Preface

**Section 6 Management of Primary and Secondary CNS**

Chapter 6 **Current Management of Brain Metastases: Overview and**

Karolyn Au, Ying Meng, Suganth Suppiah, Anick Nater, Rakesh

Mihnea Zdrenghea, Delia Dima, Ciprian Tomuleasa, Horia Bumbea

Lee Roy Morgan, Andrew H. Rodgers, Gerard Bastian, William S. Waud, Branko S. Jursic, Robert F. Struck, Gerald LaHoste and

Chapter 7 **Advances in the Treatment of Primary Brain Tumors: The Realm**

Chapter 9 **Comparative Anticancer Activity in Human Tumor Xenograft Models, Preclinical Pharmacology and Toxicology for 4- Hydroperoxyifosfamide (HOOI): A Potential Neuro-Alkylating Agent for Primary and Metastatic Cancers Involving the Central**

**Malignancies 119**

**VI** Contents

**Teaching Cases 121**

Jalali and Gelareh Zadeh

**of Immunotherapy 149**

and Cristina Bagacean

**Nervous System 189**

Edward Stevens

**Section 7 New Drugs for CNS Malignancies 187**

Michael J. Strong and Marcus L. Ware

Chapter 8 **Primary Central Nervous System Lymphoma 167**

The basic texture of research consists of dreams into which the threads of reasoning, meas‐ urements, calculations, and hard work are woven. The opportunity to edit *New Approaches to the Management of Primary and Secondary CNS Tumors* is an honor and privilege.

This book is dedicated to all students, researchers, health care professionals, and clinical in‐ vestigators who have found delight in the serious contemplation of intellectual puzzles, promises, and rewards from neuro-oncology research and patient care. The gamut of inter‐ ests in this book includes those of medicinal chemists, neurophysiologists, pharmacologists, laboratory scientists, and physicians. The chapters present reflections on the daily tasks of neuro-oncology researchers and health-care givers that include, but are not limited to, the design of new techniques, validating the best management care plans, and, in general, at‐ tempting to improve the health care for individuals with brain tumors.

Equally as important, the book includes the efforts of individuals who are contributing to the fundamental knowledge of the brain's biochemistry, physiology, chemistry, neurology, and biophysics, which are altered when cancer invades or develops in the brain and central nervous system.

The term chemobiodynamics is used in several chapters and represents the concept(s) by which the chemistry of a drug can manifest an impact on the hierarchy of molecular levels of living organisms. When cancer invades or develops in the central nervous system (CNS), there are major alterations in the normal hierarchy of cellular organization, which require different forms of cancer management (surgery, radiation, chemo-/immunotherapies, etc.). Unfortunately, therapies not only kill cancer cells but also damage normal tissues, including the immune system. Thus, the prefix "chemo" in chemobiodynamics could be replaced by immuno, neuro, radio, psycho, etc. with the same emphasis — to describe *effects that occur during the eradication of cancer involving the central nervous system*.

The present book attempts to review new approaches to the management of CNS tumors, and some chapters are presented that emphasize the development of novel chemical, radio‐ logical, and analytical techniques and therapeutics that can improve the care and manage‐ ment of subjects with neuro-oncological malignancies.

Since the book *Tumors of the Central Nervous System* (InTech) was published in 2014, neurooncology has made significant major progress; Phase I trials for new drugs have increased by 20-fold, and several drugs have been approved as target specific immuno-/chemothera‐ pies for CNS malignancies. In addition, in the world of neuro-oncology, radiation therapy has radically evolved giving improved long-term survival and quality of life.

The authors that have written the chapters herein are "living their dreams and weaving their fibers" and are blessed. And, it is our wish that all of the readers are also able to pursue their dreams. Only through new concepts and endeavors are there any possibilities of con‐ verting cancers involving the brain and central nervous system into chronic illnesses fol‐ lowed by eradication.

Please continue to follow your dreams, because "Each of us has been chosen to accomplish our mission—we did not choose it!"

In summary, we have tried to bring together a wide range of interests and contributions from dozens of scientists and researchers to allow the readers to appreciate advancements in the management of neuro-oncology.

> **Lee Roy Morgan, MD, PhD** CEO Dekk-Tec, Inc. New Orleans, LA, USA

**Principles of Neuropharmacology**

The authors that have written the chapters herein are "living their dreams and weaving their fibers" and are blessed. And, it is our wish that all of the readers are also able to pursue their dreams. Only through new concepts and endeavors are there any possibilities of con‐ verting cancers involving the brain and central nervous system into chronic illnesses fol‐

Please continue to follow your dreams, because "Each of us has been chosen to accomplish

In summary, we have tried to bring together a wide range of interests and contributions from dozens of scientists and researchers to allow the readers to appreciate advancements in

**Lee Roy Morgan, MD, PhD**

New Orleans, LA, USA

CEO

Dekk-Tec, Inc.

lowed by eradication.

VIII Preface

our mission—we did not choose it!"

the management of neuro-oncology.

#### **NeuroPharmacology: As Applied to Designing New Chemotherapeutic Agents NeuroPharmacology: As Applied to Designing New Chemotherapeutic Agents**

Andrew H. Rodgers and Lee Roy Morgan Andrew H. Rodgers and Lee Roy Morgan

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67591

#### **Abstract**

Neurooncology anticancer drugs are no exception—their distribution and tissue interactions follow the general rules of classical pharmacology. In an attempt to assist with the new therapeutic approaches to manage cancers involving the central nervous system, classical chemobiodynamic compartment and pharmacokinetic models are discussed and illustrated. In addition, strategies and approaches for penetrating the blood brain barrier (BBB) are reviewed and modeled. Finally, in support of classical pharmacology, a new anticancer agent in clinical trial for brain tumors is reviewed as an example of clinical onco-neuropharmacology.

**Keywords:** neurooncology, pharmacology, chemotherapeutics in clinical trials

#### **1. Introduction**

A basic assumption in cancer management is that all cancer cells must be killed or removed. When surgical and radiotherapies fail to achieve this goal, anticancer agents become the hope for control of the advanced disease.

Classically, when a drug is injected or orally administrated, ideally it is 100% absorbed and enters the systemic circulation and distributed into the various body compartments. The drug then develops equilibrium (distribution) between metabolism, storage, target tumors, nontumor organs, and final elimination [1].

The various body components and physiological barriers, which a cancer chemotherapeutic agent encounters from the time of administration until reaching the target site—the tumor are depicted in **Figure 1** [2, 3].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Figure 1.** Drug distribution.

The intensity and duration of drug action at any one site depends upon absorption, distribution, affinity, excretion, and metabolism for the drug.

It is anticipated that the drug's tumor selectively will be such that it is absorbed preferentially, with relatively low toxicity to the host organs, such as bone marrow, liver, kidney, gastrointestinal tract, etc. In addition, the accumulation of drug in the tumor will depend upon lipid storage, metabolic activation, and elimination. The liver has a principal role in the metabolism of cancer chemotherapeutic agents, but the other organs such as bone marrow, liver, intestines, kidneys, and even brain also contain low levels of drug-metabolizing enzymes [1, 2].

**Table 1** outlines the major types of biotransformation which anticancer drugs can be expected to undergo. These include oxidative, reductive, and conjugation reactions, which usually result in increased product polarity. The resulting product(s) are either activated or detoxified metabolites of the parent drug. The conjugated reactions usually result in water-soluble products, which are excreted *via* the biliary and urinary systems.


**Table 1.** Biotransformation of drugs [4].

## **2. Cancer Cells Involving CNS**

Cancer cells are the target of cancer chemotherapeutic agents, and the rate at which cancer cells interact with these agents is controlled by the hierarchy of molecular organization shown in **Figure 2**.

However, for tumor cells colonized in the brain and associated central nervous system structures, drugs/chemicals have an "additional hurdle," they must penetrate the blood brain barrier (BBB) before classical interactions and pharmacological principles can be applied. Evidence supports anticancer agents exerting their antitumor activities *via* cytotoxic, cytostatic and/or initiating immunotherapeutic mechanisms of action resulting in cancer cell death. All the chemotherapeutics interfere/interact with pathways in the cellular organization (**Figure 2**), thus inhibiting the synthesis of cancer cell DNA, RNA, proteins, and initiating lymphocyte—cancer cell recognition.

Although chemotherapeutics have their initial interactions on the molecular levels, they must first reach their targets. Thus, the abilities of chemotherapeutic agents to reach and interact with their targets are controlled by the hierarchy of distribution (**Figure 1**) and disposition (**Table 1**). These responses or changes are then transmitted to the respective molecular and/or cellular levels of cells (**Figure 2**).

**Figure 2.** Hierarchy of cellular components. Molecular organization of cells.

#### **3. Clark's correlates**

The intensity and duration of drug action at any one site depends upon absorption, distribu-

It is anticipated that the drug's tumor selectively will be such that it is absorbed preferentially, with relatively low toxicity to the host organs, such as bone marrow, liver, kidney, gastrointestinal tract, etc. In addition, the accumulation of drug in the tumor will depend upon lipid storage, metabolic activation, and elimination. The liver has a principal role in the metabolism of cancer chemotherapeutic agents, but the other organs such as bone marrow, liver, intestines, kidneys, and even brain also contain low levels of drug-metabolizing

**Table 1** outlines the major types of biotransformation which anticancer drugs can be expected to undergo. These include oxidative, reductive, and conjugation reactions, which usually result in increased product polarity. The resulting product(s) are either activated or detoxified metabolites of the parent drug. The conjugated reactions usually result in water-soluble

> **1.**Glucuronides **2.**Ethereal sulfates **3.**Mercapturic acids **4.**Amino acid conjugates **5.**Acetylated aromatic amines

tion, affinity, excretion, and metabolism for the drug.

4 New Approaches to the Management of Primary and Secondary CNS Tumors

products, which are excreted *via* the biliary and urinary systems.

**Oxidation reactions Reductive reactions Conjugation reactions**

**1.**Keto reduction **2.**Nitro reduction **3.**Azo bond cleavage

enzymes [1, 2].

Aromatic hydroxylation

**2.**Alkyl chain oxidation

**4.**Oxidative deamination

**3.**S-Oxidation

, De-alkylation

**Table 1.** Biotransformation of drugs [4].

**1.**O<sup>−</sup> , N<sup>−</sup> , S<sup>−</sup>

**Figure 1.** Drug distribution.

In his classic work on general pharmacology, A.J. Clark divided the possible quantitative drug action(s) into five types [4]:

Relationship between:


The first three classes of Clark's correlates are expressions of kinetics and are the rate(s) of actions for drugs, while the last two classes summarize equilibrium conditions between drugs and their target sites. The reactivity of an agent with a molecular target in a biological system, is dependent upon the concentration of the "active therapeutic available" and often more important, is the rate at which the active form of the drug finds its way to the therapeutic sites/targets.

The selection of an optimal drug source requires consideration of:


Consideration is also required for recovery time for the target organ, as well as nontarget organs, such as the bone marrow and gastrointestinal tract to recover prior to the administration of additional drugs. This depends on the pharmacologic disposition of the drug, since absorption, distribution, elimination, and metabolism affect the toxicity and efficacy, which can be achieved in the treatment of cancer.

#### **4. Pharmacokinetics**

Since most aspects of pharmacology involve dynamic processes, it is necessary to consider the rates or time courses for this process [5]. Pharmacokinetics is the quantitative measurement of concentration *vs*. time for drug and metabolite(s) in respective biological fluids, tissues, and for excretion. Pharmacokinetics is not the measurement of a solution to a problem; it is merely the scientific analysis of a drug's chemobiodynamics— the distribution of a drug in an organism [6].

Common questions in which applications of pharmacokinetics have proven to be useful include:


The initial step in a pharmacokinetic study is to determine if a drug is distributed by first or second-order reactions. The second step is to develop models for documentation.

#### **4.1. First Order Kinetic Reactions**

(3) Concentration and time of appearance of a selected action.

The selection of an optimal drug source requires consideration of:

(1) The qualitative and quantitative nature of the drug's known toxicity.

(2) The influence of drug concentration with time on tumor cell kill.

efficacy, which can be achieved in the treatment of cancer.

(1) How a drug is eliminated and how fast?

(2) What factors affect the rate of elimination?

(3) What is the optimal drug regimen for a drug?

(4) How can drugs and radiotherapy be combined?

(6) Does drug distribution change with multiple dosing?

(5) Is the pharmacological response due to the parent drug or a metabolite?

The first three classes of Clark's correlates are expressions of kinetics and are the rate(s) of actions for drugs, while the last two classes summarize equilibrium conditions between drugs and their target sites. The reactivity of an agent with a molecular target in a biological system, is dependent upon the concentration of the "active therapeutic available" and often more important, is the rate at which the active form of the drug finds its way to the therapeutic sites/targets.

Consideration is also required for recovery time for the target organ, as well as nontarget organs, such as the bone marrow and gastrointestinal tract to recover prior to the administration of additional drugs. This depends on the pharmacologic disposition of the drug, since absorption, distribution, elimination, and metabolism affect the toxicity and

Since most aspects of pharmacology involve dynamic processes, it is necessary to consider the rates or time courses for this process [5]. Pharmacokinetics is the quantitative measurement of concentration *vs*. time for drug and metabolite(s) in respective biological fluids, tissues, and for excretion. Pharmacokinetics is not the measurement of a solution to a problem; it is merely the scientific analysis of a drug's chemobiodynamics— the distribution of a drug in

Common questions in which applications of pharmacokinetics have proven to be useful

(4) Concentration and amount of quantitative response.

6 New Approaches to the Management of Primary and Secondary CNS Tumors

(5) Concentration and incidence of all-or-none effects.

(3) The drug's pharmacology.

**4. Pharmacokinetics**

an organism [6].

include:

First-order reactions usually produce parallel curves for different doses of a drug with proportional shifts in the ordinate. If not, one must determine, which saturation processes or enzymatic reactions or zero order reactions are present.

Once the reaction kinetics is found to be first order, a model must be formulated. Models are based on the concepts of compartments. The simplest first order pharmacokinetics normally fits a one compartment model; for example, a drug is administered by intravenous injection and eliminated only in the urine or some other single route.

The rate of disappearance of the drug from the blood is proportional to the actual concentration of drug (*x*) in the blood (**Figure 3**).

**Figure 3.** Pharmacokinetics of a one-compartment system.

Plotting the log [*x*] *vs*. time produces a slope equal to: −k/2.303.

The half-life (*t* 1/2) of the drug (*x*) is the time in which the concentration in the primary compartment decreases by 50%:

$$t\_{1/2} = 0.693/\text{km}$$

The half-life is only meaningful as long as there is a one compartment model and the reaction is first-order. The half-life is also related to the clearance (*Cl*) and distribution (*V*d) of the drug:

$$t\_{1/2=}0.693\text{ V}\_d/\text{Cl},\quad\text{where }\text{Cl}=k\times V\_d$$

and

and 
$$\mathbf{v}\_a = \mathbf{v}\_a \quad \text{and} \quad \mathbf{v}\_a = \mathbf{v}\_a \quad \text{and} \quad \mathbf{v}\_a = \mathbf{v}\_a$$
 
$$\text{and}$$
 
$$\begin{aligned} V\_{d\_{12}} \text{dose/} \mathbf{x}\_0 &\text{is obtained by extrapolating the curve to } t = 0. \\ \text{Also } -t\_{12} &= 0.693 \text{J/k} = 0.693 \text{ V}\_d / \text{Cl, where:} \text{:} \text{Cl} = k \, V\_d \text{ and } V\_d = \text{dose/} \mathbf{x}\_0. \end{aligned}$$

Thus, the elimination is calculated as – *dx*/*dt* = −*kx* (with *k* = elimination constant)

#### **4.2. Second Order Kinetic Reactions**

Second-order reactions are best described in models where there are both elimination and distribution to other compartments and the curve would look like **Figure 4**. The upper portion of the curve represents distribution, while the lower flatter portion represents elimination [7].

The slope of the elimination phase or *β* is calculated by extending or extrapolating the lower portion of the curve to the ordinate (intercept) at B. The slope of the distribution phase or *α* is calculated by taking the differences between times for actual curve A and extrapolating to (*B*) back to *T*<sup>0</sup> .

**Figure 4.** Pharmacokinetics of a two-compartment system [2].

Here, *t*1/2 (*α*) = 0.693/α and *t*1/2 (*β*) = 0.693/β – **Figure 4**.

There are some disadvantages to this type of feathering—data can be biased when converting from linear to log scale and objectivity lost (too much importance placed on the terminal part of the curve where there is often least confidence). Computer models are best employed, if possible.

In this type of example, it is meaningless to speak of *T*1/2, since the whole curve is determined by two *T*1/2 values analogous to *K*<sup>1</sup> and *K*<sup>2</sup> , and one cannot combine these two values directly. It is no longer true that the *T*1/2 values remain constant for greater than two compartments.

#### **4.3. Drug Distribution**

Plotting the log [*x*] *vs*. time produces a slope equal to: −k/2.303.

8 New Approaches to the Management of Primary and Secondary CNS Tumors

*<sup>V</sup>*<sup>d</sup> <sup>=</sup> dose/ *<sup>x</sup>*<sup>0</sup> ; *<sup>x</sup>*<sup>0</sup> is obtained by extrapolating the curve to *<sup>t</sup>* <sup>=</sup> 0.

1/2) of the drug (*x*) is the time in which the concentration in the primary compart-

1/<sup>2</sup> = 0.693/k The half-life is only meaningful as long as there is a one compartment model and the reaction is first-order. The half-life is also related to the clearance (*Cl*) and distribution (*V*d) of the drug:

1/<sup>2</sup> <sup>=</sup> 0.693 *V*<sup>d</sup> /Cl, where *Cl* = *k* × *V*<sup>d</sup>

Second-order reactions are best described in models where there are both elimination and distribution to other compartments and the curve would look like **Figure 4**. The upper portion of the curve represents distribution, while the lower flatter portion represents elimination [7]. The slope of the elimination phase or *β* is calculated by extending or extrapolating the lower portion of the curve to the ordinate (intercept) at B. The slope of the distribution phase or *α* is calculated by taking the differences between times for actual curve A and extrapolating to

1/<sup>2</sup> = 06.93/k = 0.693 *V*<sup>d</sup> /*Cl*, where:*Cl* = *k V*<sup>d</sup> and *V*<sup>d</sup> = dose/*x*<sup>0</sup>

.

Also <sup>−</sup> *<sup>t</sup>*

Thus, the elimination is calculated as – *dx*/*dt* = −*kx* (with *k* = elimination constant)

The half-life (*t*

and

(*B*) back to *T*<sup>0</sup>

.

**Figure 4.** Pharmacokinetics of a two-compartment system [2].

ment decreases by 50%:

*t*

**4.2. Second Order Kinetic Reactions**

*t*

Another reason for the success or failure in drug activity is related to the pharmacologic disposition of drugs in subjects. Even if the tumor is sensitive to a drug, the latter is not useful unless it reaches the tumor site and remains there in cytotoxic (therapeutic) concentrations long enough to kill the tumor cells. In general, the purpose of pharmacology studies is to inform the treating physicians what is an effective concentration (*C*) of the drug that can be administered by a certain route and be present (available) for a sufficient period of time (*T*) to bring about the desired effect. This is referred to as the "optimal *C* × *T*," and in most diseases, this can be approximated for dosing in humans through preclinical studies in animal models. Generally, 10% of the LD10 in mice is the acceptable starting dose [1].

#### **4.4. Correlation of Pharmacokinetic Profile**

What makes cancer different from other diseases is the need to relate optimal *C* × *T* to the phases of the cell cycle [1]. First, the optimal *C* × *T* for the tumor must be estimated for the real target—the tumor cells that are susceptible to be killed by the drug. Second, calculations are required to define the optimal *C* × *T* for human safety (e.g., the *C* × *T* that will be tolerated by normal organ tissues (bone marrow or gastrointestinal tract in most cases). Third, the cell population kinetics of both tumor cells and normal cells will be perturbed as a result of the drug's administration; however, the cancer cell growth fraction should be reduced to a greater degree, with sparing of normal tissues. Thus, the potential for drug's usefulness is a balance between anticancer activity and damage to healthy organs/tissues. Understanding the failure of active drugs to cause regression of cancer will depend to a significant extent upon successful delineation of this complex pharmacology.

Thus, the effectiveness of an antitumor agent is directly related to *C* × *T*, which is markedly affected by dose, schedule, and its pharmacokinetics discussed above. The sensitivities of the cancer cells, as well as, normal tissue to drugs are the variable factors, which determine the potential usefulness of a drug. Documentation of the optimal *C* × *T* is usually conducted in Phase I studies and will relate clinical responses to acceptable doses and schedules necessary to standardize drug use in humans.

 *The optimum C* × *T should kill the maximum tumor cells with minimum lethality to cells of normal tissue*.

The *C* × *T* product is also known as the area under the curve (AUC) and discussed and illustrated latter in this chapter.

#### **5. Blood brain barrier**

The chemobiodynamic relationship of a drug with the blood brain barrier (BBB) evaluated using *in vivo, in vitro*, and *in silico* (computational) models in attempt to appreciate the best design for novel anticancer agents to be used in subjects with malignant tumors involving the brain and central nervous system.

The blood brain barrier was discovered over 100 years ago by Paul Ehrlich who found that water soluble dyes stained all organs of animals except for their brains and central nervous system (CNS) [8]. Subsequently, other researchers found that Ehrlich's dye injected into the brain did not enter the blood stream and hence a barrier existed between the two compartments. These compartments could be traversed by more lipophilic substances however [9]. In general, more lipid soluble drugs can traverse the blood brain barrier by passive diffusion, while other molecules can cross the blood brain barrier (BBB) by active transport by proteins such as P-glycoprotein (P-gp) [10].

The BBB differs from normal capillaries in that it has tight junctions in the endothelial cell walls with specialized pores and junctions (formed by terminal surfaces of endothelial cells, neurons, astrocytes, etc.) that allow selective transport through the openings. The BBB is also highly electrically resistant confirming that it is very fatty and free of aqueous electrolytes [5].

To treat cancers involving the CNS, the BBB is the protective "no man's land" must be penetrated by anticancer agents. **Figure 5** depicts two modes of drug transport into the brain and intracerebral cancers. **Figure 5(a)** requires drug to penetrate *via* diffusion or a transfer pathway [12]. **Figure 5(b)** allows drugs to penetrate the CNS *via* the association with RBCs or transport through cancer-associated breaks in the BBB [11].

**Figure 5a.** Primary tumor mass involving the CNS. Drugs can only penetrate the BBB by passive diffusion or active transport.

**Figure 5b.** Breaks (leaks) in the BBB 2° to cancer cell penetration and tumor growth allow RBCs and associated drugs easily penetration into tumors growing in the brain.

#### **5.1. Calculation of Log** *P*

**5. Blood brain barrier**

brain and central nervous system.

10 New Approaches to the Management of Primary and Secondary CNS Tumors

such as P-glycoprotein (P-gp) [10].

transport through cancer-associated breaks in the BBB [11].

electrolytes [5].

transport.

The chemobiodynamic relationship of a drug with the blood brain barrier (BBB) evaluated using *in vivo, in vitro*, and *in silico* (computational) models in attempt to appreciate the best design for novel anticancer agents to be used in subjects with malignant tumors involving the

The blood brain barrier was discovered over 100 years ago by Paul Ehrlich who found that water soluble dyes stained all organs of animals except for their brains and central nervous system (CNS) [8]. Subsequently, other researchers found that Ehrlich's dye injected into the brain did not enter the blood stream and hence a barrier existed between the two compartments. These compartments could be traversed by more lipophilic substances however [9]. In general, more lipid soluble drugs can traverse the blood brain barrier by passive diffusion, while other molecules can cross the blood brain barrier (BBB) by active transport by proteins

The BBB differs from normal capillaries in that it has tight junctions in the endothelial cell walls with specialized pores and junctions (formed by terminal surfaces of endothelial cells, neurons, astrocytes, etc.) that allow selective transport through the openings. The BBB is also highly electrically resistant confirming that it is very fatty and free of aqueous

To treat cancers involving the CNS, the BBB is the protective "no man's land" must be penetrated by anticancer agents. **Figure 5** depicts two modes of drug transport into the brain and intracerebral cancers. **Figure 5(a)** requires drug to penetrate *via* diffusion or a transfer pathway [12]. **Figure 5(b)** allows drugs to penetrate the CNS *via* the association with RBCs or

**Figure 5a.** Primary tumor mass involving the CNS. Drugs can only penetrate the BBB by passive diffusion or active

Measuring or calculating log *P* is the most important molecular attribute to defining lipophilicity and the ability of the drug to diffuse across the lipophilic BBB. This is measured by dissolving the drug in octanol and then shaking with equal volumes of water. The concentration of drug is then measured in both phases and the ratio of octanol-water is calculated according to Eq. (1) [6].

$$\log P\_{\text{actual}|\text{water}} = \log \left( \left| \text{solute} \right|\_{\text{actual}} / \left| \text{solute} \right|\_{\text{water}} \right) \tag{1}$$

Since, very lipophilic compounds tend to be highly lipoprotein bound and associate/bind to lipid membranes, thus the ideal octanol-water partition coefficient for a neurotargeted drug (at pH 7.4) to diffuse from the serum into BBB into the CSF should be ≤ log *P* 5 [2, 12].

The estimation or determination of BBB permeability as log**BBB** (the concentration of drug in the brain is divided by concentration in the blood) is accomplished as follows:


$$
\log\_{\text{mass}} = \left\langle \log P - 0 / 1725 \right\rangle / 2.808. \tag{2}
$$

**Table 2** lists compounds with known brain and/or CNS activity and from their structure log *P* is calculated. From this value and Eq. (2) log**BBB** is calculated; the latter is compared to literature values in **Table 2**. The calculated and literature values are in good agreement indicating that log *P* is a good predictor of passive diffusion through the BBB. However, one must realize



**Table 2.** Calculated and structure related activities for molecules with known intracerebral activity [15].

that this is just a predictor of drug penetration across the BBB. Some drugs have higher cytotoxicity and selectivity than others and as such are active at lower concentrations than other drugs, e.g., temozolomide. Other caveats include the fact that drugs that penetrate the BBB can be "pumped out" — P-glycoprotein (GgP), thus the log *P* is not predictive that all drugs will be active [10, 15].

## **6. Clinical applications**

**Compound Structure Calculated log** *P* **Calculated logBBB Calculated BBB Actual BBB [15]**

Cis-platinum −2.83 −1 0.09 0.05–1

12 New Approaches to the Management of Primary and Secondary CNS Tumors

Cytarabine −2.77 −1 0.1 1

Pentostatin −2.35 −0.9 0.13 0.1-0.13

Temozolamide −1.9 −0.7 0.18 0.19

Cladribine −0.38 −0.2 0.64 0.25

Dacarbazine −0.35 −0.19 0.69 0.14

Melphalan −0.01 −0.06 0.86 0.01–0.1

Busulfan 0.08 −0.03 0.9 1

Topotecan 1.41 0.44 2.76 0.42

Carmustine 1.67 0.5 3.44 2.3–9

The above introductory information provides the general principles, which must be considered when designing or planning on using a drug to treat cancer involving the brain.

4-Demethyl-4-cholesteryoxycarbonylpenclomedine (DM-CHOC-PEN) [**Figure 6**] is a lipophilic cholesterol carbonate polychlorinated pyridine that is cytotoxic and penetrates the BBB, both because of its log**BBB** (**Table 2**), as well as an affinity for red blood cells (RBCs) [16–18].

#### **6.1. DM-CHOC-PEN PK Profile With Cell Cycle**

DM-CHOC-PEN's PK profile is best modeled *via* a two compartment model with ~5% being excreted unchanged in the urine [17]. The use of plasma pharmacokinetics is of great importance in considering its use. The drug has produced excellent responses in primary cancers (glioblastomas) as well as metastatic (lung, melanoma, breast) cancers involving the CNS [18]. DM-CHOC-PEN is lipophilic and penetrates the BBB, as well as transported and activated in metastatic cancers involving the CNS through a 4-tier mechanism: (1) transport per RBCs into the brain via breaks in the BBB; (2) entry into cancer cells per the l-glutamine (GLM) transfer system; (3) activation to DM-PEN (active molecule) *in situ* in the acidic microenvironment of cancer cells; and (4) *bis*-alkylation of DNA at N7 -guanine and N<sup>4</sup> -cytosine—with cellular death [11].

**Figure 6.** DM-CHOC-PEN and metabolite DMPEN.

It's a large molecule and if there are liver metastases or other hepatic disease involving the liver there can be biliary congestion resulting in reversible jaundice [17].

The pharmacokinetics of DM-CHOC-PEN's disappearance from plasma after a single intravenous dose consist of an initial phase having a *T*1/2 of 5 hours and a final phase *T*1/2 of 245 hours (**Figures 7** and **12**). The slow, final phase of DM-CHOC-PEN elimination is the reason for the single high dose schedules that are currently being employed [18].

#### **6.2. DM-CHOC-PEN Degradation**

It has been found that the hydrolysis of DM-CHOC-PEN to DM-PEN (**Figure 7**) is the principle route of degradation and elimination of the drug in animals and humans [16].

Results vary with individual patients but on a mass balance analysis 1–10% of DM-CHOC-PEN are excreted unchanged and the metabolite, DM-PEN is excreted 10–100% in the urine. **Figure 8** shows a pattern seen for 12 subjects treated once with 70–85.8 mg/m2 plasma and urine drug and metabolite levels [17].

#### **6.3. Area under the curve**

Increasing the dose of DM-CHOC-PEN increases the plasma concentration of drug and metabolites. The Cmax increased with the dose giving rise to an increase in area under the curve (AUC) (**Figure 9**). **Figures 9** and **10** combine and summarize the AUCs for DM-CHOC-PEN *vs*. time [16, 17].

#### **6.4. Distribution and elimination**

DM-CHOC-PEN follows a standard two compartment model for elimination [17].

The preclinical and Phase I trial results suggest that the brain and central nervous system is targeted, but that all tissues including cancer tumors will absorb drug [17, 19]. So the second step in decreasing DM-CHOC-PEN blood levels is drug elimination. From bioavailability kinetic studies, this has found to be about 4%. The third step of elimination is after the metabolic degradation to a more water soluble and excreted as DM-CHOC-PEN. For DM-CHOC-PEN, the drug is primarily eliminated as DMPEN in the urine, which accounts for 57% of the dose on a mass balance basis. The metabolite on average has maximal plasma concentration 14 hours after drug administration (**Figure 8**) [17, 19].

**Figure 7.** Plasma decay curve for DM-CHOC-PEN: 85.8 mg/m2 IV once.

It's a large molecule and if there are liver metastases or other hepatic disease involving the

The pharmacokinetics of DM-CHOC-PEN's disappearance from plasma after a single intravenous dose consist of an initial phase having a *T*1/2 of 5 hours and a final phase *T*1/2 of 245 hours (**Figures 7** and **12**). The slow, final phase of DM-CHOC-PEN elimination is the reason for the

It has been found that the hydrolysis of DM-CHOC-PEN to DM-PEN (**Figure 7**) is the prin-

Results vary with individual patients but on a mass balance analysis 1–10% of DM-CHOC-PEN are excreted unchanged and the metabolite, DM-PEN is excreted 10–100% in the urine.

Increasing the dose of DM-CHOC-PEN increases the plasma concentration of drug and metabolites. The Cmax increased with the dose giving rise to an increase in area under the curve (AUC) (**Figure 9**). **Figures 9** and **10** combine and summarize the AUCs for DM-CHOC-

The preclinical and Phase I trial results suggest that the brain and central nervous system is targeted, but that all tissues including cancer tumors will absorb drug [17, 19]. So the second step in decreasing DM-CHOC-PEN blood levels is drug elimination. From bioavailability

plasma and

ciple route of degradation and elimination of the drug in animals and humans [16].

**Figure 8** shows a pattern seen for 12 subjects treated once with 70–85.8 mg/m2

DM-CHOC-PEN follows a standard two compartment model for elimination [17].

liver there can be biliary congestion resulting in reversible jaundice [17].

single high dose schedules that are currently being employed [18].

**6.2. DM-CHOC-PEN Degradation**

**Figure 6.** DM-CHOC-PEN and metabolite DMPEN.

14 New Approaches to the Management of Primary and Secondary CNS Tumors

urine drug and metabolite levels [17].

**6.4. Distribution and elimination**

**6.3. Area under the curve**

PEN *vs*. time [16, 17].

**Figure 8.** DM-CHOC-PEN + DM-PEN plasma and urine levels.

**Figure 9.** AUC—1 subject–doses of 39 mg/m2, then 21 days later—55 mg/m2 .

**Figure 10.** Area under the curve (AUC) for DMCHOCPEN (decadron patients excluded) as a function of DMCHOCPEN dose.

The whole point of the above discussion is to illustrate that there are differing kinetic processes involved in drug elimination such that elimination is not linear with time. In classical pharmacokinetics, this is described as two compartment model and you know you have one when you plot Log Drug Plasma Concentration *vs*. time and you see two slopes (**Figure 12**).

Thus, from the DM-CHOC-PEN and DM-PEN study, the drug is eliminated in a two compartment model (see **Figures 11** and **12**). In addition, DM-CHOC-PEN has been identified in the CNS and tumors as DNA adducts [17, 19].

**Figure 11.** Distribution of DM-CHOC-PEN into the CNS and Cancer Cells.

The whole point of the above discussion is to illustrate that there are differing kinetic processes involved in drug elimination such that elimination is not linear with time. In classical pharmacokinetics, this is described as two compartment model and you know you have one when you plot Log Drug Plasma Concentration *vs*. time and you see two slopes

**Figure 10.** Area under the curve (AUC) for DMCHOCPEN (decadron patients excluded) as a function of DMCHOCPEN

.

**Figure 9.** AUC—1 subject–doses of 39 mg/m2, then 21 days later—55 mg/m2

16 New Approaches to the Management of Primary and Secondary CNS Tumors

(**Figure 12**).

dose.

**Figure 12.** Elimination of DM-CHOC-PEN identified as two-compartment model as log plasma concentration *vs*. time is bi-linear two slopes evident initial α or distribution phase: terminal β or elimination phase.

#### **7. Conclusion**

An attempt to review neuropharmacology and distribution of anticancer agents in the central nervous system has been made. However, actually little is known about the interactions of drugs with the various levels of the CNS. We combined drugs in neurooncology but actually know little about the neuropharmacology of any single agent. In fact, Clark's basic pharmacological questions that should have been answered for all the agents we use but have been answered in only a few cases. With the current interests in neurooncology, we may finally make some progress in the specialty—but let's do it correctly.

#### **Acknowledgements**

Supported by NCI/SBIR grants – 5R44CA85021 and 3R43CA132257.

#### **Author details**

Andrew H. Rodgers\* and Lee Roy Morgan

\*Address all correspondence to: ahrodgers@gmail.com

DEKK-TECK, Inc. New Orleans, LA, USA

#### **References**


**7. Conclusion**

**Acknowledgements**

Andrew H. Rodgers\* and Lee Roy Morgan

DEKK-TECK, Inc. New Orleans, LA, USA

\*Address all correspondence to: ahrodgers@gmail.com

**Author details**

**References**

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Phys., 17, 20–24,1974.

An attempt to review neuropharmacology and distribution of anticancer agents in the central nervous system has been made. However, actually little is known about the interactions of drugs with the various levels of the CNS. We combined drugs in neurooncology but actually know little about the neuropharmacology of any single agent. In fact, Clark's basic pharmacological questions that should have been answered for all the agents we use but have been answered in only a few cases. With the current interests in neurooncology, we may finally

[1] Morgan, L.R., Principles of Pharmacology, Practical Oncology Today. Part II. Adra Labs,

[2] Morgan, L.R. and Weatherall, T.J., "*Pharmacology and drug distribution. In: Combined Modalities. Chemotherapy/Radiotherapy*." Phillips, T.L. (ed.) Int. J. Radit. Oncol., Biol.

[3] Oliverio, V.T. and Guarino, A.M., "*Absorption, protein binding, distribution, and excretion of* 

[4] Clarke, A.J., General Pharmacology, in A. Heffter (ed.), "*Handbuch der experimentellen* 

[5] Goodman & Gilman's The Pharmacological Basis of Therapeutics, edition 11, Brunton,

[6] Schuler, F.W., Chemobiodynamics and Drug Design, McGraw-Hill Book Co. New York, 1960. [7] Germain, R., Bastian, G., Serota, D., Struck, R.F., Morgan, L.R., Isophosphoramide mustard (IPM): preclinical pharmacology and toxicology in rodents, dogs and primates.

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LL, Lazo, JS, Parker, KL, McGraw-Hill, New York, 2006,.

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make some progress in the specialty—but let's do it correctly.

18 New Approaches to the Management of Primary and Secondary CNS Tumors

Supported by NCI/SBIR grants – 5R44CA85021 and 3R43CA132257.

