

The renewed interest in topoisomerase 1 inhibitors, based on new insights o n the mechanism of action and the development of semi-synthetic derivates o f camptothecin with a more favourable toxicity profile, has led to extensiv e preclinical and clinical research. Significant levels of anti-tumor activ ity in human tumor xenografts were seen especially with prolonged duration of exposure. Since oral drug delivery is a more convenient method for prolo nged drug administration, and preferred by patients, further development of oral formulations seems attractive. Common concerns in the development of oral formulations are their sometimes low oral bioavailability and the frequently large intra- and interpatient variation in systemic exposure. Efforts to improve absorption and minimize intestinal metabolism/efflux of the oral chemotherapeutic agent using new f ormulas might lead to better bioavailability. Pharmacokinetic and pharmacod ynamic evaluations have enabled guidance in recommendations of schedules. G iven the interpatient variation in exposure it is interesting to note that flat dosing of topotecan resulted in the same systemic exposure compared wi th the more complex dosing per body surface area. In order to diminish the interpatient variation in exposure to 9-AC a limited sampling model for ora l 9-AC was developed, enabling prediction of the systemic exposure for 9-AC and optimizing treatment for any given patient. Drug sequencing plays a ke y role in the combination topotecan/cisplatin and might be important for co mbination with other classes of drugs. Therefore, forthcoming phase 1 trial s on combination therapy with oral topoisomerase 1 inhibitors should includ e studies on sequence dependence and pharmacokinetic analyses to evaluate a ny mutual interaction.