1. Academic Validation
  2. Population pharmacokinetic/pharmacodynamic modeling of drug-induced adverse effects of a novel homocamptothecin analog, elomotecan (BN80927), in a Phase I dose finding study in patients with advanced solid tumors

Population pharmacokinetic/pharmacodynamic modeling of drug-induced adverse effects of a novel homocamptothecin analog, elomotecan (BN80927), in a Phase I dose finding study in patients with advanced solid tumors

  • Cancer Chemother Pharmacol. 2012 Aug;70(2):239-50. doi: 10.1007/s00280-012-1906-y.
Iñaki F Trocóniz 1 Josep-María Cendrós Elena Soto Joan Pruñonosa Ana Perez-Mayoral Concepción Peraire Paola Principe Patrick Delavault Frédérique Cvitkovic Thierry Lesimple Rosendo Obach
Affiliations

Affiliation

  • 1 Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31080 Pamplona, Spain. itroconiz@unav.es
Abstract

Purpose: To characterize the pharmacokinetic profile of elomotecan, a novel homocamptothecin analog, evaluate the dose-limiting toxicities, and establish the relationship between exposure and toxicity in the first Phase I study in patients with advanced malignant solid tumors. Preliminary antitumor efficacy results are also provided.

Design: Elomotecan was administered as a 30-min intravenous infusion at doses ranging from 1.5 to 75 mg once every 3 weeks to 56 patients with advanced solid tumors. Plasma concentration data and adverse effects were modeled using the population approach.

Results: Elomotecan showed linear pharmacokinetics, and clearance was decreased with age. The model predicts a 47 and 61 % reduction in CL for patients aged 60 and 80 years, respectively, when compared with younger patients (30 years). Neutropenia represented the dose-limiting toxicity. The maximum tolerated dose and the recommended dose (RD) were 75 and 60 mg, respectively. Elomotecan elicited a 20, 5, 2, and 2 % severe (grade 4) neutropenia, asthenia, nausea, and vomiting at the RD, respectively. Of the subjects in the RD cohort, 41.7 % had a stable disease mean duration of 123.6 ± 43.4 days.

Conclusions: The pharmacokinetic parameters and the toxicity pattern of elomotecan suggest that this novel homocamptothecin analog should be further explored in the clinical setting using a dose of 60 mg administered as a 30-min intravenous infusion, once every 3 weeks.

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