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
- 221 Downloads
- 9 Citations
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.
Keywords
Elomotecan Dose finding Pharmacokinetics Adverse effects Population modelingNotes
Acknowledgments
The authors would like to thank Veronique Fohanno and Josep Solà from Ipsen Group for managing the clinical study and the pharmacogenetic analysis respectively and to Epidauros Biotechnologie AG for the genotyping execution.
Conflict of interest
Elena Soto and Iñaki F. Trocóniz have received financial research support from Ipsen Pharma S. A. Josep-María Cendrós, Ana Perez-Mayoral, Joan Pruñonosa, Concepción Peraire, Rosendo Obach, Paola Principe, and Patrick Delavault are employees of Ipsen Pharma S. A. Frédérique Cvitkovic and Thierry Lesimple were principal investigators for the clinical study.
Supplementary material
References
- 1.Bailly C (2003) Homocamptothecins: potent topoisomerase I inhibitors and promising anticancer drugs. Crit Rev Oncol Hematol 45:91–108PubMedCrossRefGoogle Scholar
- 2.Demarquay D, Coulomb H, Huchet M et al (2000) The homocamptothecin, BN 80927, is a potent topoisomerase I poison and topoisomerase II catalytic inhibitor. Ann N Y Acad Sci 922:301–302PubMedCrossRefGoogle Scholar
- 3.Huchet M, Demarquay D, Coulomb H et al (2000) The dual topoisomerase inhibitor, BN 80927, is highly potent against cell proliferation and tumor growth. Ann N Y Acad Sci 922:303–305PubMedCrossRefGoogle Scholar
- 4.Demarquay D, Huchet M, Coulomb H et al (2004) BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo. Cancer Res 64:4942–4949PubMedCrossRefGoogle Scholar
- 5.Lesimple T (2010) Phase I dose-finding study of BN80927 as an intravenous infusion every 21 days in patients with advanced malignant solid tumors. J Clinical Oncology 28(suppl):3072Google Scholar
- 6.Beal SL, Sheiner LB, Boeckmann A (eds) (2006) (1989–2006) NONMEM User’s Guides. Icon Development Solutions, Ellicott CityGoogle Scholar
- 7.Karlsson MO, Sheiner LB (1993) The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 21:735–750PubMedGoogle Scholar
- 8.Friberg LE, Henningsson A, Maas H et al (2002) Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20:4713–4721PubMedCrossRefGoogle Scholar
- 9.Mandema JW, Verotta D, Sheiner LB (1992) Building population pharmacokinetic-pharmacodynamic models. I. Models for covariate effects. J Pharmacokinet Biopharm 20:511–528PubMedGoogle Scholar
- 10.Jonsson EN, Karlsson MO (1999) Xpose-an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58:51–64PubMedCrossRefGoogle Scholar
- 11.Lindbom L, Ribbing J, Jonsson EN (2004) Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Programs Biomed 75:85–94PubMedCrossRefGoogle Scholar
- 12.Bergstrand M, Hooker AC, Wallin J, Karlsson MO (2011) Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J 13:143–151PubMedCrossRefGoogle Scholar
- 13.Sheiner LB, Stanski DR, Vozeh S et al (1979) Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 25:358–371PubMedGoogle Scholar
- 14.Hing J, Perez-Ruixo JJ, Stuyckens K et al (2007) Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of trabectedin (ET-743, Yondelis®) induced neutropenia. Clin Pharmacol Ther 83:130–143PubMedCrossRefGoogle Scholar
- 15.Trocóniz IF, Garrido MJ, Segura C et al (2006) Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours. Cancer Chemother Pharmacol 57:727–735PubMedCrossRefGoogle Scholar
- 16.Mould DR, Holford NH, Schellens JH et al (2002) Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther 71:334–348PubMedCrossRefGoogle Scholar
- 17.Xie R, Mathijssen RH, Sparreboom A et al (2002) Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin Pharmacol Ther 72:265–275PubMedCrossRefGoogle Scholar
- 18.Schellens JH, Heinrich B, Lehnert M et al (2002) Population pharmacokinetic and dynamic analysis of the topoisomerase I inhibitor lurtotecan in phase II studies. Invest New Drugs 20:83–93PubMedCrossRefGoogle Scholar
- 19.Veltkamp SA, Witteveen EO, Capriati A et al (2008) Clinical and pharmacologic study of the novel prodrug delimotecan (MEN 4901/T-0128) in patients with solid tumors. Clin Cancer Res 14:7535–7544PubMedCrossRefGoogle Scholar
- 20.Bigioni M, Parlani M, Bressan A et al (2009) Antitumor activity of delimotecan against metastatic melanoma: pharmacokinetics and molecular determinants. Int J Cancer 125:2456–2464PubMedCrossRefGoogle Scholar
- 21.Sparreboom A, Gelderblom H, Marsh S et al (2004) Diflomotecan pharmacokinetics in relation to ABCG2 421C > A genotype. Clin Pharmacol Ther 76:38–44PubMedCrossRefGoogle Scholar