WO2001037882A2

WO2001037882A2 - Use of fenoldepam for protecting against radio-contrast medium-induced renal dysfunction

Info

Publication number: WO2001037882A2
Application number: PCT/US2000/042230
Authority: WO
Inventors: Vandana Mathur
Original assignee: Elan Pharmaceuticals, Inc.
Priority date: 1999-11-24
Filing date: 2000-11-21
Publication date: 2001-05-31
Also published as: AU3440601A; WO2001037882A3

Abstract

A method and a composition for preventing renal failure following administration of a radio-contrast medium is described. Contrast agent-induced acute renal failure in patients exhibiting moderate to advanced renal insufficiency is obviated by administering a dose of fenoldopam prior to, during, and/or after delivery of a radio-contrast agent.

Description

Method and Composition for Protecting Against Radio-Contrast Medium-Induced Renal Dysfunction

Field of the Invention The present invention relates to methods and compositions for preventing renal dysfunction induced following administration of a radio-contrast medium.

Background of the Invention

Remote imaging of body organs using X-rays has become increasingly important as a diagnostic tool. The X-ray absorption characteristics of internal structures, such as the abdominal aorta, kidneys and other organs, are nearly identical to those of the surrounding tissue structures. The gray densities of these tissues blend together when viewed radiographically, making visualization of discrete anatomical details nearly impossible. In order to differentiate the soft tissues, e.g. , particular organs, vessels and the like, a radiopaque, radiographic contrast medium is introduced into a patient prior to imaging. The contrast medium, when localized in particular organs and tissues, increases that tissues ability to absorb x-ray photons. The anatomical structure filled with contrast medium produces a lighter, whiter image relative to the surrounding tissues having darker or grayer images. The edges of the contrast medium-filled areas are clearly outlined, and anatomical details are sharper and more apparent than on radiographs taken without contrast medium.

Today, many radiological examinations, from urinary examinations to coronary angiograms to myelography, require the administration of a contrast medium prior to and/or during the procedure. Typically, the contrast medium is administered parenterally to bypass the digestive system.

Most of the contrast media employed are iodinated compounds. The iodine component of contrast media absorbs more radiation than the average tissues or organs of the body. When the contrast medium is introduced into an organ or vessel, the iodine increases the opacity of the structure and can delineate the anatomical details of the organ or vessel on fluoroscopy or on a radiographic film. Most types of iodinated contrast media used during radiological procedures are water-based, however, oil-based iodinated contrast media are available and are used in cases where it is desired that the contrast medium persist during the procedure. An iodinated contrast medium after injection into a patient is reabsorbed into the blood stream by the surrounding body tissues and is eventually excreted by the kidneys.

Contrast media are considered safe for use in many patients, however in certain patient populations administration of contrast agents are a leading cause of hospital- acquired acute renal failure. Renal failure due to the administration of contrast media has been reported to be the third most common cause of in-hospital renal failure, after hypotension and surgery (Manual on Contrast Media, 4^th Edition, American College of Radiology, October 1998).

Acute renal failure as a result of a contrast agent administered during a medical procedure is termed radio-contrast nephropathy (RCN) and is caused by reduction in renal blood flow, particularly to the renal medulla. This condition occurs most frequently in patients with a pre-existing renal insufficiency, as evidenced by a serum creatinine level of greater than or equal to 1.5 mg/dL. Persons with such pre-existing renal insufficiency are typically those suffering from diabetes mellitus, dehydration, cardiovascular disease, hypertension, multiple myeloma, and hyperuricemia or patients using diuretics or older than about 70 years. Particularly at risk are persons with both diabetes and pre-existing renal insufficiency.

A number of phaπnacologic interventions have been proposed to minimize the risk of these patients from developing contrast-media induced acute renal failure. These interventions include administration of mannitol, prostaglandin inhibitors, calcium channel blockers, and dopamine. However, none of these compounds have been shown to be more effective to mitigate the renal effects of radiocontrast agents than a simple saline infusion.

Fenoldopam (CORLOPAM^®) is a dopamine agonist that causes peripheral vasodilation, apparently via stimulation of dopamine, receptors. The drug is presently used in clinical situations where, either due to underlying disease or induced by trauma or a medical procedure, an elevation in blood pressure occurs requiring immediate correction.

A recent study (Bakris, G.L., et al. Kidney International 56: 206-210 (1999)) showed that in healthy dogs, infusion of fenoldopam at a dose of 0.01 μg/kg/min during administration of the radio-contrast agent RENOGRAFIN^® prevented reduction in glomerular filtration rates and renal blood flow when compared to healthy dogs receiving the contrast agent alone. It is unknown, however, if fenoldopam would be effective in human patients, particularly in human patients at risk for developing contrast-media induced acute renal failure, e.g, humans with pre-existing renal insufficiency.

Summary of the Invention

Accordingly, it is an object of this invention to provide a method of preventing acute renal failure induced by a radio-contrast agent.

It is a more particular object of the invention to provide a method of inhibiting induction of acute renal failure in a human patient at risk for contrast-media induced acute renal failure.

In one aspect, the invention includes a method of preventing radio-contrast media induced acute renal failure in a human patient exhibiting moderate to advanced renal insufficiency. The method includes administering to the patient a dose of fenoldopam effective to maintain renal blood flow above baseline renal blood flow following delivery of a radio-contrast agent. In one embodiment, the dose of fenoldopam is effective to produce, after delivery of a radio-contrast agent, a renal blood flow at least about 20%, more preferably at least about 30%, and still more preferably at least about 40%, above the baseline renal blood flow taken prior to delivery of a radio-contrast agent.

The dose of fenoldopam, in one embodiment, is administered via intravenous infusion at a dose of between about 0.01 μg/kg/min and 1.0 μg/kg/min prior to and/or during administration of the radio-contrast agent. In a preferred embodiment, the dose is between about 0.01 μg/kg/min and 0.1 μg/kg/min.

In another embodiment, administration of fenoldopam is initiated at least 60-90 minutes prior to administration of the radio-contrast agent. In yet another embodiment, administration of fenoldopam continues for at least two hours after administration of radio- contrast agent, and, in another embodiment, for at least four hours after administration of radio-contrast agent.

In other embodiments, fenoldopam is administered by continuous subcutaneous infusion or by a bolus subcutaneous injection. Alternatively, fenoldopam is entrapped in particles, such as polymer microparticles or liposomes, effective to maintain a depot of fenoldopam at the site of subcutaneous injection for slow release of fenoldopam. liposomes.

The fenoldopam can be administered as the racemic mixture or as the active R- fenoldopam enantiomer. The radio-contrast agent is, in one embodiment, a high-osmolality contrast agent or an agent with a high iodine content. In another embodiment, the radio-contrast agent is selected from the group consisting of diatrizoate, diatrizoate, iodipamide, iophendylate, iothalamate, ethiodized oil, metrizamide, iohexol, iopamidol, ioversol, iotrolan, ioxaglate, ioxilan, iopromide and iodixanol.

In another aspect, the invention includes a renal-sparing infusible radio-contrast agent formulation comprised of an amount of a selected radio-contrast agent, wherein said amount is effective to provide a dosage effective for imaging a selected organ, and an amount of fenoldopam effective to provide a concentration of between about 0.01 μg/kg/min and 1.0 μg/kg/min, when the formulation is administered to a patient via intravenous infusion.

In one embodiment of this aspect, the radio-contrast agent is a high-osmolality contrast agent and the amount of fenoldopam is sufficient to maintain a renal blood flow above baseline following administration of the contrast agent. These and other objects and features of the invention will be more fully appreciated when considered in conjunction with the following detailed description of the invention.

Detailed Description of the Invention

I. Definitions In describing and claiming the present invention, the term "fenoldopam" as used herein refers to the compound having the chemical name 6-chloro-2,3,4,5-tetrahydro-l- (4-hydroxyphenyl)-lH-3-benzazepine-7,8-diol with the following structure:

and is intended to include the racemic mixture, the R-enantiomer and the S- enantiomer and to mixtures of the R and

S enantiomers in any proportion. The racemate and the enantiomers can be a free base or a salt, such as hydrochloride, mesylate, hydrobromide, tromethamine, or the like, for example as described in U.S. Patent 4,197,297, incorporated herein by reference. The term "R-fenoldopam" as used herein refers to the active enantiomer of fenoldopam free base and its pharmaceutically effective salts, the active enantiomer being substantially free of the inactive enantiomer, S-fenoldopam. Methods for resolution of the enantiomers and isolation of R-fenoldopam are known in the art, for example, as described in Acta Pharmaceutica Suecica, Suppl. 2:132-150 (1983). The term "racemic fenoldopam" or "racemate" as used herein refers to an equal mixture of the active and inactive enantiomers of fenoldopam.

The phrase "moderate to advanced renal insufficiency" intends a human having a serum creatinine level of greater than about 2.0 mg/dL, more preferably between 2.0-5.0 mg/dL, and most preferably between 2.5-5.0 mg/dL, prior to administration of a radio- contrast agent.

The term "pre-existing renal insufficiency" intends a human having a serum creatinine level greater than 1.5 mg/dL prior to administration of a radio-contrast agent.

II. Method of the Invention In one aspect, the invention includes a method of preventing or inhibiting the onset of acute renal failure caused by administration of a radio-contrast agent. More particularly, the invention is directed to a method of preventing acute renal failure induced by administration of a radio-contrast agent to patients having pre-existing renal insufficiency or having advanced to moderate renal insufficiency. As noted above, certain patients are at risk for renal failure due to the administration of contrast media. These patients include those with a pre-existing renal insufficiency, as evidenced by a serum creatinine level of greater than about 1.5 mg/dL, diabetes mellitus, dehydration, cardiovascular disease, multiple myeloma, hypertension, or hyperuricemia. Patients using diuretics and patients above the age of 70 are also at risk. More particularly, patients with moderate or advanced pre-existing renal insufficiency, i.e. , patients with a serum creatinine level of between about 2-5 mg/dL, are at risk for renal failure.

In these patient populations, administration of a contrast agent can induce nephrotoxicity, or acute renal failure. Acute renal failure is usually recognized by a rising blood urea nitrogen and/or serum creatinine concentration. A reduction in the glomerular filtration rate of between about 20-40 percent usually occurs before significant increases in serum creatinine concentrations are detected. Thus, the glomerular filtrationrate can also be used as a guide to onset of nephrotoxicity. A falling urine output is also frequently associated with acute renal failure. In accordance with the invention, administration of fenoldopam prior to, during, or after administration of the radio-contrast agent is effective to prevent acute renal failure in at-risk patients, as will now be described.

In a study performed in support of the invention, fenoldopam was administered to human subjects with moderate to acute renal insufficiency (baseline serum creatine level of greater than 2.0 mg/dL). The subjects were in need of a radiographic procedure, typically coronary angiography, using a radio-contrast agent. As described in Example 1, the fourteen patients were randomized into two treatment groups, a control group, which received 0.45% NaCl saline, and a treatment group, which received fenoldopam at a dose of 0.1 μg/kg/min diluted to 40 mg/ml in V∑ normal saline (0.45% NaCl).

Fenoldopam was given 60-90 minutes prior to injection of a low-ionic contrast medium, iohexol, and continued for four hours after injection of iohexol. Iohexol was infused at a rate of between 6-18 ml/hour, depending on patient weight. The renal blood flow in each patient was measured at the time of initial administration of fenoldopam and at hourly intervals for four hours after administration of the contrast agent. The percent change in renal blood flow, averaged for the patients in each test group, are reported in Table 1.

Table 1

Percent Change in Renal Blood Flow from Baseline following Radio-contrast Injection

As seen in Table 1, the patients receiving fenoldopam had an average increase in renal blood flow of about 163% upon administration of fenoldopam. One hour after administration of the radio-contrast agent, the renal blood flow was 124% higher than baseline, and at three hours, the renal blood flow was 42% higher than baseline. At four hours post radio-contrast injection, the renal blood flow was 190% higher than baseline renal blood flow. In contrast, the patients receiving saline only, the control patient group, experience a small initial vasodilation during the first hours after administration of the radio-contrast agent, but a reduction in the renal blood flow occurred over the next two hours, with the renal blood flow at the three hour time point 57% lower than baseline.

The three hour time point is illustrative of the effect of fenoldopam on inhibiting onset of renal failure. The fenoldopam was effective to maintain a renal blood flow 42% higher than the baseline blood flow. The patients not receiving fenoldopam had a renal blood flow 57% lower than baseline.

Accordingly, the invention provides a method of preventing contrast media- induced renal failure by maintaining the renal blood flow above the baseline renal blood flow after administration of a radio-contrast agent. Preferably, the method of the invention provides for a renal blood flow at least about 20%, more preferably about

30%, still more preferably about 40% , even still more preferably about 50% , above than the baseline renal blood flow after administration of a radio-contrast agent.

The fenoldopam is administered by any route suitable to achieve the desired result of an above baseline renal blood flow after administration of a radio-contrast agent. Suitable routes include parenteral, including intravenous, intramuscular, intra-arterial, intrathecal, topical, intradermal and subcutaneous.

In a preferred embodiment, the fenoldopam is administered subcutaneously. The subcutaneous route of administration of drugs is recognized as generally safe and reliable. For subcutaneous admimstration, fenoldopam may be prepared in a pharmaceutically acceptable medium suitable for infusion, typically 0.9% sodium chloride USP or 5% dextrose USP. Such subcutaneous administration includes, for example, continuous administration, intermittent administration and bolus administration. By way of an example of continuous admimstration, fenoldopam is administered by an infusion pump for a period of time sufficient to achieve and maintain a therapeutic blood level for 1-2 hours prior to administration of the radio-contrast agent and for any selected time, e. ., 1, 2, 3, 4 or more hours, after administration of the radio-contrast agent. Intermittent administration is achieved by administering the drug subcutaneously for a defined period of time at defined intervals.

Typically, fenoldopam is administered in a dosage of between 0.01-1 mg/kg/min, more preferably between 0.01-0.1 mg/kg/min. The total dose administered will, of course, depend on the patient's weight and condition, and some patients can tolerate an infusion for as long as a week. The maximum tested dose of fenoldopam for other indications is 1.6 μg/kg/min. The appropriate route of admimstration, e.g. , continuous infusion, intermittent or a bolus, and drug dosage can be readily selected by one of skill in the art and monitored by observing clinical symptoms or by monitoring glomerular filtration rate or serum creatinine levels or the like.

Fenoldopam is a chiral compound and exists as a racemic mixture of its optical isomers, called enantiomers. Enantiomers are structurally similar compounds having identical physical properties, except for the direction in which they rotate polarized light.

Although enantiomers are physically similar, they can have profoundly different effects in biological systems, where one enantiomer is biologically active while the other has little or no biological activity.

This is the case for the enantiomers of fenoldopam, where the therapeutic activity of the drug is due to the R-enantiomer, the S-enantiomer being relatively or essentially inactive. Thus, in one embodiment, the R-enantiomer of fenoldopam is administered to the patient.

In another embodiment, fenoldopam is incorporated into particles, such as polymer microparticles or liposomes. The entrapped drug is administered subcutaneously, generally as a bolus injection or as an intermittent infusion, to achieve prolonged release of fenoldopam from the injection site, typically an intradermal or subcutaneous injection site. Formation of such particles and liposomes is readily done by one of skill in the art. Polymer particles formed of, for example, poly vinyl alcohol, polyvinylpyrrolidone, poly aery lie acid and celluloses, are known to those of skill in the art. Liposome preparation has been described, for example, by Szoka, F., et al. (Ann.

Rev. Biophys. Bioeng. 9:467 (1980)) and in U.S. Patent No. 4,235,871, both of which are incorporated by reference.

Contrast media can be grouped according to their chemical configurations: ionic monomer, non-ionic monomer, ionic dimer and non-ionic dimer. An ionic monomer iodinated contrast medium is configured by three iodine atoms (tri-iodinated) attached to a substituted benzoic acid ring derivative. Added to this ring structure is a cation such as sodium or meglumine; an anion radical, such as diatrizoate, iothalamate or metrizoate; and a carboxyl group. When the iodinated contrast medium is placed in solution, such as blood, the carboxyl group causes a compound to be formed in which the anion and cation disassociate or dissolve. Diatrizoate (HYPAQUE^®, RENOGRAFIN^®), iodipamide

(CHOLOGRAFIN^®), iophendylate (PANTOPAQUE^®), iothalamate (CONRAY^®) and ethiodized oil (ETHIODOL^®) are examples of an ionic monomer contrast media.

An ionic dimer contrast medium molecule is based on the same benzoic acid ring derivative. However, in this class of agents, two tri-iodinated benzoic acid rings are linked together and share an ionizing radical. On one of the benzoic acid rings a non- ionizing amide is substituted for the carboxyl group, leaving only one carboxyl group on the molecule. The ionic dimer contrast media have low osmolality and tend to be less toxic than the ionic agents. Ioxaglate (HEXABRIX^®) is an example of an ionic dimer contrast medium.

The non-ionic iodinated contrast media are also lower-osmolality compounds relative to the ionic monomers. The non-ionic monomer contrast medium has a basic structure consisting of a benzoic acid ring in which the carboxyl group is replaced with a non-ionizing side chain. Iohexol (OMNIPAQUE^®), iopamidol (ISOVUE^®), metrizamide (AMIPAQUE^®) and ioversol (OPTIRAY^®) are examples of non-ionic monomers.

The non-ionic dimer contrast medium consists of two non-ionic monomers attached to each other any an ionizing radical. These agents have a lower osmolality that the non-ionic monomer agents. Iotrolan (OSMOVIST^®) and iodixanol (VISIPAQUE^®) are examples. Other non-ionic contrast media include ioxilan (OXILAN^®) and iopromide

(ULTRAVIST^®).

The osmolality of a contrast medium is determined by the number of particles in the solution. The osmolality of human blood is about 300 milliosmoles (mOsm) per kilogram. Ionic contrast media have a minimum osmolality of 1000 mOsm/kg, and non- ionic contrast media have a minimum osmolality of 600 mOsm/kg. The osmolality for both ionic and non-ionic contrast media is well above that of human blood. Thus, contrast media can penetrate red blood cells.

The toxicity of a contrast medium on body tissues and organs is related to the contrast medium's chemical configuration, osmolality, iodine concentration and rate of injection. Contrast media that are non- ionic, have a low osmolality and low iodine concentration and which are injected slowly tend to be less toxic.

In one embodiment of the invention, fenoldopam is administered prior to administration of a contrast medium having a high osmolality. High-osmolality contrast media are those with an osmolality of greater than about 1000 mOsm/kg, more preferably those agents with an osmolality of greater than about 1200 mOsm/kg. In another embodiment of the invention, fenoldopam is administered in conjunction with a contrast medium having a high iodine content. The iodine concentration of a contrast medium determines its ability to absorb x-ray photons, with a higher concentration of iodine absorbing more photons and said to be more radiopaque. However, the increase in radiopacity is offset by an increase in toxicity with increasing iodine concentration.

Contrast agents and their approximate osmolality and iodine concentrations are listed in Table 2.

Table 2

The route of administration of contrast media varies according to the radiological procedure to be performed. For example, contrast media are typically administered as a intravenous injection via infusion or bolus prior to and/or during a radiological examination of the urinary tract and the biliary system. For myelography, a radiological examination of the spinal cord, the contrast medium is introduced into the subarachnoid space through a spinal needle via a lumbar or cisternal puncture. In arteriography, a radiological examination of arterial structures, and venography, a radiologcal examination of venous structures, the blood vessel under examination is usually approached through a catheter advanced from the femoral artery to the point of interest. The contrast medium is injected through the angiographic catheter.

In accord with the invention, fenoldopam is administered prior to administration of the contrast agent or concomitantly with the contrast agent. The fenoldopam can be administered by the same route as the contrast agent or by a different route. In a preferred embodiment, fenoldopam is administered via an intravenous infusion beginning 60-90 minutes prior to administration of the contrast agent and continuing for several hours after administration of the contrast agent. In another embodiment, fenoldopam is administered subcutaneously via a slow infusion prior to, during and after administration of the radio-contrast agent.

It will be appreciated by those of skill in the art, that any number of treatment modalities are suitable.

III. Example

The following example illustrates the invention described herein and is in no way intended to be limiting.

Example 1

Administration of Fenoldopam to Human Subjects

Undergoing Infusion of Radiocontrast Dves

Human subjects with moderate to acute renal insufficiency (baseline serum creatine level of greater than 2.0 mg/dL) undergoing coronary angiography, vascular angiography, or contrast-enhanced computerized tomographic (CT) scanning were randomized in a 1 : 1 ratio to receive fenoldopam (0.1 μg/kg/min diluted to 40 mg/ml in

Vi normal saline (0.45% NaCl)) or placebo (1/2 normal saline, 0.45% NaCl). The contrast medium Iohexol was infused at a rate of between 6-18 ml/hour, depending on patient weight. All patients also received standard intravenous fluids (1/2 normal saline starting 4-6 hours before the time of anticipated contrast agent infusion and continuing four hours following the infusion).

Baseline renal blood flow (RBF) was measured before contrast infusion, then hourly for four hours after injection of contrast agent. Blood pressure was monitored before and during infusion. Serum creatinine and electrolyte measurements were monitored 24 and 48 hours post-angiography.

In order to measure clearance rates, para-aminohippurate (PAH) (3 mg/kg) load was given as an intravenous push over 5 minutes, 4-5 hours before infusion of contrast agent, followed by continuous infusion at 60 ml/hour. PAH was infused for a total of approximately 7-9 hours. Within about ten minutes of PAH administration, a loading dose of inulin (30 mg/kg) was given as an intravenous 5 minute push, four to five hours before infusion and was immediately followed by a continuous infusion for a total of 7-9 hours. Thirty minute clearance rates were calculated according to the equation:

Clearance = Urine concentration X Urine volume Plasma concentration X 30

where baseline renal blood flow (RBF) and glomerular filtration rate (GFR) were established as the averages of two 30-minute clearance measurements of PAH and inulin, respectively.

Results from a total of 14 patients are shown in Table 1. Although the invention has been described with respect to particular embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the invention.

Claims

IT IS CLAIMED:

1. An infusible radio-contrast agent formulation, comprising a selected radio-contrast agent administered in an amount effective to provide imaging of a selected organ, and fenoldopam.

2. The formulation according to claim 2, wherein said fenoldopam is administered via intravenous infusion at a rate of 0.01 μg/kg/min and 1.0 μg/kg/min.

3. The formulation according to claim 1 or claim 2, wherein said radio-contrast agent is a high-osmolality contrast agent and said fenoldopam is administered in an amount sufficient to maintain a renal blood flow above baseline following administration of the contrast agent.

4. The formulation according to claim 1, wherein said fenoldopam is administered subcutaneously.

5. The formulation according to claim 4, wherein said fenoldopam is entrapped in particles effective to maintain a depot of fenoldopam at the site of subcutaneous injection for slow release of fenoldopam.

6. The formulation according to claim 5, wherein said particles are polymer particles are composed of a hydrophilic polymer selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid and celluloses.

7. The formulation according to claim 5, wherein said particles are liposomes.

8. The formulation according to any one of the preceding claims, wherein said fenoldopam is racemic fenoldopam or the active R-fenoldopam enantiomer.

9. The formulation according to any one of the preceding claims, wherein the radio- contrast agent has an osmolality greater than about 1000 mOsm/kg.

10. The formulation according to any one of the preceeding claims, wherein said radio-contrast agent is diatrizoate, diatrizoate, iodipamide, iophendylate, iothalamate, ethiodized oil, metrizamide, iohexol, iopamidol, ioversol, iotrolan, ioxaglate, ioxilan, iopromide, or iodixanol.

11. Use of the formulation according to any one of claims 1-10 for preventing radio-contrast nephropathy in a human patient.

12. The use according to claim 11, wherein said fenoldopam is administered at least 60-90 minutes prior to administration of the radio-contrast agent.

13. The use according to claim 11 or claim 12, wherein said fenoldopam continues to be administered for at least two hours after administration of radio-contrast agent.

14. The use according to claim 11, wherein said fenoldopam is administered by continuous or bolus subcutaneous infusion.

15. The use according to claim 14, wherein said fenoldopam is entrapped in particles effective to maintain a depot of fenoldopam at the site of subcutaneous injection.

16. The use according to claim 15, wherein said particles are polymer particles composed of a hydrophilic polymer selected from polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, and celluloses.

17. The use according to claim 15, wherein said particles are liposomes.

18. Use of a formulation according to any one of claims 1-10 for the manufacture of a medicament for preventing radio-contrast nephropathy in a human patient.