Using Pharmacokinetic and Pharmacodynamic Modeling and Simulation to Evaluate Importance of Schedule in Topotecan Therapy for Pediatric Neuroblastoma

Abstract

Purpose: The study aims to use mathematical modeling and simulation to assess the relative contribution of topotecan systemic exposure and scheduling in the activity and myelosuppression of topotecan in pediatric patients with neuroblastoma. Experimental Design: Pharmacokinetic and pharmacodynamic data were obtained from a phase II study for pediatric patients with high-risk neuroblastoma. The topotecan dosage was individualized to attain a topotecan lactone area under the plasma concentration-time curve between 80 and 120 ng/mL h and given over a protracted schedule (i.e., 10 days). Four mathematical models describing topotecan pharmacokinetics, tumor growth, and neutrophil and platelet dynamics were developed. The models were combined to simulate and compare different topotecan treatment strategies with respect to systemic exposure and schedule. Results: The median change in tumor volume was significantly different between schedules (5% increase for D Â 5 versus 60% decrease for D Â 5 Â 2; P < 0.0001) when administering the same total systemic exposure. Whereas protracted schedules showed increased neutropenia (median of 7 versus 12 days below an absolute neutrophil count of 500/AL; P < 0.0001) and thrombocytopenia (median of 3 versus 10 days below a platelet count of 20,000/AL; P < 0.00001), simulations showed that delays in topotecan therapy would not be required.Simulations showed that an increase in topotecan exposure on the D Â 5 schedule by 2.4-fold resulted in a modest decrease in tumor volume (i.e., median percentage change tumor volume of 24% versus 3%). Conclusions: The present mathematical model gave an innovative approach to determining relevant topotecan schedules for possible evaluation in the clinic, which could lead to improved tumor response with minimized toxicities.

Semimechanistic Cell-Cycle Type–Based Pharmacokinetic/Pharmacodynamic Model of Chemotherapy-Induced Neutropenic Effects of Diflomotecan under Different Dosing Schedules

“…Several pharmacokinetic (PK)/pharmacodynamic models have been published over the last decade describing myelosuppression response occurring during cancer treatment with chemotherapy agents (Minami et al, 1998;Zamboni et al, 2001;Friberg et al, 2002;Krzyzanski and Jusko, 2002;Panetta et al, 2003Panetta et al, , 2008. The most used and accepted model was developed by Friberg et al (2002), hereafter the reference model, which has demonstrated consistency among a wide variety of anticancer agents (Latz et al, 2006;Fetterly et al, 2008;Soto et al, 2010b) and has been used to describe neutropenic effects after drug combinations (Sandstrom et al, 2005;Soto et al, 2010a) and predict human hematologic toxicity from laboratory animal data (Friberg et al, 2010).…”

Role of vascular normalization in benefit from metronomic chemotherapy

“…To date, only a few mathematical models of metronomic therapy have been published, none of which accounts for interactions among cancer cells, CSCs, immune cells, and tumor blood vessels (26)(27)(28)(29)(30)(31)(32). To this end, we have developed a mathematical model for tumor growth that accounts for three different phenotypes of cancer cells-nonstem cancer cells (CCs), CSCs (which are more resistant to drugs, hypoxia, and the immune system), and CCs that are induced by chemotherapy to acquire a more stem-like phenotype, which we refer to as treatment-induced cancer cells (ICCs) (33), as well as immune cells [natural killer (NK) cells, CD8 + T cells, and Tregs], tumor vasculature, and their interactions (Fig.…”

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

“…2A). The model is based on established pharmacodynamics and known effects of each of the agents [21][22][23][24][25][26][27][28][29] on the cell cycle for 10 tumor types [31][32][33][34][35][36][37][38] and for erythroblasts 39 (erythroblasts have the highest proliferative index of marrow (Fig. 2B).…”

“…f(t) is a probability of effect based on the individual [16][17][18][19][20] or combined [21][22][23][24][25][26][27][28][29] effects of temsirolimus, topotecan, and bortezomib which have been previously described.…”