Deriving therapies for children with primary CNS tumors using pharmacokinetic modeling and simulation of cerebral microdialysis data

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Abstract

The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to support the rational testing and usage of innovative therapies in children with CNS tumors.

Introduction

Current treatment for children with primary central nervous system (CNS) tumors includes surgery, radiation, and chemotherapy. With this approach to therapy, the 5-year survival rate is 72.5%, but the cure rate is only 50% (Nageswara Rao et al., 2012). Even with new diagnostic tools and technologies, survival rates for certain CNS tumors have not increased significantly over the last twenty years (Pollack, 2011). Often, treatment of these tumors results in severe acute and long-term neurological and endocrine impairments that manifest later in life. Together, poor cure rates and adverse outcomes clearly highlight the need for innovative approaches in anticancer drug development for pediatric CNS tumors.

However, development of safe and effective anticancer drugs for children with CNS tumors is especially difficult for several reasons. One of the more challenging aspects is accruing sufficient numbers of patients for rapid evaluation of novel therapies in early phase clinical trials. Although pediatric CNS tumors are the most common cause of cancer-related deaths in children, they only account for 25% of all childhood cancers (Paul et al., 2013), and clinical trials are complicated by the heterogeneity of many CNS malignancies (Taylor et al., 2012). Pediatric CNS tumors are traditionally classified and graded by location and histology according to World Health Organization (WHO) guidelines and can be further stratified into molecular subgroups using gene expression profiling (Robinson et al. 2012). Many anticancer drugs are not necessarily efficacious in all subtypes of a tumor. Moreover, they may have non-specific mechanisms and often cause a variety of off-target side effects. Thus, an urgent need exists for the rapid evaluation of alternative, subgroup-specific therapies that can be investigated in preclinical studies with the use of molecularly relevant animal models of these subgroups.

Another significant challenge in treating CNS malignancies is reaching therapeutic drug exposures at the target site. Attaining adequate drug concentrations within a CNS tumor is complicated by the presence of different barriers in the brain, including the blood–brain barrier (BBB), the blood-CSF barrier (BCSF) and the blood-tumor barrier (BTB). These barriers regulate the flow of ions, solutes, and nutrients into the brain, CSF, and tumor and generally prevent xenobiotics from gaining access. The physicochemical properties of some anticancer drugs prevent them from diffusing across these barriers and reaching the target tumor tissue, rendering them ineffective against CNS tumors (Oldendorf, 1974, de Lange, 2013). Often, preclinical studies do not take these barriers into account (e.g., cell culture studies, murine flank xenografts). Thus, it is not surprising that so many anticancer drugs fail once they are challenged with an intact brain/CNS barrier system.

Together, these challenges highlight the need for innovative approaches to develop new effective anticancer drugs for pediatric CNS tumors. The preclinical approach we discuss here uses tumor subgroup-specific preclinical models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder progress in this field. While this approach does require a highly specialized team of researchers, the integration of pharmacologic principles into preclinical studies increases the likelihood of effectively translating preclinical findings to clinical trials of active drugs for CNS tumors.

Section snippets

Target drug exposure

Developing active anticancer drugs for patients with CNS diseases, including children with CNS tumors is daunting. In general, failure rates for oncology drugs are high, ca. 95% (Kola and Landis 2004). Specifically, failure rates for CNS drugs during Phase 2 and 3 studies are the highest of any therapeutic area, almost 2-fold higher than other indication (Kaitin and Milne, 2011, Bonate, 2013). To reduce the potential for clinical candidate attrition, our group has devised a preclinical

Lead compound selection

As noted earlier in the review, active anticancer drugs for children with CNS tumors are urgently needed. Thus, we describe in the following sections the process that was used to identify treatment leads for two very aggressive pediatric CNS tumor subtypes.

Results of recent high throughput screening (HTS) studies performed at our institution have identified multiple active drugs against two pediatric CNS tumors. The first, pemetrexed, a folate antagonist FDA-approved to treat pleural

Improving the development process for therapies to treat pediatric CNS tumors

Drug development for pediatric CNS tumors has historically followed the same paradigm as general pediatric oncology. An investigational or approved anticancer drug first shows promise in adult Phase 1–3 trials, typically for a variety of oncology indications. The anticancer drug is then tested against pediatric CNS tumors in vitro and in vivo, with the sophistication of these preclinical evaluations varying widely. Then, often with little information regarding the compound’s characteristics in

Future plans/summary

To date, our high-throughput screens, pharmacokinetic studies, and modeling and simulations thus far have focused on FDA approved compounds, however our next step is to evaluate non-FDA approved compounds and new chemical entities (NCEs) as potential anticancer drugs to treat CNS tumors in children. Since there will be little or no information available regarding formulation, systemic exposure, or tolerability for these agents, selecting an appropriate dosage for preclinical studies will be

Acknowledgements

The authors acknowledge the support of the Cancer Center Support CORE Grant P30 CA 21765 from the National Cancer Institute, The Collaborative Ependymoma Research Network (CERN), The V Foundation, and the American Lebanese Syrian Associated Charities. The authors thank the members of the St. Jude Brain Tumor Drug Development Leadership Group for their critical and helpful insights in the development of and the application of pharmacokinetic modeling and simulation to drug development for

References (38)

  • T. Ahmed et al.

    Abstract 3778: pharmacokinetic, safety and efficacy of high dose simvastatin in refractory and relapsed chronic lymphocytic leukemia (CLL) patients

    Cancer Res.

    (2012)
  • Alimta, 2013, May 1. “[Package insert].” Eli Lilly and Company, Indianapolis, IN 46285, USA,...
  • P.L. Bonate

    Editorial to the themed issue on translational modeling in neuroscience

    J. Pharmacokinet Pharmacodyn.

    (2013)
  • S. Chattopadhyay et al.

    Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications

    Mol. Cancer Ther.

    (2007)
  • M.B. d Yvoire et al.

    Physiologically-based kinetic modelling (PBK modelling): meeting the 3Rs agenda

    ATLA-NOTTINGHAM-

    (2007)
  • D.Z. D’Argenio et al.

    ADAPT 5 User’s Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software

    (2009)
  • E.C. de Lange

    The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

    Fluids Barriers CNS

    (2013)
  • H. Derendorf et al.

    Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives

    Pharm. Res.

    (1999)
  • M. Fridén et al.

    Structure−brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids

    J. Med. Chem.

    (2009)
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