Charlotte van Kesteren1, Ron A.A. Mathôt1, Luis López-Lázaro2, Esteban Cvitkovic3, Jose M. Jimeno2, Jos H. Beijnen1
1)Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute and Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. 2)Pharma Mar S.A. Clinical R&D, c/ de la Calera 3, 28760 Tres Cantos (Madrid), Spain. 3)Paul Brousse Hospital, 12-14 Avenue Paul-Vaillant-Couturer, 94804 Villejuif Cédex, France.
Ecteinascidin 743 (ET-743) is a novel anti-cancer agent isolated from the Caribbean tunicate Ecteinascidia turbinata. A phase I clinical trial was conducted with ET-743 administered as a 24 hour infusion every 3 weeks. A population pharmacokinetic model was developed to describe the pharmacokinetics of ET-743 and to investigate the influence of covariables on the pharmacokinetic parameters.
Fifty-two patients received ET-743 at 9 dose levels (50-1800 µg/m²). Plasma concentration-time profiles of all patients during the first course were fitted to a 3-compartment model using NONMEM (ADVAN 11, TRANS 4). A total of 15 covariables was considered to explain the interpatient variability: age, weight, BSA, gender, presence of liver metastases at study entry, baseline creatinine and creatinine clearance and baseline levels of AST, ALT, alkaline phosphatase, sodium, potassium, urea, glucose and total protein.
Estimated pharmacokinetic parameters were (mean [SE]): volume of the central compartment, V1, 62 [10] L; total clearance, CL, 57 [8] L/h; volume of peripheral compartment 1, V2, 6060 [1060] L; intercompartmental clearance from peripheral compartment 1, Q2, 65 [4] L/h; volume of peripheral compartment 2, V3, 89 [10] L; intercompartmental clearance from peripheral compartment 2, Q3, 30 [8] L/h. Interindividual variability could be estimated for V1, CL, V2, Q2 and V3: 100%, 110%, 63%, 24% and 64% respectively. Residual variability was determined using a combined additive and proportional error model (5.2 pg/mL and 35% respectively). BSA was identified as a significant determinant for CL.
In conclusion, a population pharmacokinetic model was developed for the novel anti-cancer agent ET-743; the data were best described by a 3 compartment model. Substantial interpatient variability was observed. Of all covariates tested, BSA partially explained the interindividual variability in CL.
Reference: PAGE 9 () Abstr 121 [www.page-meeting.org/?abstract=121]
Poster: poster