Oral topoisomerase 1 inhibitors in adult patients: present and future.
The renewed interest in topoisomerase 1 inhibitors, based on new insights on the mechanism of action and the development of semi-synthetic derivates of camptothecin with a more favourable toxicity profile, has led to extensive preclinical and clinical research. Significant levels of anti-tumor activity in human tumor xenografts were seen especially with prolonged duration of exposure. Since oral drug delivery is a more convenient method for prolonged 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 formulas might lead to better bioavailability. Pharmacokinetic and pharmacodynamic evaluations have enabled guidance in recommendations of schedules. Given the interpatient variation in exposure it is interesting to note that flat dosing of topotecan resulted in the same systemic exposure compared with 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 oral 9-AC was developed, enabling prediction of the systemic exposure for 9-AC and optimizing treatment for any given patient. Drug sequencing plays a key role in the combination topotecan/cisplatin and might be important for combination with other classes of drugs. Therefore, forthcoming phase 1 trials on combination therapy with oral topoisomerase 1 inhibitors should include studies on sequence dependence and pharmacokinetic analyses to evaluate any mutual interaction.
Gelderblom
H A
HA
Department of Medical Oncology, Rotterdam Cancer Institute, (Daniel den Hoed Kliniek) and Universit) Hospital Rotterdam, The Netherlands. h.gelderblom@wxs.nl
DE Jonge
M J
MJ
Sparreboom
A
A
Verweij
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors