WO2008060466A2

WO2008060466A2 - Individualized dosage determination for local administration of therapeutic particles

Info

Publication number: WO2008060466A2
Application number: PCT/US2007/023646
Authority: WO
Inventors: Kai Pinkernell
Original assignee: Cytori Therapeutics, Inc.
Priority date: 2006-11-10
Filing date: 2007-11-09
Publication date: 2008-05-22
Also published as: WO2008060466A3

Abstract

The invention provides methods for intersubject conversion of established dosages of particles, e.g., cells or microparticles, for injection into an affected tissue, e.g., heart, liver, or cancerous tissue. Using these methods, the conversion can be individualized based on the amount of affected tissue in a particular subject.

Description

PATENT CYTH.025VPC

INDIVIDUALIZED DOSAGE DETERMINATION FOR LOCAL ADMINISTRATION OF

THERAPEUTIC PARTICLES

FIELD OF THE INVENTION

[0001] The present invention relates to the field of medicine, specifically to methods for intersubject conversion of established dosages of particles for local injection.

BACKGROUND OF THE INVENTION

[0002] Particulate agents, e.g., therapeutic cell compositions or intratumorally injected drug-carrying particles, are not distributed to other parts of the body in the same manner as are solubilized drugs that are introduced either locally or systemically. In part, the larger size of the particulate agent inhibits movement of the agent through the tissue and into the bloodstream. Distribution of cellular agents is further affected by interactions between the cells' membranes and molecules in the injected tissue.

[0003] Typically, doses of agents for local injection have been established based on measurement of various parameters in test subjects, e.g. pigs, and the doses converted or adjusted for administration to other subjects, e.g., human patients. This intersubject dose conversion or adjustment is commonly made by calculating the dose per unit, of body weight or surface area, of the test subject and multiplying the dose per unit by the total units body weight or surface area of the subject or patient to be treated. For a typical body weight-based conversion, a mg/kg drug dose determined to be safe in test subjects is multiplied by the weight in kg of another subject, e.g., a human patient, to determine the total dosage. This approach has proven useful for systemic delivery, where distribution to all parts of the body is assumed. A weight-based conversion, however, is unlikely to accurately yield the best dosage for localized treatment with an agent that is dispersed in only a limited manner.

|0004] One shortcoming of converting dosages for local treatment based on total body weight is that the difference in total body weight between subjects does not necessarily directly correspond to the difference in the size of a specific treatment compartment or organ. To illustrate, using the body weight adjustment, a 70 kg human could receive twice (2X) the dosage determined for a 35 kg pig. However, the human heart and the treatment area within it are likely not two-fold greater than those in the pig heart. Furthermore, body weight can be very different among patients, while the differences in their heart size, or more specifically, the difference in the volume of their affected tissue (e.g., the amount of ischemic tissue resulting from a heart attack), is not proportional to the difference in the patients' body weight. When body weight is used as a conversion factor, the heavier the patient is, the higher the dose will be. Therefore, if the treatment area is defined as the heart, and the conversion is based on the difference in heart weight (rather than body weight), then the adjustment using the 35 kg pig mentioned above (having a heart that weighs, e.g., 175 grams) and the 70 kg human (having a heart that weighs 250 grams), would instead be less than 1.5X. The additional 25% dosage (resulting from the difference between adjustments of 2X and 1.5X) determined for the human based on body weight comparison could^" sufficient to cause fatality. This disparity becomes even more pronounced in an example wherein the human patient weighs more than 70 kg but has the same 250 g heart weight. For example, a patient weighing 105 kg and having a 250 gram heart would receive over twice the dose (i.e., 3X the pig dose) that he would get if the conversion were based on heart weight (1.4X the pig dose).

[0005] Interspecies or intersubject conversion based on the estimated mass or volume of the target organ or tissue can provide a more accurate means of determining the equivalent dosage. Measuring an organ or tissue without physically removing it from the subject requires the use of diagnostic methods, e.g., MRl or SPECT, that can necessitate transportation of the patient to the equipment. If only part of the organ is affected, then treating based on whole organ size might also result in dosing disparities. There is currently no method to individualize a local injection dosage of particles based on the amount of affected tissue.

SUMMARY OF THE INVENTION

[0006] The present invention relates to methods for individualized intersubject conversion of dosages of particulate therapeutic agents, e.g., cell therapy agents or drug-carrying microparticles, for local injection into specific tissues to be treated. In the methods of the invention, a conversion factor is calculated by determining the established dosage per unit amount of a target tissue. [0007] Specifically, the present invention relates to a method for converting an established dosage of a particulate therapeutic agent for administration by local injection, to a dosage of the therapeutic agent for use in a patient, said method comprising multiplying the established dosage expressed per unit amount of treated tissue, by the unit amount of the patient's tissue to be treated. In embodiments, the treated tissue and patient's tissue to be treated comprise damaged tissue, e.g., ischemic tissue. In other embodiments, the treated tissue and patient's tissue to be treated are tumor tissues. In yet other embodiments, the treated tissue and patient's tissue to be treated is organ tissue. Treatment of organ tissues including, but not limited to, heart, brain, kidney, lung or liver are contemplated.

[0008] Patients treated using the methods of the invention include human patients. In embodiments of the invention, the established dosage was determined in a porcine subject. In certain embodiments, the patient is a human and the established dosage was determined in a porcine subject.

[0009] The methods of the invention contemplate the use of a therapeutic agent comprising an agent used for treating cancer. Also contemplated are methods wherein the therapeutic agent comprises an agent used for treating enzyme deficiencies. Additionally contemplated are methods wherein the therapeutic agent comprises an agent used for treating a patient having a cardiac disorder, e.g., acute myocardial infarction or chronic myocardial ischemia. The therapeutic agent used in the methods of the invention can be comprised of cells, e.g., adipose derived regenerative cells.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to methods for individualized intersubject conversion of dosages of particulate therapeutic agents, e.g., cell therapy agents or drug-carrying microparticles, for local injection into specific tissues to be treated. Specifically, a conversion factor is calculated by determining the established dosage per unit amount of a target tissue. For example, if a cell therapy dosage for treating ischemic tissue in the heart were selected in an animal having 20 ml of ischemic tissue, then the dosage would be divided by 20 to yield the dosage per ml. The dosage per ml can be used as a conversion factor to determine the individualized dosage for a second subject based on the amount of ischemic tissue targeted for treatment in the second subject. Thus, the methods of the invention can yield dosages that take into account the amount of a patient's affected tissue, rather than the total size of the patient as typically represented by body weight or body surface area. These methods allow localized dosages to be adjusted individually, potentially reducing toxicity effects as well as waste.

[0011] Dosages can be established as desired. For example, dosages can be selected based on data obtained relating to safety, efficacy, distribution of the agent to the target tissue and to other parts of the body, and retention of the agent within the target tissue. Evaluation of dosages can be made according to methods described in the literature and known to those of skill in the art. The established dosage can be determined using, for example, a test subject, e.g., an animal model, or it can be derived from human patient treatment data.

[0012] Expressing the established dosage of the therapeutic agent per unit amount of treated tissue allows the dosage to be converted easily. The amount units can be, e.g., volume units including ml or cm3, or weight units, including grams. The dosage per unit amount is then used as a conversion factor by multiplying it by the total number of volume or mass units of tissue to be treated in the patient. This yields a total dosage for administration to the patient. 1. Indications

[0013] Tissues treated with doses of particulate agents converted using the methods of the present invention include injured tissue, e.g., ischemic tissue or scarred tissue.

[0014] Tissue can become ischemic due, e.g., to constriction, or partial or full occlusion of blood vessels. Occlusion can be caused by a variety of factors, including blood clots, peripheral artery diseases, tumor growth, loosening of atherosclerotic plaques, low blood pressure, trauma, sickle cell anemia, etc. The heart, kidneys, and brain are particularly sensitive to inadequate blood supply. Local treatment can also be of relevance in the lungs and liver.

[0015] The dosage conversion methods of the present invention can be used to determine dosages for use in any localized tissue requiring treatment. For example, organs affected by lack of expression of a certain protein due to genetic disease or illness can be treated with locally administered gene therapy agents. Those gene therapy agents can include but are not limited to DNA (delivered either "naked" or via a vector like an adenovirus), RNA and others. In addition, therapeutic agents like proteins, antibodies, antibody fragments, pharmaceuticals and radiation sensitization agents can be administered using the same methods described herein.

[0016] Conversion of dosages of drugs for treatment of tissues affected by cancer, e.g., solid tumor tissue, is also contemplated. Examples of solid tumor tissues treatable by doses converted using the methods of the present invention include lung, liver, kidney, brain, pancreas, breast, colon, laryngeal, ovarian, etc.

II. Particulate Therapeutic Agents

[0017] Particulate therapeutic agents include, e.g., cells used for therapies, microparticles containing or displaying drugs or biological agents, including microparticles targeted to specific tissues, and engineered viruses. Particles for which the methods of the invention will be very useful are particles wherein toxic effects have been observed or might be expected when the particles are not delivered locally, particles that show better bioavailability when administered locally, and systemically-delivered particles that do not have the ability to home to a target tissue.

[0018] For example, bone-marrow-derived cells have been used for local treatment of ischemic heart disease, as described by, e.g.: Silva, et al., 2005, in Circulation 1 1 1 : 150-156; Briguori, et al., 2006 The American Heart Journal 151(3):674-80; Dib, N., 2005, "Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy," results from the Phase I study, presented at the Amer. Coll. Cardiology Annual Scientific Press Conf., Orlando, FL; Fuchs, et al., 2003, "Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study," J. Amer. Coll. Cardiology 41(10): 1721 -1724; Herreros, et al., 2003, "Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction," Eur. Heart J. 24:2012-2020, and; Klein, et al., 2004, "Autologous bone marrow-derived stem cell therapy in combination with TMLR. A novel therapeutic option for endstage coronary heart disease: report on 2 cases," Heart Surg. Forum 7(5):E416-419.

[0019] Other considerations in determining whether the methods of the invention would be useful in conjunction with a particulate therapeutic agent are the size and shape of the particles, and the surface molecules present on the particles. In general, larger particles are expected to travel at lower rates, and for shorter distances, than are smaller particles. Particles, including cells, having surface molecules that can interact with, e.g., matrix moieties, can be slowed in their migration through tissue relative to particles that tend not to interact with environmental structures. Differences in the type of tissue can also play a role in particle migration.

III. Administration of Particulate Therapeutic Agents

[0020] Administration of particulate therapeutic agents can be performed by a number of methods known in the art, e.g., single or multiple injections, and injections made at regular or irregular intervals over a period of time. For example, in studies of cell therapy for chronic myocardial ischemia, administration of total cell dosages divided into 10 to 20 injections has been reported. The number of injections made can depend on the total amount of tissue to be treated, the dimensions of the treatment area, the health status of the patient, etc., as determined by the clinician.

[0021] Injection can be made using instruments known in the art, e.g., the NOGA Myostar injection catheter. Use of the NOGA injection catheter is described, e.g., by Perin, et al., 2003, "Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure," Circulation 107:2294-2302. IV. Patients

[0022] The invention contemplates treatment of patients including human patients. The term patient as used in the present application refers to all different types of mammals including humans and the present invention is effective with respect to all such mammals.

Modes of Carrying out the Invention

[0023] It is to be understood that this invention is not limited to particular formulations or process parameters, as these may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting. Further, it is understood that a number of methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. I. Measuring Target Tissue Volume

[0024] Target tissue can be measured according to methods commonly used by those of skill in the art. For example, computed tomography (CT) imaging methods have been described and used to visualize myocardial infarction damage, determine tumor volume, diagnose hemorrhaging, and to detect changes in the lung parenchyma. (See, e.g., U.S. Pat. Appl. Pub. No. 2006/0122500, "Imaging Method and Apparatus for Visualizing Coronary Heart Diseases, in Particular Instances of Myocardial Infarction Damage," and U.S. Pat. No. 4,856,528, "Tumor Volume Determination.") Other methods that can be used include, e.g., magnetic resonance imaging, single photon emission tomography (SPECT), 2D and 3D ultrasonography, and digital substraction radiography.

[0025] SPECT can be used to measure total tissue volume and ischemic tissue volume with, e.g., 99mTc-SestaMIBl (Cardiolite®, DuPont) or 99mTc-tetrofosmin (Myoview™, GE Healthcare).

[0026] With regard to cardiac indications, left ventricular mass has been discussed in the literature, e.g., by Celentano, et al., 2001 , "Inappropriate Left Ventricular Mass in Normotensive and Hypertensive Patients, Am. J. Cardiol. 87:361-363 and by Kaufmann, et al., 1996, "Coronary Artery

Dimensions in Primary and Secondary Left Ventricular Hypertrophy," J. Am. Coll. Cardiol. 28:745-

750.

1. Calculation

[0027] To convert dosages using the methods of the present invention, the established dosage, expressed in particles per unit amount of tissue, is multiplied by the total amount, e.g., in volume units, of target tissue. For example, if a dosage of 1 x106 therapeutic cells has been selected in a subject having 50 ml of ischemic tissue, and one wishes to convert this dosage for administration to a patient having 65 ml of ischemic tissue, then the patient's dosage would be calculated as follows:

[0028] 1 x 106 cells/50 ml ischemic tissue x 65 ml ischemic tissue

= 2 x 104 cells/ml ischemic tissue x 65 ml ischemic tissue

= 1.3 x 106 cells

[0029] Thus, the dosage per unit amount or volume of a defined tissue is used as a factor in the conversion calculation.

[0030] Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents.

[0031] The contents of all cited references, including literature references, issued patents, published patent applications, and co-pending patent applications, cited throughout this application are hereby expressly incorporated by reference in their entirety.

EXAMPLES

[0032] The present invention is further illustrated by the following examples, which should not be construed as limiting in any way.

Example I: Individual Conversion of a Dosage of ADCs Established in an Animal Model for Administration to Human Patients with Chronic Myocardial Ischemia

[0033] A dosage of ADCs for treatment of chronic myocardial ischemia (CMI) is determined in a pig model based on, e.g., a reduction in the volume of ischemic tissue and/or increased ejection fraction according to methods known in the art and described in the literature. Transendocardial injections of autologous mononuclear bone marrow cells in patients with ischemic heart disease have been described, e.g., by Perin, et al., 2003. SPECT, as described elsewhere herein, can be used to measure total tissue volume and ischemic tissue volume.

[0034] For a pig having 100 ml of myocardium and 35 ml ischemic tissue in the left ventricle, a total cell dosage of 5O x 106 cells is determined to be most efficacious. The total cell dosage is then divided by 35 ml, to obtain the established dosage of 1.43 x 106 cells/ml ischemic tissue.

[0035] The established total dosage is converted for use in a human CMI patient determined by SPECT to have 80 ml ischemic tissue, as shown below.

[0036] 1.43 x 106 cells/ml ischemic tissue x 80 ml ischemic tissue = 1 14.4 x 106 cells

Example II: Individual Conversion of a Dosage of ADCs Established in a Clinical Study for Administration to Human Patients with Chronic Myocardial Ischemia

[0037] A dosage of ADCs for treatment of chronic myocardial ischemia (CMl) is determined in patients in a clinical study. The patients are evaluated based on ejection fraction and a reduction in end-systolic volume, as described by Perin, et al., 2003.

[0038] An efficacious total cell dosage is converted for use in a different individual using the methods of the present invention. First, the dosage per ml ischemic tissue is calculated based on the SPECT measurements made on the patients in the clinical study. Then, for a human CMI patient determined by SPECT to have 100 ml ischemic tissue the calculation is made as follows:

[0039] Cells in established total dosage/ml ischemic tissue x 100 ml ischemic tissue

Example III: Conversion of an Established Dosage of Drug-Loaded Particles for Intratumoral Injection into a Patient Having Cancer of the Liver

[0040] An efficacious dosage of drug-loaded particles, e.g., a composition described in U.S. Pat. Appl. Pub. No. 2006/0034925, "Tumor targeting drug-loaded particles," incorporated by reference in its entirety, is determined in particles/ml tumor tissue based on a human clinical study. U.S. Pat. Appl. Pub. No. 2006/0034925 describes combinations of fast release and slow release formulations of agents. The present invention contemplates the use of multiple or single agents for treatments of tumors or other conditions. With regard to a combination, the methods of the present invention can be used for conversion of the dosages of one or several agents, as desired by ithe clinician.

[0041] The total drug-loaded particle dosage selected for each patient is divided by that particular patient's tumor volume as determined using, e.g., computed tomography image analysis, as known in the art and described extensively in the literature. For example, a method of determining tumor volume is described in U.S. Pat. No. 4,856,528, "Tumor Volume Determination," incorporated herein by reference in its entirety.

[0042] A dosage established in a study can be converted for use in a different patient having a tumor determined to be, e.g., 1000 ml. The converted dosage for this patient is:

[0043] Established dosage in particles/ml tumor tissue x 1000 ml tumor tissue

Claims

WE CLAIM:

1. A method for converting an established dosage of a particulate therapeutic agent for administration by local injection, to a dosage of the therapeutic agent for use in a patient, said method comprising: multiplying the established dosage expressed per unit amount of treated tissue, by the total unit amount of the patient's tissue to be treated.

2. The method of claim 1 wherein the treated tissue and patient's tissue to be treated comprise damaged tissue.

3. The method of claim 2 wherein the damaged tissue is ischemic tissue.

4. The method of claim 1 wherein the treated tissue and patient's tissue to be treated are tumor tissues.

5. The method of claim 1 wherein the treated tissue and patient's tissue to be treated are organ tissues.

6. The method of claim 5 wherein the organ tissue is heart tissue, brain tissue, kidney tissue, lung tissue or liver tissue. ^

7. The method of claim 6 wherein the organ tissue is heart tissue.

8. The method of claim 1 wherein the patient is a human.

9. The method of claim 1 wherein the established dosage was determined in a porcine subject.

10. The method of claim 1 wherein the patient is a human and wherein the established dosage was determined in a porcine subject.

1 1. The method of claim 1 wherein the therapeutic agent comprises an agent used for treating cancer.

12. The method of claim 1 wherein the therapeutic agent comprises an agent used for treating enzyme deficiencies.

13. The method of claim 1 wherein the therapeutic agent is comprised of cells.

14. The method of claim 13 wherein the therapeutic agent comprises adipose derived regenerative cells.

15. The method of claim 1 wherein the therapeutic agent comprises an agent used for treating a patient having a cardiac disorder.

16. The method of claim 15 wherein the cardiac disorder is acute myocardial infarction.

7. The method of claim 15 wherein the cardiac disorder is chronic myocardial ischemia.