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Oral Topoisomerase 1 Inhibitors in Adult Patients: Present and Future

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Abstract

The renewed interest in topoisomerase 1 inhibitors, based on newinsights on the mechanism of action and the development of semi-synthetic derivates of camptothecin with a more favourable toxicityprofile, has led to extensive preclinical and clinical research.Significant levels of anti-tumor activity in human tumor xenograftswere seen especially with prolonged duration ofexposure. Since oral drug delivery is a more convenient method forprolonged drug administration, and preferred by patients, furtherdevelopment of oral formulations seems attractive.

Common concerns in the development of oral formulations are theirsometimes low oral bioavailability and the frequently large intra- and interpatient variation in systemic exposure. Efforts to improveabsorption and minimize intestinal metabolism/efflux of the oralchemotherapeutic agent using new formulas might lead to betterbioavailability. Pharmacokinetic and pharmacodynamic evaluationshave enabled guidance in recommendations of schedules. Given theinterpatient variation in exposure it is interesting to note thatflat dosing of topotecan resulted in the same systemic exposurecompared with the more complex dosing per body surface area. Inorder to diminish the interpatient variation in exposure to 9-ACa limited sampling model for oral 9-AC was developed, enablingprediction of the systemic exposure for 9-AC and optimizingtreatment for any given patient. Drug sequencing plays a key rolein the combination topotecan/cisplatin and might be important forcombination with other classes of drugs. Therefore, forthcomingphase 1 trials on combination therapy with oral topoisomerase 1inhibitors should include studies on sequence dependence andpharmacokinetic analyses to evaluate any mutual interaction.

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Authors
  1. Hans A.J. Gelderblom
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  2. Maja J.A. de Jonge
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  3. Alex Sparreboom
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  4. Jaap Verweij
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Gelderblom, H.A., de Jonge, M.J., Sparreboom, A. et al. Oral Topoisomerase 1 Inhibitors in Adult Patients: Present and Future. Invest New Drugs 17, 401–415 (1999). https://doi.org/10.1023/A:1006394610219

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