Simultaneous Population Pharmacokinetic (PBK) Modeling of Irinotecan (CPT-11) and its Major Metabolites, SN 38 and SN-38G
Purpose: To develop a PPK model in NONMEM® that simultaneously predicts the plasma concentration (Cp) profiles of CPT-11 (C) and its metabolites, SN-38 (S) and SN-38G (G).
Methods: Data were available from 5 phase II multicenter trials for 375 patients (pts) (2505, 2499 and 715 samples for C, S, and G, respectively) with colorectal or lung cancer who were started on doses (IV over 90 mins) of 100 (235 pts), 125 (130 pts), or 150 mg/m2 (10 pts) wkly for 4 wks, followed by a 2-wk rest period. Sampling was performed immediately before infusion, at 0, 1, 2, 4, and 24 h post infusion during Week 1 and/or Week 3 of Course 1. Data were randomly selected (80%:20%) for development and validation of the model.
Results: A 5-compartment model (2 for C, 1 for S, and 2 for G) with the S+G pathway pre-specified to represent 12% of the dose was developed, with clearances of C, S, and G estimated as mean±SE (interindividual variability, %CV): 23.4±1.0 (52.7), 7.62±0.66, and 9.15±1.24 (53.1) L/hr; central volumes of distribution estimated as 108±4.7, 39.3±13.4, and 5.23±1.57 L; and conversion clearance from C to S, S to G, and G to S estimated as 3.18±0.14 (29.1), 215±34 (48.7), and 27.7 (35.5), respectively. The residual variability for C, S, and G were 27.6, 36.9, and 19.4%CV, respectively.
Conclusions: Using prior information on metabolic pathways and elimination characteristics, this model provided good simultaneous fits to the Cp profiles of C, S, and G for development and validation data.
American Society for Clinical Pharmacology and Therapeutics (ASCPT); Atlanta, Georgia; March 2002
By A. Xiao, Jill Fiedler-Kelly, L. Schaaf, J. P. McGovren, G. Elfring, Susanne M. Sardella, and M. Redman