WO2001058490A1

WO2001058490A1 - Liver-selective chemotherapy

Info

Publication number: WO2001058490A1
Application number: PCT/AU2001/000105
Authority: WO
Inventors: Howard J. Smith
Original assignee: Howard J. Smith & Associates Pty Ltd
Priority date: 2000-02-07
Filing date: 2001-02-07
Publication date: 2001-08-16
Also published as: AUPQ547100A0

Abstract

A method of treatment or prophylaxis of liver cancer comprising orally administering to a patient in need thereof a slow-release formulation of a chemotherapeutic providing a slow rate of release within the gastrointestinal tract, said dose rate being sufficient to provide a clinically effective level in the portal vein and less than required to provide a clinically effective blood level in the peripheral circulation to thereby provide a dose-delivery rate having a selective clinical effect in the liver.

Description

Liver-Selective Chemotherapy

The present invention relates to a method of drug treatment where the liver is the primary therapeutic target, and in particular to a method of administering chemotherapeutic drugs (anticancer drugs) that is selective for the liver and thereby minimizes systemic side effects of those drugs

The invention applies to the treatment of primary cancer of the liver and metastatic carcinoma (cancer) that has spread to the liver from the colon, stomach, pancreas, or other organs, or when the primary disease is at risk of spreading to the liver In particular, the invention applies to drugs that may be administered orally for treatment of these cancers

The treatment of cancer begins where possible with surgical resection of a primary lesion in order to relieve symptoms produced by the functional and/or space occupying properties of the tumour Early surgery also minimises the chance of spread to other tissues either by direct invasion or by metastasis through the blood vascular system or lymphatic system Although surgical resection of secondary deposits (metastases) is sometimes practical in specific types of tumour, the treatment of these usually involves radiotherapy or chemotherapy The application of the present invention for liver-selective treatment for liver metastases applies only to chemotherapy defined as administration of drugs that will kill or limit the growth of cancer cells

The range of established chemotherapy or of novel therapy in development for use in the clinical practice of cancer medicine, includes -

• cytotoxic drugs acting to kill cancer cells selectively, including antimetabo tes, antitumour antibiotics, heavy metal analogues alkylating agents, and other agents including natural products • cytostatic drugs that put a cell into a phase of suspended growth

• drugs acting to inhibit natural growth factors including sex hormones and other agents such as epidermal growth factor (EGF)

• drugs interfering with the vascular supply of tumours to induce ischaemia and/or infarction of the tumours • inducers of apoptosis • direct inhibitors of metastasis by interference with cell movement

• immune response activators

• drugs acting to sensitise tumours to radiotherapy

Because it is the purpose of chemotherapy to kill cancer cells or interfere in a major way with their function, it is usually inevitable that normal noncancerous cells within the rest of the body will also be affected by the treatment For these reasons, almost all patients receiving chemotherapy will experience side effects The nature of systemic side effects is generally related to the specific pharmacology or mode of action of a drug More dramatic but common side effects include hair loss bone marrow depression, gastrointestinal effects (including nausea, diarrhoea, and haemorrhage) immune suppression with a resultant susceptibility to infection, weight loss, fatigue and general disability Drugs that inhibit the action of growth factors are usually better tolerated, but according to their action, may interfere with sexual function, blood and lymph cells, and other tissues including skin and cornea The pressure to develop drugs with better patient tolerance, and therefore greater chance of compliance and therapeutic result, has generally been directed towards a selectivity toward the cancer cell so that a chemotherapeutic effect can be achieved with minimal disruption of other cells

Many anticancer drugs are administered parenterally However patient preference is for drugs that may be administered orally This route of administration also has important cost efficacy advantages since multiple and prolonged out patient attendance and hospital admission may be minimised

Carcinoma of the colon (bowel cancer) is a common malignancy in western countries In the USA, more than 155,000 cancers are diagnosed every year, representing 15% of all cancers Early diagnosis often permits a total cure by surgical treatment with minimal morbidity and mortality August, Otto, and Sugarbaker (1984) reported that in 100 patients presenting with large bowel cancer, 45 had a total cure after primary resection However, 30 had advanced cancer at presentation, and another 25 had recurrent disease after surgery Earlier diagnosis and new drugs should reduce both mortality and morbidity, but the disease still imposes a significant health burden on society.

Carcinomas of the stomach and of the pancreas are also common diseases with a pattern of metastasis similar to that of bowel cancer, but frequently with more aggressive morbidity.

Cancer cells from primary tumours within the bowel, stomach or pancreas usually spread by blood and/or lymphatic metastasis. The venous blood drainage from the stomach, colon, upper rectum, and pancreas flows into the portal circulation and thence to the liver. For this reason, the liver is the most common site of first metastasis of cancers arising in these organs. By contrast veins from the distal rectum drain via the middle and inferior haemorrhoidal veins to the inferior vena cava. Metastases from the distal rectum more frequently present in the lung.

Cancers in the colon and other organs may also spread through the lymphatic vessels draining the bowel. Extramural lymphatic vessels converge towards lymph nodes contiguous to the mesenteric arteries and ultimately to the para- aortic chain. For these reasons, surgical resection of lymphatic nodes is frequently performed at the same time as the resection of the primary tumour.

In this invention, we provide a method of treatment of metastases of the liver where the anticancer drug (chemotherapy drug) is directed selectively towards the liver to kill, or suppress activity in, cancer cells within the liver, but at the same time spare the rest of the body from the otherwise inevitable side effects of the treatment.

Accordingly we provide a method of treatment or prophylaxis of liver cancer comprising orally administering to a patient in need thereof, a slow release formulation of a chemotherapeutic providing a slow rate of release within the gastrointestinal tract, said dose rate being sufficient to provide a clinically effective level in the portal vein and less than required to provide a clinically effective blood level in the peripheral circulation, to thereby provide a dose- delivery rate having a selective clinical effect in the liver.

The slow-release formulation may contain an anticancer drug known to be active against the primary tumour, and itself metabolised by the liver. In this way clinically effective blood levels of the anticancer drug will be achieved in blood reaching the liver through the portal venous system, but not in the peripheral blood circulation.

A further component of the invention is the use of liver-selective chemotherapy as adjuvant therapy in patients who have no demonstrable hepatic metastasis, but in whom there is a substantial risk of such because of the nature of the primary tumour albeit now resected. Diagnosis of metastases anywhere in the body requires that they have sufficient mass to be detected as a space- occupying lesions. Since a mass of 1cm³ (about 1 gram) will have as many as 10⁸ cells, therapy is used in many areas of cancer therapy to suppress and hopefully kill smaller numbers of cancer cells that are not individually detectable. This form of treatment, known as adjuvant treatment, is particularly applicable to the present invention of liver-selective chemotherapy.

Preferred compounds are any anticancer drug that is active against colon cancer (or other intra abdominal tumors), administered by mouth, and is itself metabolised by the liver. Preferred compounds will be absorbed from all, or almost all of the bowel, and have a short half-life on account of metabolism by the liver. It is likely that such a compound will be lipophilic.

The clinically effective oral dose of an anticancer drug is defined by the ability of the drug to control or kill cancer and is correlated with the systemic concentration of that drug as measured in samples of peripheral blood. By definition, the effective dose for a liver-selective formulation of any drug including a liver-selective formulation of a chemotherapeutic agent is the dose that produces therapeutic concentrations of the drug in the portal circulation but not in the systemic circulation. It follows that the effective dose for a liver- selective formulation must always be less than the dose used to produce therapeutic concentrations of the drug in the systemic circulation A slow release formulation of one fifth to one tenth of the systemic oral dose of such an orally-administered anticancer drug will typically achieve effective plasma concentration within the liver without exposing the rest of the body to clinically important concentrations of the drug The relative dose of one fifth to one tenth of the systemic dose is a function of the relative volumes of the portal and systemic circulations

The chemotherapeutic drug may be any drug selected for treatment of primary or metastatic cancer within the liver Examples of such drugs may include cytotoxic drugs including antimetabolites, antitumor antibiotics heavy metal analogues and alkylating agents, cytostatic drugs, growth factor inhibiting drugs, drugs interfering with vascular supply apoptosis mducers, immune response activators, and radiotherapy sensitisers For many of these agents, the optimum dose required to achieve therapeutic concentrations in the systemic circulation remains to be determined by clinical trial However in each case, the dose required for a liver-selective formulation will be less than the systemic dose, and usually one fifth to one tenth of that dose, since the ratio is determined by the relative volume of the portal and systemic circulations

Examples of preferred compounds include analogues of 5 fluorouracil such as capecitabine, a chemotherapeutic agent approved for the treatment of both metastatic breast cancer and colon cancer Current recommended practice (US Prescribing Information 1999) is to administer capecitabine orally in systemic doses of 2500 mg/m²/day to achieve clinically effective plasma concentrations in the systemic circulation It is a key feature of the present invention that formulation of capecitabine in a slow-release formulation at one tenth to one fifth of the systemic dose, that is, 100 - 500 mg/m²/day will achieve effective plasma concentrations within the liver, but without exposing the rest of the body to clinically important concentrations of the drug

Other examples of orally-administered drugs suitable for presentation as a low- dose, slow-release formulation to achieve a clinically useful and liver-selective chemotherapeutic effect include any other analogue or prodrug of 5 fluorouracil that may be administered by mouth, taxotere, navelbine. inhibitors of tyrosine kinase selective for EGF (epidermal growth factor), or any other chemotherapeutic agent administered by mouth for treatment of gastrointestinal cancer.

Formulations that release the anticancer agent slowly over 24 hours (permitting once-a-day administration by mouth) or over 12 hours (permitting twice-a-day administration by mouth) will exert their effect on the cancer metastasis without the need to expose the peripheral circulation to active levels of the drug. The release characteristics of the slow-release formulation will provide a daily dosage of the anticancer drug at doses between one tenth to one fifth of the dose of the drug when used in full clinical or systemic doses as a conventional formulation.

The most preferred anticancer agents for use in the invention are those with a short half-life, where the short half-life is a function of metabolism by the liver. This is contrary to the discipline of drug development, which has, where possible, selected agents with longer half-lives to allow a once a day administration. In the present invention, the slow-release formulation enables a continuous low dose to be delivered to the liver and achieve therapeutic levels within the liver, without reaching clinically significant levels in the peripheral circulation.

In a further component of the first aspect of this invention, the concept of liver- selective chemotherapy also applies to primary tumours of the liver, and to any other cancer where the liver is the primary site of metastasis. Such tumours may include rare tumours of the small bowel and related malignancies.

The therapeutic agent for use as a low-dose, slow-release drug intended to have a liver-selective effect as an anticancer agent inhibitor may be formulated as a slow-release composition for oral administration using known or novel control agents and adjuvants. For example, slow-release polymer systems such as enteric polymers or cellulose derivatives may be used in a single layer or multilayer slow-release pellet formulation. Other slow-release formulations, for example, in the form of powders, syrups, tablets, capsules or emulsions may also be used.

Accordingly, in a further aspect the invention provides a pharmaceutical composition for liver-selective therapy including treatment or prophylaxis of metastatic cancer comprising an active therapeutic agent and slow-release polymer components.

The principle of liver-selective delivery of drugs can be illustrated in two ways:

1. Mathematical Analysis of Kinetic Theory

Consider a drug administered by mouth as a slow-release formulation to achieve steady state release into the bowel with uptake into the portal venous circulation. The drug is then partly metabolised by the liver.

Let the volume of blood passing through the portal circulation in unit time = V_P litres.

Let the total volume of the systemic circulation = V_s litres.

Let the concentration of drug in the portal vein = C_P mg/litre. Let the concentration of drug in the systemic circulation = Cs mg/litre.

Drug absorbed from the Gl tract in unit time - D_A mg.

Drug metabolised by the liver in unit time = D_M mg

Drug not metabolised by the liver in unit time = D_A - D_M mg = D_NM mg

Let the metabolic clearance = M This must range from 0 (no clearance) to 1.0 (total clearance).

Then Cp is determined by the amount of drug absorbed into the finite V_P plus the concentration in the drug recirculated.

i.e., D_A = V_P (C_P - C_s ) equation. 1

Drug metabolised is a function of clearance rate, portal venous concentration and portal volume per unit time.

D_M = M x Cp x V_P equation. 2 Systemic concentration of drug is determined by the volume of the systemic circulation and the amount of drug not metabolised

Cs = D M / V_s i e , D_NM = Cs x Vs equation 3

By definition, D_A = D_M + D_NM

Substituting equations 1 ,2, and 3,

V_P (C_P - Cs ) = M x Cp x V_P + Cs x Vs and Cp [V_P (1 - M)] = C_s (V_s + V_P ) such that Cp / Cs = (V_s + V_P ) / V_P (1 - M)

This relationship may be interpreted in the following way

1 When there is no metabolic clearance of a drug by the liver, (M = 0), the concentration gradient between portal and systemic vessels during steady state release of a drug from a slow-release formulation is a function of their relative volumes of the two circulations C_P / Cs = (V_s + V_P ) / V_P

2 With total hepatic clearance, M = 1 , and Cp / C_s tends towards infinity

3 If the rate of metabolism by the liver saturates, M will decline at higher dose levels Therefore liver selectivity will be greater at lower dose levels, and be maximal when there is no effective saturation of metabolism

4 Portal venous flow does vary Therefore Cp / Cs will be higher under low- flow conditions, for example in cirrhosis, but be low in high-flow situations such as when there is an abnormal shunting of blood perhaps through fistulae

The invention will now be described with reference to the following examples It is to be understood that the examples are provided by way of illustration of the invention and that they are in no way limiting to the scope of the invention 2. Exemplification of the Kinetic Principle of Liver-Selective Therapy

One of the most studied drugs with respect to pharmacokinetic theory is the beta-ad renergic antagonist (beta-blocker) propranolol This agent is well absorbed from the bowel into the blood stream but is then metabolized by the liver so that the drug has a relatively short half-life The presentation of propranolol as a low-dose, slow-release formulation to create a liver-selective formulation is disclosed in our copending International Application PCT/AU00/01337 While propranolol is not a chemotherapeutic drug, the kinetic handling when presented in this way illustrates the principles of liver- selective therapy, and applies to any agent with similar kinetic properties including chemotherapeutic drugs

Until recently, the majority of chemotherapeutic agents used to treat primary or metastatic cancer in the liver have been administered parenterally usually by intravenous injection or infusion The present invention does not apply to drugs of this class However, the trend in drug development is to search for agents that can be administered by mouth These present cost advantages to health care because hospita zation and outpatient care, which are usually required for parenteral treatment, can be avoided, a patient can take medication at home

The present invention applies to any form of oral chemotherapeutic therapy used to treat or prevent primary or metastatic cancer or other tumour including metastatic cancer of the colon or other intra-abdominal organ

Melphalan is an older drug that can be used to treat myeloma, ovarian adenocarcinoma and advanced breast cancer The drug is frequently administered intravenously, but may also be given orally While the gastrointestinal absorption is variable, and maybe poor in the dog, the kinetic handling of melphalan with hepatic metabolism and its similarities to propranolol are sufficient to illustrate the principles of liver selectivity

Experiments were undertaken in five dogs under general anaesthesia induced with halothane and then maintained with ketamine and xylazme In four dogs, propranolol was administered by mouth on the evening before, and then again one hour before the study as a dose of 40mg in granules taken from a 160 mg slow-release formulation of propranolol (Cardinol, Pacific Pharmaceuticals New Zealand) In one further dog melphalan was administered by infusion into duodenum to simulate the release of drug from a slow-release formulation 50 mg melphalan was suspended in 120 ml saline and administered over one hour as 10 ml aliquots at 5 minute intervals

In all animals, cardiovascular status was monitored by measurement of heart rate and blood pressure and by measurement of arterial blood gases Ventilation was assisted to maintain blood gases within physiological limits A catheter was placed in the femoral artery to permit sampling of arterial blood After laparotomy, a catheter was placed in a mesenteπc vein and advanced to the portal vein to permit sampling of portal venous blood samples

Paired blood samples were then taken from systemic artery and femoral vein at baseline and then at 30 minute intervals up to 120 or 150 minutes for measurement of the blood concentration of propranolol (4 dogs) or melphalan (1 dog) The animals were sacrificed at the end of the experiment Results are displayed in the Table Propranolol ( ug/ml) Melphalan (ug/ml)

Dog 1 Dog 2 Dog 3 Dog 4 Dog 5

Portal Vein

Baseline <5 28 8 21 36 0 12

30 mm 1 1 5 1 1 8 13 2 0 23

60 mm 5 8 10 9 10 6 0 33

90 mm 22 14 4 10 5 0 22

120 mm <5 13 4 0 18

150 mm 0 13

180 mm 0 09

Systemic Baseline <5 <5 3 <2 0 08 30 mm <5 <5 2 <2 0 13 60 mm 6 2 <5 2 <2 0 17 90 mm 5 8 <5 2 <2 0 15 120 mm <5 2 <2 0 13 150 mm 0 1 180 mm 0 09 In this series in dogs, the data indicate concentration gradients between portal and systemic vessels sufficient to provide liver-selective therapy. It is likely that the concentration gradients for these and similar drugs will be greater in patients compared with those in anaesthetized dogs because of the known vasodilator effect of anaesthetic agents on the portal and splenic circulations in the dog.

While the measured blood levels of melphalan were low, consistent with poor absorption or metabolism of the drug within the gut wall, there was still a significant ratio of concentration from portal vein to systemic circulation while the drug was being infused into the duodenum. This is consistent with liver- selective delivery of the drug, and would be expected to be sustained when the drug was being administered as a slow-release formulation.

It is to be understood that the invention herein above is susceptible to variations, modifications, and/or additions other than those specifically described and that the invention includes all such variations, modifications and/or additions which fall within the spirit or scope of the above description.

Claims

Claims:

1. A method of treatment or prophylaxis of liver cancer compπsing orally administering to a patient in need thereof a slow-release formulation of a chemotherapeutic providing a slow rate of release within the gastrointestinal tract, said dose rate being sufficient to provide a clinically effective level in the portal vein and less than required to provide a clinically effective blood level in the peripheral circulation to thereby provide a dose-delivery rate having a selective clinical effect in the liver.

2. A method according to claim 1 wherein the chemotherapeutic pharmaceutical is administered in a low dose of a slow-release formulation to provide a clinically effective level in the portal vein and wherein the dose- delivery rate is less than required to provide a clinically effective blood level in the peripheral circulation.

3. A method according to claim 1 wherein said pharmaceutical is selected from the group consisting of:- cytotoxic drugs, including antimetabolites, antitumour antibiotics, heavy metal analogues, alkylating agents, and other agents including natural products; cytostatic drugs; drugs acting to inhibit natural growth factors including sex hormones and other agents such as epidermal growth factor (EGF); drugs interfering with the vascular supply of tumours to induce ischaemia and/or infarction of the tumours; inducers of apoptosis; direct inhibitors of metastasis; immune response activators; drugs acting to sensitise tumours to radiotherapy

4. A method according to claim 1 where the drug is to be administered to a patient suffering from primary or metastatic cancer of the liver including metastatic cancer of the colon or other intra-abdominal organ. 5 A method according to claim 1 where the drug is administered to a patient as adjuvant treatment for prevention of metastatic cancer of the liver including metastatic cancer of the colon or other mtra-abdominal organ

6 A method of treatment of a patient suffering from primary or metastatic cancer of the liver comprising administering orally to the patient a slow-release formulation of a chemotherapeutic to provide dose-delivery rate sufficient to provide a chemotherapeutic or anticancer effect in the liver but not in elsewhere in the body

7 A method of treatment of a patient with adjuvant treatment to prevent metastatic cancer of the liver compπsing administering orally to the patient a slow-release formulation of a chemotherapeutic to provide a dose-delivery rate sufficient to provide a chemotherapeutic effect in the liver but not in elsewhere in the body

8 A method according to claim 1 wherein the chemotherapeutic is administered at a dose rate in the range of one fifth to one tenth of that required to provide clinically effective systemic levels of the drug

9 A method according to claim 1 wherein the chemotherapeutic is selected from the group consisting of 5-fluorouracιl and its analogues capecitabine melphalan, taxotere, navelbine, and inhibitors of typrosme kenase selective for epidermal growth factor

10 A method according to claim 1 wherein the chemotherapeutic is capecitabine and is administered at a dose of from 100 to 500 mg per square metre of body surface of the patient per day