1 Introduction

The aim of a safe and efficient drug therapy is to direct the agent as near as possible to its target where it generates its maximum pharmacological effect while keeping side effects at a minimum.

Contrary to effects of a drug on the organism (pharmacology), the organism itself exerts an effect on the fate of a drug in man in a time-dependent manner. This pharmacokinetic fate comprises absorption, distribution, metabolism, and complete elimination from the body (ADME).

Although these processes are rather complex and determined by various endogenous and exogenous factors, pharmacokinetic parameters for each single drug are available. Table 1.1 gives an overview for the most relevant parameters for clinical evaluation.

Table 1.1 Clinical relevant pharmacokinetic parameters [1]
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The concentration of a drug in the target organ can be increased by using special applications such as regional drug administration. By changing the actual physiological conditions of the target organ (for instance by occlusion of a blood vessel), regional administration increases the absorption rate of the chemotherapeutic agent from the blood into tumor tissue. As a consequence, blood flow is decreased through the affected organ, and tissue-extraction rate is accelerated or increased.

So regional administration combined with a temporary occlusion of the supplying vessels is a valuable therapeutic option, especially for the chemotherapeutic treatment of liver tumors and liver metastases, respectively.

2 Hepatic Blood Flow (Q hep)

The perfusion of the liver is a main factor of the regional administration. Hepatic blood flow is the sum of portal vein (1050 mL/min) and common hepatic artery (300 mL/min) blood flow. Therefore Q hep is about 1500 mL/min (≈ 90 L/h).

3 Hepatic Extraction Rate (E hep)

E hep is calculated as follows by the arterial and venous drug concentration during liver passage.

$$ {E}_{\mathrm{hep}}=\frac{{\mathrm{conc}}_{\mathrm{arterial}}-{\mathrm{conc}}_{\mathrm{venous}}}{{\mathrm{conc}}_{\mathrm{arterial}}}={\mathrm{Cl}}_{\mathrm{freedrug}}\times {\mathrm{conc}}_{\mathrm{freedrug}} $$

E hep ranges from 0.0 (=no extraction) to 1.0 (=complete extraction). An E hep of 0.8 indicates the elimination and metabolism of 80% of the drug entering the liver leaving 20% of the administered drug to exit the liver through the liver veins.

4 Hepatic Clearance (Clhep)

Clhep is defined as the volume of blood passing through the liver that is cleared from a compound per time. Hepatic clearance is based on the whole-body clearance minus the renal clearance and the mostly quantitative not relevant non-hepatic, non-renal clearance by other organs (e.g., the skin or lung). Clhep depends on the blood flow through the liver, the liver cell mass, and the activity of drug-metabolizing enzymes. It is the product of E hep and the blood flow through the organ (Q hep).

$$ {\mathrm{Cl}}_{\mathrm{hep}}={Q}_{\mathrm{hep}}\times {E}_{\mathrm{hep}} $$

Considering the hepatic extraction of a drug, its tissue penetration does not only depend on physiological conditions (as already mentioned) but also on the physicochemical properties of the molecule as well. Besides the drug there are some other factors with impact on the hepatic clearance (see Table 1.2).

Table 1.2 Factors that have an influence on E hep of a drug
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Despite their chemical heterogeneity, a number of different cytostatic agents can be used for regional intra-arterial treatment (see Table 1.3). The most important assumption for the drug is a so-called first-pass metabolism or first-pass effect. Per definition first-pass effect is the sum of all processes (distribution and metabolism) occurring during the first liver passage of a drug before the drug reaches systemic blood circulation and becomes available in the whole body. New investigational approaches represent the combination of HAI irinotecan plus 5-fluorouracil, oxaliplatin, and intravenous cetuximab or bevacizumab [2, 3].

Table 1.3 Pharmacokinetic parameters (after i.v. administration) of cytostatic agents that are suitable for intra-arterial administration due to their first-pass effect [4,5,6,7]
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By comparing the intra-arterial/intravenous AUC ratio, chemoembolization leads to a therapeutic advantage (TA), calculated as follows:

$$ \mathrm{TA}=\frac{\frac{{\mathrm{AUC}}_{\mathrm{hep}}}{{\mathrm{AUC}}_{\mathrm{blood}}}}{\frac{{\mathrm{AUC}}_{\mathrm{hep}}}{{\mathrm{AUC}}_{\mathrm{blood}}}}\frac{\mathrm{i}.\mathrm{a}.}{\mathrm{i}.\mathrm{v}.} $$

In comparison to i.v. administration, decreasing hepatic perfusion results in a higher regional distribution rate.

$$ \mathrm{RA}=1+\frac{{\mathrm{Cl}}_{\mathrm{tot}}}{Q_{\mathrm{hep}}\times \left(1-{E}_{\mathrm{hep}}\right)} $$

Regional application combines decreasing side effects and higher levels of toxicity (increased apoptosis rate) [8]. The RA gets more intense the faster the cytostatic distributes into the tissue and the higher its extraction rate from the body.

5 Pharmacokinetic Data Using Degradable Starch Microspheres (DSM)

A successful embolization can be characterized by comparing the main pharmacokinetic parameters with data obtained after conventional administration. AUClast and C max are the most suitable values for calculating the shift of the drug’s concentration from the blood to the tissue.

Depending on the chemotherapeutic agent, the administration of DSM leads to a decrease of systemic circulation from 20 to 60%. It is the most important requirement that the chemotherapeutic does not bind to DSM or red blood cells [9].

So far most of the studies concerning pharmacokinetic data of cytostatic agents after the embolization of the common hepatic artery used DSM. The findings in Table 1.4 from several studies show between 19 and 98% reductions in plasma drug concentrations. The reduced systemic drug exposure may be seen as an increased first-pass extraction during the prolonged time of the drug in the occluded target area. The higher first-pass extraction of the drug in the target compartment will lead to a lower dose of drug reaching the systemic circulation and subsequently to fewer side effects [10, 11]. Besides the chemotherapeutics given in Table 1.4, one of the most currently irinotecan is administered intra-arterial after chemoembolization as well [12]. Irinotecan (CPT-11) is a pro-drug and needs to be activated in the body. The drug shows poor affinity to the responsible enzyme (human carboxy esterase), therefore only small amounts of the pharmacologic active metabolite SN-38 are formed (about 10% of the parent compound). This activation can be improved by regional administration to the liver leading to higher amounts of SN-38 in the blood and tissue.

Table 1.4 Mean reduction of plasma AUC in patients with HCC using DSM
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Numerous investigations characterized the combination of mitomycin C (MMC) with different amount of DSM. The AUC ratio is relatively consistent from 0.55 to 0.80 as can be seen in Table 1.5. Administration of 60 mg DSM did not show any effect, obviously this amount was too low for any occlusion of blood vessels.

Table 1.5 Average AUC ratio, measured as peripheral plasma AUC of MMC with and without DSM in patients with HCC
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More data about the distribution of other cytostatic agents into tumor and healthy tissue using DSM in animals and patients are in Tables 1.6 and 1.7. Table 1.6 gives an overview of experimental findings in animals.

Table 1.6 Ratio of cytostatic drugs in tumor and healthy liver tissue (with and without DSM) in vivo (rat, rabbit)
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Table 1.7 Mean ratio of drug concentration in tumor and healthy liver tissue (with and without DSM) in patients with secondary liver cancer or oral cancer
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Table 1.7 presents data of human biopsy samples indicating that DSM leads to an increased uptake of drug into tumor tissue. Intra-arterial application of DSM and a cytotoxic drug leads to an increased drug concentration in the tumor compartment as well as DSM-induced increase of tumor versus normal tissue drug concentration ratio.

6 Further Chemoembolization Tools

Besides DSM other materials for chemoembolization have been developed recently. In transarterial chemoembolization (TACE) DSM, polyvinyl alcohol polymers, Gelfoam, and gelatin-based microspheres (Embosphere) are used to keep systemic circulation of a chemotherapeutic at a minimum. Polyvinyl alcohol polymers and superadsorbent polymer microspheres (SAP, HepaSphere®, QuadraSphere®) can be loaded with a compound to become drug-eluting beads (DEB, DEBDOX, DEBIRI). In the following Tables 1.8, 1.9, 1.10, and 1.11, various agents used for chemoembolization and their effect on maximum plasma concentrations of antineoplastic drugs as well as corresponding tumor concentrations and tumor/liver ratios in animals and patients are listed.

Table 1.8 Effects of different permanent embolization materials on maximum plasma concentrations in animals
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Table 1.9 Effects of different permanent embolization materials on concentration in tumor tissue and on tumor/liver ratios in animals
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Table 1.10 Effects of different permanent embolization materials on maximum plasma concentrations in patients
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Table 1.11 Effects of different permanent embolization materials on concentration in tumor tissue and on tumor/liver ratios in patients
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Combination of DSM or other occlusion agents and chemotherapy i.a. reduced systemic exposure to chemotherapy in animals and patients manifested not only in pharmacokinetic parameters but also in reduced hematological toxicity [10]. Comparative pharmacokinetic studies between various occlusion agents still need to be investigated in further studies. In conclusion, chemoembolization with DSM and other agents is a valuable therapeutic option in palliative and neo-adjuvant medicine as evident in the following chapters.

HAI administration of superparamagnetic nanoparticles makes it possible to visualize the distribution mechanism from the blood to the liver by magnetic resonance imaging. Besides, these particles are capable of drug targeting as a drug carrier [45]. The role of Kupffer cells in drug distribution into the liver has been discussed recently [46].

Another alternative chemotherapy strategy comprises HAI plus chemoembolization plus administration of liposomal drug preparations. This has been investigated for paclitaxel [47] and fluorouracil [26] in tumor-bearing rats.

The advantage of transarterial chemoembolization (TACE) combined with drug-eluting beads (DEB) versus conventional TACE treatment has been discussed to show a lower associated toxicity, due to reduced systemic drug circulation [48].