Use of CFU-GM assay for prediction of human maximum tolerated dose of a new antitumoral drug: Yondelis (ET-743).
Acute cytotoxic exposure causes decreases in bone marrow progenitors that precedes the neutrophil nadir. Experiments in animal models reveal a relationship between the reduction in granulocyte-macrophage progenitors (CFU-GM) and the decrease in absolute neutrophil count [Toxicol. Pathol. 21 (1993) 241]. Recently, the prevalidation of a model for predicting acute neutropenia by the CFU-GM assay has been reported [Toxicol. In Vitro 15 (2001) 729]. The model was based on prediction of human MTD by adjusting the animal-derived MTD for the differential sensitivity between CFU-GM from animal species and humans. In this study, this model has been applied on a new antitumoral drug, Yondelis (Ecteinascidin; ET-743). Preclinical studies showed that hematotoxicity was the main side effect in mice, being the MTD of 600 microg/m2 [Drugs Future 21 (1996) 1155]. The sensitivity of myeloid progenitors was higher in mice than in humans, with IC90 values of 0.69+/-0.22 nM and 1.31+/-0.21 nM for murine and human CFU-GMs respectively. This study predicts a human MTD of 1145 microg/m2. The reported human MTD of ET-743 given as a 24-h continuous infusion every 3 weeks is 1800 microg/m2 [J. Clin. Oncol. 19 (2001) 1256]. Since our predicted MTD is within fourfold of the actual MTD (the interspecies variation in tolerated dose due to differences in clearance rates, metabolism pathways and infusion rate) the result confirms the profit of the prediction model.
PharmaMar, S.A. Polígono Industrial La Mina, Avda de los Reyes, 1. 28770 Colmenar Viejo, Madrid, Spain.
Susana G
SG
Gómez
Juan A
JA
Bueren
Glynn
G
Faircloth
Beatriz
B
Albella
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D003114:Colony-Forming Units Assay; D004149:Dioxoles / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007546:Isoquinolines / Q000633:toxicity*; D020714:Maximum Tolerated Dose; D051379:Mice; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D011237:Predictive Value of Tests; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin